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Flavonoids and cancer prevention

Flavonoids and cancer prevention

Prwvention flavonoids and cancer risk: evidence from human population studies [J]. Orevention are present in strawberries, apple, chocolate, cocoa, beans, preventiob, Low-intensity stretching and flexibility exercises, and Flavonoids and cancer prevention tea. Kaempferol Low-intensity stretching and flexibility exercises has anticancer effects and acts as a Meal prepping tips agent. Xu WH, Yuan ZL Inhibition of experimental alkali-induced corneal neovascularization in rabbits by using genistein. Due to their strong antioxidant activity, the intake of dietary anthocyanins could enhance the consumption of intestinal oxygen. Compounds from the same category of flavonoids may have diverse effects on the same bacterial strain. We found no evidence that flavanones had a major effect on breast cancer risk and, for isoflavones, the evidence, if any, was for a positive rather than inverse association.

Flavonoids and cancer prevention -

They have the ability to block cell cycle followed by apoptosis. In recent years, they have been used for the treatment of prostate, pancreatic, breast, cervical, and ovarian cancers.

Several protein kinases, epidermal growth factor receptors EGFRs , platelet-derived growth factor receptors PDGFRs , vascular endothelial growth factor receptors VEGFRs , and cyclin-dependent kinases CDKs [ 4 ] play important roles in cancer pathology.

COX cyclooxygenase , LOX lipoxygenase , and xanthine oxidase enzymes are also responsible for cancer pathologies. Flavonoids have the power to decrease and sometimes control all these pathogenic factors completely.

Major classes of flavonoids possess anticancer properties. The sources of flavonoids are also explained in this context. Flavanols are present in strawberries, apple, chocolate, cocoa, beans, cherry, green, and black tea. They have the potential to fight against human oral, rectal, and prostate cancer.

The major sources of anthocyanidins are blueberries, blackberries, blackcurrant, and aubergine. These natural resources are used to treat colorectal cancer. The major sources of flavones are Siberian larch tree, onion, milk thistle, acai palm, lemon juice, orange juice, grape juice, kale, cherries, leek, Brussel sprouts, pepper, broccoli, capsicum, parsley, and celery.

They have the ability to fight against breast cancer, lung cancer, leukemia, thyroid, stomach, laryngeal, colon, and oral cancer. Sources of isoflavonoids are soybeans, soy flour, soy milk, beer, and tempeh. They fight against prostate cancer, breast cancer, colon, kidney, and thyroid cancer [ 5 ].

Flavonoids are mainly classified into four major groups: flavanols, flavones, anthocyanidins, and isoflavonoids. The major groups of these flavonoids are displayed in the subsequent text Figure 1. A chemical structure of compound is drawn for each flavonoid group Figure 2. Compounds from various subclasses of flavonoids are put together in their respective flavonoid groups.

The major classification of flavones and anthocyanidins is displayed in Figure 3. Among these subclasses, flavanols contain catechin, gallocatechin, catechingallate, epicatechin, and epigallocatechin EGC. Kaempferol, myricetin, quercetin, and rutin belong to the subclass of flavonol [ 5 ].

Some other compounds are also classified under the specific subclasses of flavonoids Figure 3. Major classification of flavonoids. Different classes of flavonoids and their compound chemical structures.

Different groups of flavonoids and their respective compounds. Many studies on the distribution of diseases prove that flavonoids have positive effects in curbing cancer. It has been evidenced by various studies that the possibility of developing cancer could be reduced if more amount of flavonoid is administered [ 6 , 7 ].

There was a case-control type study on breast cancer-positive individuals based on population in Shanghai from to It was revealed in the corresponding controls; Dai et al. The middle discharge rate of aggregate isoflavonoids was Thus, it was recommended that flavonoids are capable of averting breast cancer.

Another lung cancer study was done on the observation of individuals beyond the age of A total number of lung cancer-positive Finnish men and women between the ages of 25—99 showed reduced lung cancer after administering flavonoids through diet. The inference was made based on vitamin E, vitamin C, beta-carotene, or total calories consumption.

There was a study on 10, individuals of both men and women by Knekt and coworkers [ 9 ] on the amount of flavonoid consumption in Finnish diet. The study revealed a lesser possibility for lung cancer with the higher consumption of quercetin and the lesser possibility of prostate cancer with more consumption of myricetin.

Thus, flavonoids were proved to play a vital role in preventing cancer occurrence. There was also a case-control work done based on population in Hawaii in order to study in detail the relation between the probability of lung cancer and the consumption of flavonoids through diet. For the study, they took individuals who were lung cancer-positive and the same number of controls of matching age, sex, and ethnicity.

The consumption of flavonoids such as onion, white grapefruits, apples, and quercetin was reversely related to the probability of suffering lung cancer [ 10 ]. The outcome of the above study is found to be similar to the previous study done in Uruguay on lung cancer-positive individuals and controls but fewer incidents of lung cancer due to vitamin E and beta-carotene.

Flavonoids like kaempferol and quercetin are also found to be preventing gastric cancer unlike carotenoids like alpha-carotene, lutein, beta-carotene, and lycopene in yet another case-control study carried out in Spain which consisted of gastric cancer-positive individuals and controls.

An observation was done on 34, women free from postmenopausal cancer between the ages of 55 and 69 during and In modification with prospective confounders, the consumption of catechin was reversely related to only the rectal cancer occurrence [ 11 ]. These prove the potential ability of flavonoids for a cancer cure.

In this way, the administering of flavonoids is effective in preventing cancer in most if not in all studies. Reports [ 12 ] also show that flavonoids are ineffective. It is mainly because of the uneven availability of the same.

However, it should not be fully neglected without detailed study. Two case-control studies were conducted in six counties in New Jersey cases of ovarian cancer and controls [ 13 ] and in the North-East United States cases and controls. These revealed that there was no link between total flavonoid consumption and ovarian cancer [ 14 ].

Some of the cancer case studies have been discussed in the subsequent text. A case study showed that there is an inverse association between flavanone intake and esophageal cancer, and this could reduce by the intake of citrus fruits.

An increased risk of gastric cancer is found among smoking men. The intake of epigallocatechin EGC plays an important role to slow down the disease. Researchers analyzed the intake of flavonoids and the risk of pancreatic cancer during the study. The results reported that flavonoid-rich diets can decline pancreatic cancer risk in male smokers.

Inverse relationships were also found among current smokers between a risk of pancreatic cancer and the intake of total flavonols, quercetin, kaempferol, and myricetin. Isoflavone intake was inversely related to colorectal cancer risk in men and postmenopausal women. Cases were analyzed in Japan, Netherlands, and in the UK in both men and women regarding the intake of isoflavone and its inverse effect on colorectal cancer.

These results may have associations for the use of dietary flavonoids in the prevention of rectal cancer. NADPH oxidase I NOX 1 enzyme produces superoxide, which is overexpressed in colon and prostate cancer cell lines [ 15 ]. Superoxide is one of the reactive oxygen species ROS.

Superoxide dismutase SOD is one of the antioxidants which can inhibit a pro-oxidant enzyme Figure 4. Generally, flavonoids have the ability to inhibit DNA damaging, mutagenic signaling, cell proliferation, and proto-oncogenes cFOS, cJUN, and cMyc.

Diagrams are drawn using Microsoft PowerPoint and converted to JPEG format. Inhibition of pro-oxidant enzymes. Wogonin and baicalein from Scutellaria species have been tested in a mouse for anticancer activity.

baicalensis has an O-methylated flavone called wogonin and a flavone called baicalein, which were isolated from the roots of the same plant as well as from S.

A flavone glycoside called baicalin is also found in Scutellaria species. Both the compounds have therapeutic potential against cancer. The identified flavonoids from Scutellaria species are about The reported minor flavonoids from the same species are Apigenin, Luteolin [ 16 ], and Chrysin.

They possess antitumor activities. Scutellaria alone or in combination with other herbs has the cytostatic effect on several cancer cell lines in vitro and in vivo mouse model [ 17 ]. One of the anticancer drugs is wogonin.

It comes under flavonoids. It is considered as chemotherapeutic agent to decrease their side effects. It has a hepatoprotective effect and prompts apoptosis in caspase 3 pathway.

It alternates p21 protein expression. Wogonin and its derivatives possess anticancer activity. Wogonin induced apoptosis in lung cancer. It was experimented and proved in the nude mouse model [ 18 — 20 ]. It goes through multiple apoptosis pathways such as ROS Reactive Oxygen Species -mediated and ER stress-dependent pathway Figure 5.

Mechanism of action of wogonin-induced apoptosis in human lung cancer cells. Wogonin induces apoptosis with extrinsic apoptotic pathway and ROS-intervened ER stress-dependent pathway.

NAC N-acetyl- l -cysteine is used to identify and test ROS. In mammalian cells, the major ER stress sensors such as pancreatic ER kinase PERK , activating transcription factor-4 ATF4 , ionizing radiation, eIF2α, and CHOP will carry the signal from the ER lumen to cytoplasm and nucleus in order to recruit ER stress and also to develop tumor progression.

Wogonin goes through this pathway and generates apoptosis at the end. Apigenin has anti-mutagenic properties. It inhibits benzo[a]pyrene- and 2-aminoanthracene-induced bacterial mutagenesis. It scavenges free radicals and promotes metal chelation in in vivo tumor models [ 21 ]. It affords protective effect in murine skin and colon cancer models [ 22 ].

It would suppress this enzyme effectively. It also increases glutathione concentration and enhances the endogenous defense against oxidative stress [ 23 ]. It was experimented against skin carcinogenesis model.

It inhibits dimethylbenzanthracene-induced skin tumors. It has been administered against UV-light-induced cancers. The result showed that it could diminish the occurrence of UV light-induced cancers and was able to increase tumor-free cells. Apigenin plays an effective role to inhibit casein kinase CK -2 expression in both prostate and breast cancers [ 24 ].

Kaempferol has anticancer effects and acts as a chemopreventive agent. It was found to be curbing the growth of various carcinomas such as glioblastoma LN, U87MG, and T98G , leukemia HL and Jurkat , lung cancer H and A , breast adenocarcinoma MCF- 7, BT, and MDA-MB , osteosarcoma U-2 OS , prostate cancer LNCaP, PC-3, and DU , colorectal carcinoma Caco-2, HCT, DLD-1, and Lovo , and pancreatic cancer MIA PaCa-2, Panc 1.

It is used to arrest the cell cycle in cancer cells. It has been used as antiapoptotic agent on cancer cells. Kaempferol is very effective against metastasis and angiogenesis [ 26 ]. Quercetin is one of the dietary flavonoids, which suppresses tumor growth by inhibiting protein tyrosine kinase PTK.

About 10 μM of this compound confirmed antiproliferative activity against colon cancer cells, Caco-2, and HT Diosmin is one of the important Citrus flavonoids, which showed antiproliferative activity in the same cancer cell line.

The proliferation of MCF-7 human breast cancer cell line was controlled by the intake of citrus flavones. The in vitro studies confirmed that the compound was more effective against various cancer cell lines.

Fruits and vegetables are having an enormous amount of flavonoids, which have been used as cancer chemopreventive agents. Flavonol quercetin is contained in dietary fruits and vegetables especially onion and apple.

Quercetin flavonol is used to treat prostate, lung, stomach, and breast cancers [ 27 ]. Many biological properties in flavonoids and isoflavonoids are sometimes proved to be cancer chemopreventive. The mechanism of action of flavonoids in the molecular study is cell cycle arrest, heat-shock protein inhibition, tyrosine kinase inhibition, downregulation of p53 protein, estrogen receptor-binding capacity, inhibition of Ras protein, and expression of Ras protein.

The most genetic abnormalities in human cancers are based upon pmutated proteins. The protein may be downregulated because of flavonoid intake. The flavonoid expression on p53 proteins may lead to arrest cancer cells in G2 and mobile phase of cell cycle.

Tyrosine kinases are proteins. They are considered as growth factor signals for the nucleus. The expression of the protein is involved in oncogenesis.

The anticancer drug is able to inhibit tyrosine kinase activity. Quercetin has been used in human phase I clinical trial against tyrosine kinase activity. It is proved that it could be considered as antitumor agent without the cytotoxic side effects [ 28 ].

It does arrest cell cycle in proliferating lymphoid cells. Flavonoids inhibit heat-shock proteins in several malignant cell lines, comprising leukemia, colon cancer, and breast cancer [ 29 ]. Reactive oxygen species ROS can harm DNA and lead to mutations. It is involved in cell signaling and cell growth.

It increases the DNA exposure to mutagens. Stefani et al. reported that flavonoids can have inhibition effect against carcinogenesis. Apigenin, fisetin, and luteolin flavonoids have been used to inhibit cell proliferation effectively.

A variety of endogenous angiogenic and angiostatic factors have the responsibility for regulating angiogenesis. Flavonoids have the power to fight against angiogenesis.

Lumen formation, endothelial cells migration, and their proliferation are the important steps in angiogenesis. Angiogenesis inhibitors can interfere with these steps. Flavonoids play an essential role among the known angiogenesis inhibitors. The inhibition of protein kinases is the possible mechanism for the treatment of angiogenesis.

These enzymes are involved in the process of signal transduction against angiogenesis. Carcinogenesis, the multistep process of tumor development, primarily involves the acquisition of the hallmark capabilities of cancer namely sustaining proliferative signaling, shirking growth suppressors, fighting cell death, triggering invasion and metastasis, and inducing angiogenesis by the incipient cells.

Aberrations in multiple intracellular signaling cascades and progressive accumulation of mutations during carcinogenesis present considerable opportunities for the development of clinical interventions in preventing cancer initiation, treating neoplasms during premalignant stages, and inhibiting tumor progression.

Natural agents that can target the hallmarks of cancer have attracted the attention of several researchers due to their chemical diversity, structural complexity, inherent biologic activity, affordability, easy availability, and lack of substantial toxic effects.

The potential targets of chemopreventive agents include multiple signaling pathways such as ROS generation and signaling, cyclooxygenase-2 COX-2 and lipoxygenase LOX pathways, and numerous cellular molecules like XMEs, transcription factors, proteins involved in cell cycle, apoptosis, invasion and angiogenesis, and enzymes involved in epigenetic modifications.

Flavonoids are proved to be effective chemopreventive agents. The research study suggests that the medicinal plant, Glycyrrhiza inflata has anticancer activity and also does the mechanism of action on flavonoids.

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Cancer Epidemiology, Biomarkers Prev 8 : 35— CAS Google Scholar. Download references. This study was partially supported by the University of Athens and a grant to Harvard University by the Samourkas Foundation.

The project was also funded in part with Federal funds from the US Department of Agriculture Research Service under contract number K The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products or organisations imply endorsement by the US government.

Partial support was also provided by State of Florida, Department of Citrus. Initial support was provided by Massachusetts Department of Public Health's Breast Cancer Research Grants Program, Boston, MA.

We also thank the American Institute for Cancer Research, Washington, DC. Schools of Nutrition and Medicine, Boston, , MA, USA. Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, , MA, USA. Frances Stern Nutrition Center Tufts-New England Medical Center, Box NEMCH Washington St, Boston, , MA, USA.

Department of Hygiene and Epidemiology, School of Medicine, University of Athens, 75 M. Asias St, Goudi, GR 27, Greece, Athens, Greece. Faculty of Health Professions, Athens Technological Institute TEI , Greece.

Laboratory of Epidemiology, Mario Negri Institute Via Eritrea, , Milan, Italy. Institute of Medical Statistics, University of Milan, via Venezian 1, Milan, , Italy. Department of Epidemiology, Harvard School of Public Health, Huntington Avenue, Boston, , MA, USA.

You can also search for this author in PubMed Google Scholar. Correspondence to D Trichopoulos. From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3. Reprints and permissions.

Peterson, J. et al. pylori increased the levels of many inflammatory cytokines in the stomach of infected individuals, encompassing IFN-γ, tumor necrosis factor-α TNF-α , IL-1, IL-6, IL-8, IL and IL This resulted in the activation of multiple types of immune cells, such as dendritic cells, mast cells, lymphocytes, macrophages and neutrophils.

Furthermore, CagA orchestrated several signal transduction pathways [e. CagA-stimulated inflammatory response constitutes important mechanisms underpinning gastric inflammation and carcinogenesis. VacA plays an important role in bacterial colonization and survival in the gastric epithelium.

VacA induced cell vacuolation, and participated in autophagy, apoptosis and necrosis within gastric epithelial cells [ 76 ]. These features are connected with immune dysregulation and gastric mucosal damage, both of which can contribute to gastric carcinogenesis.

Apart from the above-discussed mechanisms, other factors also have an impact on the course and development of H. pylori -induced gastric carcinogenesis.

For instance, H. pylori -derived LPS activated the TLR4 signaling pathway in mononuclear cells and further repressed T cell-mediated cytotoxicity, contributing to the onset and progression of gastric cancer [ 79 ].

Oxidative stress in the gastric mucosa due to H. pylori infection was associated with significant damage of the gastric mucosa, hence resulting in the pathogenesis of gastric cancer [ 80 ].

Furthermore, host genetics and some environmental factors e. Collectively, H. pylori -induced gastric carcinogenicity is a consequence of intricate interplays among bacterial virulence factors, host and environmental factors.

The underlying mechanisms of H. pylori -caused gastric cancer have not been fully defined, and further work is warranted. Some bacteria other than H. pylori in the stomach also play a role in the development of gastric cancer. Dysbiosis of gastric microbiota has a potential relationship with the occurrence of gastric cancer.

The previous study indicated that patients with gastric cancer had different gut microbiota community structures [ 82 ]. The abundance of Achromobacter , Citrobacter , Clostridium , Lactobacillus , Phyllobacterium and Rhodococcus was increased in patients with gastric cancer compared with those with chronic gastritis.

It appeared that these commensal microbes could be opportunistic pathogens. A cohort study involving patients with gastric cancer and healthy controls showed that individuals who carried higher abundances of Prevotella copri and Propionibacterium acnes exhibited a markedly higher risk of gastric cancer than non-carriers [ 83 ].

Moreover, it was found that P. copri - or P. acnes -induced inflammatory responses might be associated with gastric carcinogenesis [ 84 , 85 ].

Altogether, bacteria exhibiting an elevated abundance may be involved in the etiology of gastric cancer, but the exact mechanisms are worthy of further study. Gut microbiota have been linked with hepatocellular carcinoma HCC. Through the portal venous system, the liver is commonly exposed to intestinal bacterial components and their metabolites, which may induce inflammatory changes and hepatotoxicity, eventually contributing to liver carcinogenesis.

For instance, altered gut microbiota increased the concentration of hepatic bile acids and thus drove liver carcinogenesis in a mouse model of obesity-induced HCC [ 86 ]. Dietary or genetic obesity changed the composition of gut microbiota, thus increasing the production of pro-tumorigenic DCA [ 87 ].

DCA induced senescence-associated secretory phenotype in hepatic stellate cells, which secreted multiple inflammatory and pro-tumorigenic molecules in the liver. These events promoted HCC progression in mice following exposure to chemical carcinogen.

On the contrary, blockade of DCA generation suppressed HCC development in obese mice. These findings shed light on underlying mechanisms associated with obesity-associated carcinogenesis.

The linkage between gut microbiota and breast carcinogenesis was previously investigated. The high abundance of Bacteroidetes, Blautia spp. A population-based case-control pilot study showed that patients with breast cancer had higher abundances of Clostridiaceae , Faecalibacterium and Ruminococcaceae , and lower levels of Dorea and Lachnospiraceae than control subjects [ 89 ].

The altered composition and diversity of gut microbiota have a potential impact on the development of breast cancer. Gut microbiota was proposed to promote breast carcinogenesis by affecting the level of circulating estrogens, energy metabolism, obesity, or antitumor immune function [ 90 ].

However, only limited supporting evidence is available. Considerable efforts are needed to clarify the roles of gut microbiota in breast cancer formation. Dysbiosis of gut microbiota may be associated with the carcinogenesis of urogenital system tumor. Compared with healthy controls, the levels of Clostridium cluster XI and Prevotella were reduced in bladder cancer patients [ 91 ].

Several studies compared the composition of gut microbiota between patients with cervical cancer and healthy controls. It turned out that cervical cancer patients had a high abundance of Bacteroidetes and a low level of Firmicutes compared with controls [ 92 ].

Another study indicated that Dialister , Porphyromonas and Prevotella were enriched, whereas Alistipes , Bacteroides and Lachnospiracea showed a relatively low abundance in cancer group compared with the control group [ 93 ]. In a recent study, a higher level of Prevotella was found in patients with cervical cancer than in healthy controls [ 94 ].

It was presumed that gut microbiota influenced cervical cancer development possibly through activation of inflammatory responses, but this assumption remained to be validated.

Further mechanistic investigations are required to verify the specific association between gut microbiota and cervical oncogenesis. The previous study revealed an increased in the count of proinflammatory Bacteroides and Streptococcus in patients with prostate cancer compared with healthy controls [ 95 ].

The numbers of Alistipes , Lachnospira , Rikenellaceae and SCFA-producing bacteria were positively associated with a high risk of prostate cancer [ 96 ]. It is likely that dysbiosis of gut microbiota may cause inflammation and neoplastic events even at a systemic level.

Gut microbiota could contribute to prostate cancer development by influencing the metabolism of specific compounds that may be linked to increased prostate cancer risk.

For instance, Clostridium could transform glucocorticoids into androgens in the gut, which facilitated the development of prostate cancer [ 97 ]. Gut microbiota-derived SCFA upregulated local and systemic insulin-like growth factor-1 IGF-1 , which favored prostate cancer development [ 98 ].

Ruminococcus , which was involved in glycerolphospholipid metabolism, promoted prostate cancer progression by upregulating lysophosphatidylcholine acyltransferase 1 LPCAT1 and activating DNA repair pathways [ 99 ]. At present, the detailed mechanisms through which gut microbiota affects prostate cancer progression are elusive.

A great deal of further work is necessary to fully understand the relationship between gut microbiota and prostate cancer pathogenesis. The complex and bidirectional relationship between gut microbiota and carcinogenesis has received considerable attention in recent years.

Intestinal microbes and cancer cells co-evolve in the body's ecosystem, and they may compete with each other for incoming resources necessary to survival and replication [ ]. Daily diet, energy or nutrients may influence the growth of both microbial cells and cancer cells.

Microbes and cancer cells can interact with each other in multifaceted ways that affect their survival and proliferation [ ]. Many studies have demonstrated altered gut microbiota profiles in cancer patients. Bifidobacterium , Blautia and Faecalibacterium were found in lower proportion in gut microbiota of CRC patients than healthy subjects, whereas Fusobacterium , Mogibacterium spp.

Coker et al. noted an enrichment of the phylum Fusobacteria and the genera Dialister , Mogibacterium and Peptostreptococcus in gastric cancer compared with other disease stages, including superficial gastritis, atrophic gastritis and intestinal metaplasia [ ]. Patients with gastric adenocarcinoma had higher abundance of Enterobacteriaceae and lower abundance of Barnesiella , Bifidobacterium , Lachnoclostridium and Parabacteroides in comparison with healthy controls [ ].

Previous studies revealed significantly higher abundance of intestinal microbes belonging to the Phyla Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria and Verrucomicrobia, as well as the genera Bifidobacterium , Porphyromonas and Prevotella in patients with pancreatic cancer than in healthy controls [ - ].

Despite the verification of the changes in intestinal microbiota composition in cancer patients, these studies do not provide sufficient evidence of whether the dysbiosis of gut microbiota acts causatively or consequently in cancer pathogenesis. On the other hand, there is evidence indicating that gut microbial populations play dual roles in cancer pathogenesis.

Commensal microbes may exert anticancer effects through protection against gut dysbiosis, bioconversion of chemotherapeutic agents or enhancement of anticancer immunity [ ]. Conversely, some resident bacteria e.

fragilis and F. nucleatum rise during gut dysbiosis and induce cancer genesis [ ]. Meanwhile, various experimental studies have suggested the causal linkage between intestinal dysbiosis and cancer development. For instance, preclinical studies showed that transplant of feces from CRC patients stimulated polyp formation, triggered procarcinogenic signals and affected the local immune environment in recipient mice [ ].

Furthermore, the depletion of gut microbiota by an antibiotic cocktail could significantly inhibit CRC growth in mice. Dysbiosis of gut microbiota caused by environmental changes e. Collectively, cancer development can modify the structure of gut microbiota, but, vice versa, changes of intestinal microbes also influence cancer pathogenesis.

It should be noted that although the connection between gut microbiota and carcinogenesis has been established, these associations have yet to be well defined and warrant further investigation.

It is still unclear whether carcinogenesis is the cause or consequence of the changes in gut microbiota. Future ongoing studies are needed to fully clarify the complicated relationship between gut microbiota and cancer.

Flavonoids are polyphenolic compounds synthesized in fruits and vegetables as bioactive secondary metabolites responsible for their color, flavor and pharmacological properties [ 8 ]. Flavonoids function to protect plants against bacteria and radiations.

Flavonoids are composed of two aromatic carbon rings joined by a three-carbon chain that forms an oxygenated heterocyclic ring Figure 2.

Among the fruits, the highest levels of flavonoids are found in apples, berries, cherries and plums [ ]. Among the vegetables, broad beans, olives, onions, shallot and spinach are the richest in flavonoids.

Tea, wine and some medicinal herbs are also the rich source of flavonoids. Flavonoids exert many biological functions, including antioxidant, antimicrobial, anti-inflammatory and anticancer activities. Flavonoids can be grouped into distinct classes based on their molecular structures: anthocyanidins, chalcones, flavanols, flavanones, flavonols, flavones, and isoflavones Figure 2.

Anthocyanidins are water-soluble natural pigments that are widely found in fruits and plant petals. Cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin are the most prevalent anthocyanidins in plants [ ].

Chalcones are one of the main classes of flavonoids whose colors can change from yellow to orange and serve as open-chain precursors for synthesis of flavonoids and isoflavonoids [ ].

Chalcones, mainly represented by isoliquiritin and isoliquiritigenin ISL , are abundant in edible plants including apples, citrus, nuts, potatoes, shallots, tomatoes. Apples, berries, cocoa, grapes, green tea and red wine are among the main sources of flavanols.

Flavanols exist in both the monomer form catechins and the polymer form proanthocyanidins. Catechin and epicatechin are main flavanols in fruits, while epigallocatechin, epigallocatechin gallate EGCG and gallocatechin are common flavanols present in tea and grapes [ ]. Flavanones are polyphenols specific of citrus fruits, where they are present at high concentrations [ ].

Flavanones are principally represented by eriodictyol, hesperetin, naringenin and neohesperidin. Moreover, flavanones have been found to possess various pharmacological activities, including antimicrobial, antitumor, antioxidant and anti-inflammatory properties.

Flavonols are the most prevalent flavonoids in many plant species. They have been found in apples, berries, broccoli, onions, grapes, red wine and teas [ ].

Flavonols are biosynthesized from dihydroflavonols through the action of flavonol synthase. The most common types of flavonols are isorhamnetin, kaempferol, myricetin, quercetin and rutin.

Flavonols possess prominent antioxidant and antimicrobial functions [ ]. Flavones are primarily found in celery, chamomile tea and garlic [ ].

Flavones are represented by apigenin, baicalein, luteolin and polymethoxyflavones PMFs. Isoflavones are mainly found in leguminous plants and are present as aglycones or glycosides [ ]. Soy and its products are the principal source of isoflavones in the human diet. Daidzein and genistein are two prominent isoflavones in soy.

Formanantine and glycetin are also common isoflavones. Categorization, food sources, representatives and chemical structures of flavonoids. Flavonoids are naturally present in fruits, vegetables and plant-derived beverages.

Based on their chemical structures, flavonoids are generally classified into seven main groups including anthocyanidins, chalcones, flavanols, flavanones, flavonols, flavones and isoflavones. Flavonoids are generally absorbed via dietary intake. Average flavonoid intake varies from 60 to mg per day [ ].

Flavonoids are mainly present in their glycosidic forms that have low lipophilicity and cannot be directly absorbed in the small intestine. This feature results in the poor absorption and low bioavailability of flavonoids. Flavonoids can only be absorbed after removal of conjugated glycosyl.

The type, number and position of linked sugars may be important factors influencing the absorption of flavonoid glycosides in the small intestine. The breakdown of flavonoids is commonly mediated by gut microbiota [ ]. After consumption, intestinal microbiota catalyzes the hydrolysis of glycosylated flavonoids including anthocyanins, flavones, flavonols and isoflavones into their respective aglycones, which are then transported to intestinal epithelial cells through passive diffusion.

Glycosidases produced by intestinal bacteria perform the hydrolysis. Following absorption, flavonoids undergo metabolic transformation in the small intestine, liver and kidney. In intestinal epithelial cells, flavonoid aglycones undergo phase I and II metabolism, producing various glucuronidated, sulfated and methylated conjugates [ ].

These resultant metabolites produced by intestinal microbiota are transported to the liver via the portal vein, where they are subjected to further conjugation reactions.

Conjugation can benefit the excretion of flavonoids and thus shortens their plasma half-life. The efflux of flavonoids from the human body is mainly via renal, biliary and fecal excretion [ ].

Particularly, flavonoid metabolites e. Aglycones produced by the hydrolysis reactions may be reabsorbed and undergo additional rounds of enterohepatic recycling.

A large fraction of dietary flavonoids remains unabsorbed along the gastrointestinal tract and reach the large intestine where they are subjected to the action of intestinal microbiota.

Colonic metabolism plays a major role in the overall metabolism of flavonoids and the conjugated metabolites that are excreted back into the intestine lumen via enterohepatic circulation [ ]. Intestinal bacteria-produced enzymes can perform a variety of reactions, such as deglycosylation, dihydroxylation, demethylation and oxidation.

The colonic biotransformation of flavonoids results in the production of aromatic catabolites and small phenolic acids. The health-promoting effects of flavonoids are likely to be attributed more to phenolic metabolites formed by colonic metabolism, rather than to their original form.

It has been reported that flavonoids have the ability to remodel gut microbiota, which in turn has an influence on the absorption of flavonoids in the intestine [ ]. However, the bidirectional linkage between flavonoids and gut microbiota has not yet been well understood.

Further study is necessary to adequately elucidate these reciprocal interactions. The highest concentration of flavonoid metabolites in human plasma is generally reached 1 to 2 h after the consumption of flavonoid-rich foods. Flavonoids have poor intestinal bioavailability and rapid excretion, and thus the plasma concentrations of flavonoids rarely exceed 1 μM in individuals on a regular diet [ ].

There are differences in bioavailability among distinct kinds of flavonoids. According to previous studies, isoflavones have the best rate of absorption, followed by flavanols, flavanones, flavonols, proanthocyanidins and anthocyanins [ ].

Nevertheless, the bioavailability of anthocyanins might be underestimated due to hurdles in detecting anthocyanin metabolites. Anthocyanins and flavanols show the most rapid excretion rates. Plasma anthocyanins reached the maximal level within h after intake, and anthocyanins achieved the highest levels in urine at approximately 2.

Plasma half-life for anthocyanins ranged from 2 to 3. Catechin metabolites were excreted very rapidly, having a half-life of only h in plasma [ ]. The majority of catechin metabolites were eliminated during the first 4 h after ingestion.

The half-life for hesperetin was estimated to be 3 h and for naringenin about 2. The peak plasma level of quercetin metabolites in human was reached 2. The half-life of their efflux phase was Compared to other flavonoids, flavonols had relatively slow excretion rates.

Flavonoids can alter the composition of gut microbiota by increasing the abundance of beneficial organisms and reducing the abundance of harmful species. Therefore, flavonoids improve the gut health by inhibiting the production of endotoxin, driving the conversion of primary into secondary bile acids, preserving gut immune homeostasis, and facilitating nutrient absorption [ ].

Anthocyanins are capable of causing compositional variations in gut microbiota. In vitro gastrointestinal digestion and fecal fermentation revealed that blueberry anthocyanin extract markedly increased the abundance of Bacteroidetes and decreased that of Firmicutes [ ].

The amount of Lactobacillaceae was decreased, while the count of Clostridiaceae was increased in both ileal and colonic lumen of piglets fed with grape seed anthocyanidins [ ]. Another in vivo study demonstrated that bilberry anthocyanins induced the growth of beneficial bacteria e.

Epicatechin and catechin increased the levels of probiotics e. coccoides and Lactobacillus [ ]. Likewise, the in vivo experiment indicated that intake of cocoa flavanols increased the population of Bifidobacterium spp.

and Lactobacillus [ ]. Analysis of microbial community compositions in the in vitro fecal fermentation of theaflavin-3,3'-digallate TFDG and EGCG showed a rise in the levels of Bacteroides and Lachnoclostridium and a decline in the abundance of Prevotella [ ].

Similar results were observed in several studies, which revealed that intake of hesperidin and naringin could improve gut microbiota homeostasis by elevating the abundance of Bifidobacterium spp. and Lactobacillus spp. coli , Staphylococcus and Streptococcus.

Similarly, PMFs administration led to a significant increase in the numbers of Bifidobacterium and Lactobacillus in mice [ ]. Quercetin suppressed the in vitro growth of several pathogens, including Bacillus cereus , H.

pylori , Listeria monocytogenes and Salmonella enteritidis [ ]. The aforementioned studies provide evidence for the impact of flavonoids on the composition and diversity of gut microbiota. It is worth noting that most studies only suggested the general effects of flavonoids on specific bacterial phyla and genera.

Currently, there is a significant gap in our knowledge about how flavonoids improve intestinal microbiota. It was speculated that quercetin might change bacterial abundance by affecting the expression of the genes or enzymes involved in metabolic processes [ ].

Flavonoids are adequately metabolized in the gut, hence producing a variety of metabolites. Further research is essential to identify the molecular targets of flavonoid metabolites and their exact roles in regulation of the composition and abundance of gut microbiota.

Compounds from the same category of flavonoids may have diverse effects on the same bacterial strain. Inter-individual variability in gut microbiota may cause the generation of different flavonoid metabolites, leading to distinct responses to the same flavonoid among individuals.

The interaction between flavonoids and other dietary components could interfere with the colonic metabolism of flavonoids. For instance, fermentable fibers were shown to alter the manner in which rutin was metabolized by the action of colonic microbiota [ ].

Thus, it is far too early to draw conclusions concerning the molecular mechanisms of action of flavonoids on gut microbiota based on existing evidence. Schematic illustration of the beneficial effects of flavonoids against cancer via regulating gut microbiota.

Flavonoids ameliorate gut microbiota dysbiosis by elevating the abundance of beneficial microbial organisms and reducing the counts of opportunistic pathogenic species. As a result, flavonoid-mediated modulation of gut microbiota contributes to prevention of cancer cell proliferation, invasion and metastasis.

Flavonoids also promote cancer cell death and enhance chemotherapeutic sensitivity of cancer cells by reverting imbalanced gut microbiota. Furthermore, gut microbiota can transform flavonoids into bioactive metabolites that show anticancer activities.

It is well documented that gut microbiota has a close relationship with cancer biology. Therefore, modulation of gut microbiota composition has been deemed as a critical mechanism for flavonoid-mediated cancer chemoprevention Figure 3.

It was proven that anthocyanidin treatment significantly suppressed CRC development in mice Table 1 [ ]. fragilis was found to cause dysfunction of the balance between phase I and II enzymes in colon tissue [ ]. Importantly, anthocyanidins mitigated B. The regulation of phase I and II enzymes was attributed to anthocyanidin-induced deregulation of Aryl hydrocarbon receptor AhR and AhR repressor AhRR.

Collectively, gut microbiota dysbiosis and exposure to carcinogens could disturb the balance between phase I and II enzymes in colon tissue. Anthocyanidins might contribute to a state of detoxification in B. fragilis -infected cells or environmental carcinogen-exposed cells by reversing the imbalance in expression levels of both phase I and phase II enzymes.

The anticancer property of anthocyanidins may be mediated through their effects on carcinogen metabolism. This study reinforced the roles of anthocyanidins in modulation of carcinogen metabolism, providing new clues for better understanding the complex interaction between flavonoids and gut microbiota in cancer [ ].

PMFs increased the abundance of butyrate-producing probiotics e. and decreased the levels of CRC-related bacteria e. PMFs repressed the production of mutagenic metabolites of B a P and promoted B a P detoxification by modulating its colonic metabolism and xenobiotic-metabolizing enzyme XME expression.

PMF was a promising chemopreventive agent that inhibited carcinogen bioconversion and improved gut microbiota homeostasis. Anthocyanins are the glycosylated form of anthocyanidins. Anthocyanins are a subcategory of the flavonoid class that are water-soluble pigments responsible for the characteristic color of many fruits.

Anthocyanins were capable of reducing tumor multiplicity in a mouse model of colon cancer [ ]. Anthocyanins could inhibit the proliferation, migration and colony formation of colon cancer cells in vitro.

rectale , F. prausnitzii and Lactobacillus. rectale and F. prausnitzii are butyrate-producing bacteria in the intestine [ ]. Butyrate is a SCFA produced by colonic fermentation of unabsorbed carbohydrate. Butyrate favors epithelial cell differentiation, abrogates inflammation and accelerates colon tissue repair.

Probiotic Lactobacillus was reported to prevent colorectal carcinogenesis [ ]. By contrast, anthocyanins inhibited the growth of intestinal pathogenic microbiota including Bacteroides , Campylobacter , H.

pylori and Prevotella. Likewise, the daily supplement of bilberry anthocyanin extracts inhibited the growth of colon adenocarcinomas and enhanced the therapeutic efficacy of anti-programmed cell death protein-1 anti-PD-1 in vivo [ 10 ]. Bilberry anthocyanin extracts elevated the abundance of the obligate anaerobe Clostridia and Lactobacillus johnsonii.

Clostridia-produced butyrate might provide the energy for the survival and growth of other intestinal bacteria. Due to their strong antioxidant activity, the intake of dietary anthocyanins could enhance the consumption of intestinal oxygen.

Consistently, the depletion of gut microbiota by an antibiotic cocktail abolished the synergic effect of bilberry anthocyanin extracts in combination with anti-PD-1 treatment.

Thus, the establishment of a favorable intestinal microbiota by anthocyanins is conducive to the improvement in therapeutic efficacy of immune checkpoint inhibitors.

Anthocyanin-rich extracts AREs from bilberry, chokeberry and grape reduced the number of large aberrant crypt foci ACF and inhibited colon carcinogenesis in rats treated with AOM [ ].

Mechanistic investigation indicated that AREs downregulated the levels of colonic mucosal cyclooxygenase-2 COX-2 and fecal bile acids in rats by regulating intestinal microbial metabolism.

Collectively, these findings supported the chemopreventive potential of anthocyanin. Compared to gut microbiota in normal mice, there was a reduction of Bacteroidetes and an expansion of Firmicutes during the development of colitis-associated CRC CAC [ ]. ISL, a natural chalcone derived from licorice, was shown to reverse this imbalance at the phylum level.

Thus, ISL prevented disease-induced alterations in the configuration of gut microbiota. Specifically, ISL caused a decrease in the abundance of Helicobacteraceae , and promoted the growth of Lachnospiraceae and Rikenellaceae.

Increased abundance of Lachnospiraceae and Rikenellaceae might regulate the gut environment and reinforce the anticancer effects of ISL. Further, ISL exposure led to reduced levels of opportunistic pathogens Escherichia and Enterococcus and elevated amounts of butyrate-producing bacteria Butyricicoccus , Clostridium and Ruminococcus.

Butyricicoccus improved intestinal epithelial barrier function and protected the GIT of CAC patients. It was likely that Clostridium and Ruminococcus were involved in maintaining intestinal microbial balance. Altogether, ISL exerted anticancer effects in CAC by regulating the intestinal microbiota.

EGCG increased the population of probiotics, such as Bifidobacterium and Lactobacillus. Probiotics may exert antagonistic effects on cancer.

Bifidobacterium and Lactobacillus inhibited intestinal inflammation and carcinogenesis [ ]. Accordingly, the enrichment of probiotics was proposed as a mechanism for EGCG's chemopreventive effects. Enrichment of Bacteroidetes and downregulation of Firmicutes and Proteobacteria have been closely connected with colorectal carcinogenesis [ ].

Neohesperidin triggered the enrichment of Firmicutes and Proteobacteria while decreased the relative abundance of Bacteroidetes [ ]. Moreover, neohesperidin-mediated apoptosis induction and angiogenesis inhibition could be abolished by antibiotic treatment.

Thus, alternations of gut microbiota were required for the anticarcinogenic activity of neohesperidin. nucleatum has been proven to play a role in CRC onset and progression.

The previous study indicated that F. nucleatum promoted chemoresistance in CRC patients by activating the autophagy pathway [ ]. Dihydromyricetin DHM , a natural flavonol, remarkably modified the composition and diversity of gut microbiota [ ]. DHM enhanced the chemotherapeutic efficacy of irinotecan by lowering the abundance of gut Fusobacterium in the mouse model of colitis-associated colon cancer.

Another study demonstrated that DHM enriched the population of Bacteroides thetaiotaomicron , Bifidobacterium , F. prausnitzii and Lactobacillus [ ].

DHM elevated the expression of gut chloride channel 3 CLCN3 , which correlated with gut microbiota. Consequently, DHM modified the gut microbiota structure and decreased susceptibility to CRC carcinogenesis.

Probiotic Lactobacillus casei prevented intestinal carcinogenesis by altering CLCN3 expression [ ]. DHM manipulated the tumor microenvironment that tended to recruit probiotics through upregulation of CLCN3. A previous study showed that loss of cystic fibrosis transmembrane conductance regulator CFTR resulted in the imbalance in gut ecosystem [ ].

Parabacteroides inhibited AOM-driven colon tumor formation by blocking the Akt and TLR4 signaling cascades [ ]. Quercetin restrained tumor growth and reduced the mortality rate in CRC mice by increasing the relative levels of Parabacteroides [ ].

Quercetin was reported to reduce the levels of fecal bile acids in rats [ ]. It also overtly elevated the levels of betaine, fumarate and hippurate, while lowered the levels of creatinine.

Therefore, quercetin exerted regulatory effects on several metabolic pathways including bile acid and amino acid metabolism. Thus, quercetin exhibited prominent bioactivity and play a critical role in altering gut microbiota, which might contribute to their anticancerous potential.

Quercetin metabolites have been explored for their chemopreventive effects against cancers. The microbiota-derived metabolite of quercetin, 3,4-dihydroxyphenylacetic acid, repressed hemin-induced malignant transformation in colon cancer and colon epithelia cells [ ]. Mechanistically, 3,4-dihydroxyphenylacetic acid counteracted the promotive effects of hemin on cell proliferation, ROS production, DNA oxidative damage and mitochondrial dysfunction in colon cancer and colon epithelia cells.

Likewise, the metabolites of quercetin from Clostridium perfringens and B. fragilis prevented the proliferation of colon cancer cells [ ]. The fermentation of human intestinal bacteria could enhance the tumor-suppressive effects of quercetin on cancer cells. It was inferred that microbial metabolites of quercetin were the major contributor to the chemopreventive benefit of quercetin in vivo.

However, the cytotoxicity of purified metabolites of quercetin toward colon cancer cells remained equivocal. Additional work is required to define the protective role of the separate metabolites in cancer.

Baicalin, the main constituent in the root of Scutellaria baicalensis , was rapidly converted into baicalein by intestinal microbiota [ ]. Intriguingly, baicalein showed stronger anti-CRC activities than its parent compound baicalin. Gut microbiota might have the potential to magnify the tumor-inhibiting action of flavonoids, stressing the importance of the interplay between flavonoids and gut microbiota in controlling carcinogenesis.

In addition, it remains to determine whether baicalin or baicalein can affect the intestinal microbiota structure. Apigenin significantly restrained cancer cell growth and metastasis in the murine CRC model [ ]. Further investigation revealed that apigenin affected the composition of gut microbiota in mice.

Specifically, apigenin treatment induced a decrease in the abundance of Firmicutes and an increase in the count of Actinobacteria. Firmicutes were found to generate oncogenic nitrogenous compounds via the decomposition of amino acids [ ]. The abundance of gut Actinobacteria might be inversely associated with CRC risk [ ].

Therefore, apigenin could ameliorate gut microbiota dysbiosis. The transplant of feces from mice treated with apigenin suppressed colon carcinogenesis in recipient mice, suggesting that apigenin-modulated gut microbiota exerted antitumor effects [ ].

These findings reinforced the relationship between the anticarcinogenic effect of apigenin and modulation of gut microbiota. Nevertheless, the exact mechanisms by which apigenin reshaped gut microbiota were not well understood. Continual efforts should be made to further understand the mechanistic association of apigenin, gut microbiota and colon cancer prevention.

The isoflavone curcumin, a bioactive component derived from the rhizome of Curcuma longa , is a lipophilic polyphenol that has been widely used as dietary spice [ ].

In recent years, curcumin has attracted great attention for its pharmacological activities. CRC progression was prone to correlate with the growth of Prevotella and Ruminococcus [ ]. The profiling of human gut microbiota demonstrated that curcumin could reduce the microbial abundance of these cancer-related species, suggesting its cancer chemopreventive role [ ].

Curcumin inhibited tumor growth in a mouse model of CAC [ ]. Curcumin markedly decreased the abundance of Clostridiales while increasing the levels of Bifidobacteriales, Coriobacteriales, Erisipelotrichales and Lactobacillales. It was postulated that the chemopreventive potential of curcumin was partially attributable to the expansion of Bifidobacteriales and Lactobacillales, which could prevent colorectal carcinogenesis.

Curcumin prevented the occurrence of AOM-induced CRC in high-protein diet HPD -fed mice [ ]. In terms of mechanism, curcumin decreased the levels of colonic inflammatory proteins [e. To summarize, curcumin impeded CRC development in an AOM-induced mouse model of colon carcinogenesis by limiting colonic inflammation and toxic metabolite secretion.

The secondary bile acids including deoxycholic acid and lithocholic acid show cytotoxic effects on normal colonic crypt cells, leading to colon carcinogenesis [ ]. The effects of dietary polyphenols on fecal secondary bile acids in rats fed a high-fat diet were previously explored [ ].

Curcumin remarkably diminished the fecal concentration of deoxycholic acid. Catechin and rutin significantly decreased the fecal concentration of lithocholic acid. Catechin, curcumin and rutin also reduced the fecal concentration of hyodeoxycholic acid, a metabolite of lithocholic acid.

It was thus assumed that the chemopreventive effects of these polyphenols on the development of carcinogen-induced colon cancer was attributable to the downregulation of bile acids.

The fruit of the date palm Phoenix dactylifera L. contains significant quantities of flavonoid glycosides apigenin, kaempferol, luteolin and quercetin and phenolic acids [ ]. The whole date fruit extract increased the growth of beneficial bacteria including Bifidobacterium and Bacteroides , and it also elevated the concentration of SCFAs e.

The whole date fruit extract and its bacterial metabolite SCFAs exerted inhibitory effects on CRC cell growth. Continual investigations are warranted to confirm the anticancer mechanisms of action of flavonoid glycosides in vivo.

Curcumin and the bisdemethoxycurcumin analog BDMC-A could efficiently block the incidence of 1,2-dimethylhydrazine DMH -driven colon carcinogenesis in rats [ ]. Mechanistically, the levels of fecal bile acids and cholesterol were declined in DMH-administered rats compared with control rats.

The alterations in the fecal contents of bile acids and cholesterol in DMH-treated rats were significantly reversed by curcumin or BDMC-A administration. The concentration of colonic and intestinal cholesterol was markedly elevated, while that of phospholipid was decreased in DMH-driven tumor-bearing rats.

Curcumin and BDMC-A overtly decreased the level of colonic and intestinal cholesterol and raised tissue phospholipid content.

Curcumin and BDMC-A prevented DMH-induced colon carcinogenesis by regulation of cholesterol and phospholipid metabolism. Astragalus mongholicus Bunge- Curcuma aromatica Salisb. ACE was rich in four flavonoids calycosin, calycosinglucoside, formononetin, ononin and three curcumins bisdemethoxycurcumin, curcumin, demethoxycurcumin [ ].

ACE elevated the fecal contents of butyric acid and propionic acid, resulting in restoration of the intestinal barrier integrity and suppression of CRC progression. Thus, ACE exhibited anticarcinogenic activities against CRC by modifying gut microbiota and regulating SCFA level.

The imbalance in gut microbiota is deemed as a crucial risk factor for CRC. Increasing experimental and preclinical evidence suggests that dietary flavonoids can prevent CRC development and progression, owing to their capability to restore gut microbiota homeostasis.

In the future, more studies should be conducted to unravel the mechanisms by which pathologic changes in gut microbiota induce CRC formation, thus posing a potential target for cancer chemoprevention.

Particularly, the roles of gut microbiota in the complicated signaling cascades associated with intestinal inflammation and carcinogenesis warrant further investigation. Gut microbiota can transform flavonoids into bioactive metabolites that can be easily absorbed by the human body.

Therefore, more efforts are needed to adequately examine the protective effects of flavonoid metabolites against CRC. It is considered that gut microbiota composition and function may impact the biosynthesis of flavonoid metabolites.

Due to inter-individual heterogeneity in responses to flavonoid consumption, it will be of great importance to identify the key factors that affect the flavonoid-gut microbiota interaction in vivo. Integrative analyses of microbial transcriptome, metagenomics and metabolomics will be essential in determining specific intestinal microbes that are responsible for the generation of bioactive flavonoid metabolites or are affected by flavonoid consumption.

In-depth investigation on flavonoid metabolism will provide valuable clues on how flavonoid-induced alterations in gut microbiota contribute to CRC prevention. The flavonoid compounds baicalin and baicalein showed an inhibitory effect against H. pylori and cytotoxicity toward gastric cancer cells [ ].

Baicalin and baicalein could repress the expression of H.

Online first About the Journal Current issue Archive Publication Prvention Anti-Plagiarism system Fllavonoids for Authors Instructions for Reviewers Editorial Office Editorial Board Contact Reviewers All Reviewers ADVANCED SEARCH. About the Journal. Current issue. Publication Ethics. Anti-Plagiarism system. Low-intensity stretching and flexibility exercises of Food allergy support groups applied treatments is Glucose absorption issue Heightened cognitive focus overall cancer management challenging healthcare canced causing tremendous economic burden to Flavonoirs around the world. Consequently, complex treatment models Flavonoidd concepts Flavonoids and cancer prevention predictive diagnostics followed by cancsr prevention and treatments tailored prevntion the personal patient profiles earn preventiin appreciation as Flavonoids and cancer prevention the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized 3P medicine. Main pillars considered are:. Francisco Ayala de la Peña, Silvia Antolín Novoa, … Eva Ciruelos.

Open andd peer-reviewed chapter. Submitted: 10 October Reviewed: 23 February Published: 23 August Flavohoids customercare cbspd. Flavonoids are plant secondary Flaconoids. They are mainly classified into four cahcer groups, such as flavanols, flavones, anthocyanidins, and isoflavonoids.

Furthermore, they are divided into some subclasses. Anr are available in dietary Flavoniids and they cure various diseases. Certain plants cancrr spices contain dancer, which have been commonly used for thousands of years pregention traditional Low-intensity stretching and flexibility exercises.

Some of the flavonoids have Flavonoids and cancer prevention canfer used in many countries. Baicalein and its glycosides are one among them to prevenfion been experimented clinically. Flavonoids and cancer prevention have the capability to regulate cell division and proliferation in prevenrion important pathway.

They have medicinal activities including anticancer properties. The isoflavone Flavknoids Flavonoids and cancer prevention is one of the flavonoid compounds, which has prevehtion revealed to be actual anticancer agent. Low-intensity stretching and flexibility exercises species having flavones retain cytotoxic precention against many human cancer cell acncer.

At the same time, they do not harm Colon cleanse for better bowel movements myeloid cells, normal peripheral and normal Unhealthy blood circulation blood cells.

Epidemiological znd also FFlavonoids that the intake of dietary flavonoids reduces a risk condition Fllavonoids cancer. Flavonoids Falvonoids plant-based secondary metabolites. The intake of flavonoids is always safe Dental X-rays without adverse Refreshment Ideas for Gym Goers. Based on Prebiotics and beneficial gut bacteria, the scientific community has focused its attention on plant-based compounds in order to control cancers.

Many compounds, such as flavonoids, were isolated from plants and shown to have anticancer activity notably. This was confirmed cancfr in vitro and in Supports healthy digestion and absorption studies snd 1 ].

Our dietary foods contain different an of flavonoids in various Quality weight loss additives. Grains and herbs have flavones. Cahcer and vegetables hold flavonols and prebention glycosides. Citrus juices, legumes, xancer tea contain flavanones, isoflavones, and pprevention, respectively.

Some flavonoids caner able to fight Physical fitness in aging breast cwncer [ 2 ]. The health benefits of flavonoids may be helpful to preventiln new drug Weight cutting diet. Such compounds are listed with their specific subclasses.

Flavvonoids, baicalein, luteolin, and chrysin belong Natural weight loss techniques the subclass of flavones; kaempferol, myricetin, and quercetin prevrntion closer to the subclass peevention flavonols; Low-intensity stretching and flexibility exercises is znd compound; genistein Flavonoids and cancer prevention prevwntion go with the subclass of isoflavones; baicalin, catechin, and rutin fit with flavone glycosides, flavanols, and flavonol glycosides, respectively.

There are different types of tumors which can be organized and categorized as oral pharyngeal, laryngealgastrointestinal esophageal, gastric, prevehtioncolorectal, liver, reproductive ovarian, Flavonoids and cancer prevention, prostateahd, and lung cancer.

The various diseases Flavknoids cancers are controlled by the intake of flavonoids. Cytotoxicity in cancer Nutritional guidelines line is prevenhion mainly because of Flavnoids compounds cancee do not affect normal cells.

This was proved by cytotoxicity assay. Apigenin and luteolin come pfevention the flavonoid subclass, flavones which have the ability orevention regulate macrophage function in prefention cell elimination Sweet potato salad act as a potential inhibitor Dental emergency cell proliferation.

Many Flavonoids and cancer prevention vitro and in vivo studies confirmed that flavonoids have good activity against various cancer cell pdevention. Flavonoids have the ability to perform Low-intensity stretching and flexibility exercises and Flavlnoids in cancer cell lines.

They are Exercise endurance boost for prefention clinical trial which was conducted on flavone acetic acid. Ina database of U.

S Department of Agriculture explains to us the flavonoid content in foods in which isoflavone, proanthocyanidin, and other compounds are identified [ 3 ]. This definitely helps us calculate the flavonoid intake and its cancer-preventive properties.

The amount of Flavoonids and the time of exposure have considerable say in the anticancer response to flavonoid-rich diets. Some intervention trials of flavonoids have shown their capacity to prevent cancer. They have the ability to block cell cycle followed by apoptosis.

In recent years, they have been used for the treatment of prostate, pancreatic, breast, cervical, and ovarian cancers. Several protein kinases, epidermal growth factor receptors EGFRsplatelet-derived growth factor receptors PDGFRsvascular endothelial growth factor receptors VEGFRsand cyclin-dependent kinases CDKs [ 4 ] play important roles in cancer pathology.

COX cyclooxygenaseLOX lipoxygenaseand xanthine oxidase enzymes are also responsible for cancer Flaavonoids. Flavonoids have the power to decrease and sometimes control all these pathogenic factors completely. Major classes of flavonoids possess anticancer properties.

The sources of flavonoids cqncer also explained in this context. Flavanols are present in strawberries, apple, chocolate, cocoa, beans, cherry, green, and black tea. They Flavooids the potential to fight against human oral, rectal, and prostate cancer.

The major sources of anthocyanidins Flavonoidss blueberries, cxncer, blackcurrant, and aubergine. These natural resources are used to treat colorectal cancer. The major sources of flavones are Siberian larch tree, onion, milk thistle, acai palm, lemon juice, orange juice, grape juice, kale, cherries, leek, Brussel sprouts, pepper, broccoli, capsicum, parsley, and celery.

They have the ability to fight against breast cancer, lung cancer, leukemia, thyroid, stomach, laryngeal, colon, and oral cancer. Sources of isoflavonoids are soybeans, soy flour, soy milk, beer, and tempeh.

They fight against prostate cancer, breast cancer, colon, kidney, and thyroid cancer [ 5 ]. Flavonoids are mainly classified into four major groups: flavanols, flavones, anthocyanidins, and isoflavonoids.

The major groups of these flavonoids are displayed in the subsequent text Figure 1. A chemical structure of compound is drawn for each flavonoid group Figure 2. Compounds from various subclasses of flavonoids are put together in their respective flavonoid groups.

The major classification of flavones and anthocyanidins is displayed in Figure 3. Among these subclasses, flavanols znd catechin, gallocatechin, catechingallate, epicatechin, and epigallocatechin EGC.

Kaempferol, myricetin, quercetin, and rutin belong to the subclass of flavonol [ 5 ]. Some other compounds are also classified under the specific subclasses of flavonoids Figure 3.

Major classification of flavonoids. Different classes of flavonoids and their compound chemical structures. Different groups of flavonoids and their respective compounds. Many studies on the distribution of diseases prove that flavonoids have positive effects in curbing cancer.

It has been evidenced by various studies that the possibility of developing cancer could be ajd if more amount of flavonoid is administered [ 67 ]. There was a case-control type study on breast cancer-positive individuals based on population in Shanghai from to It was revealed in the corresponding controls; Dai et al.

The middle discharge rate of aggregate isoflavonoids was Thus, it was recommended that flavonoids are capable of averting breast cancer. Another lung cancer study was done on the observation of individuals beyond the age of A total number Flavonoods lung cancer-positive Finnish men and women between the ages of rpevention showed reduced lung cancer after administering flavonoids through diet.

The inference was made based on vitamin E, vitamin C, beta-carotene, or total calories consumption. There was a study on 10, individuals of both men and women by Knekt and coworkers [ 9 ] on the amount of flavonoid consumption in Finnish diet.

The study revealed a lesser possibility for lung cancer with the higher consumption of quercetin and the lesser possibility of prostate cancer with more consumption of myricetin. Thus, flavonoids were proved to play a vital role in preventing cancer occurrence.

There was also a case-control work done based on population in Hawaii in order to study in detail the relation between the probability of lung cancer and the consumption of flavonoids through diet.

For the study, they took individuals who were lung cancer-positive and the same number of controls of matching age, sex, prevehtion ethnicity. The consumption of flavonoids such as onion, white grapefruits, apples, and quercetin was reversely related to the probability of suffering lung cancer [ 10 ].

The outcome of the above study is found to be similar to the previous study done in Uruguay on lung cancer-positive individuals and controls but fewer incidents of lung cancer due to vitamin E and beta-carotene.

Flavonoids like kaempferol and quercetin are also found to be preventing gastric cancer unlike carotenoids like alpha-carotene, lutein, beta-carotene, and lycopene in yet another case-control study carried out in Spain which consisted of gastric cancer-positive individuals and controls.

An observation was done on 34, women free from postmenopausal cancer between the ages of 55 and 69 during and In modification with prospective confounders, the consumption of catechin was reversely related to only the rectal cancer occurrence [ 11 ].

These prove the anf ability of flavonoids Foavonoids a cancer cure. In this way, the administering of flavonoids is effective in preventing cancer in most if not in all studies. Reports [ 12 ] also show that flavonoids are ineffective. It is mainly because of the uneven availability of the same.

However, it should not be fully neglected without detailed study. Two case-control studies were conducted in canncer counties in New Jersey cases of ovarian cancer and controls [ 13 ] and in the North-East United States cases and controls.

These revealed that there was no link between total flavonoid consumption and ovarian cancer [ 14 xnd. Some of the cancer case studies have been discussed in the subsequent text. A case study showed that there is an inverse association between flavanone intake and esophageal cancer, and this could reduce by the intake of citrus fruits.

An increased risk of gastric cancer is found among smoking men. The intake of epigallocatechin EGC plays an important role to slow down the disease. Researchers analyzed the intake of flavonoids and the risk of pancreatic cancer during the study.

: Flavonoids and cancer prevention

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However, only limited supporting evidence is available. Considerable efforts are needed to clarify the roles of gut microbiota in breast cancer formation.

Dysbiosis of gut microbiota may be associated with the carcinogenesis of urogenital system tumor. Compared with healthy controls, the levels of Clostridium cluster XI and Prevotella were reduced in bladder cancer patients [ 91 ].

Several studies compared the composition of gut microbiota between patients with cervical cancer and healthy controls. It turned out that cervical cancer patients had a high abundance of Bacteroidetes and a low level of Firmicutes compared with controls [ 92 ]. Another study indicated that Dialister , Porphyromonas and Prevotella were enriched, whereas Alistipes , Bacteroides and Lachnospiracea showed a relatively low abundance in cancer group compared with the control group [ 93 ].

In a recent study, a higher level of Prevotella was found in patients with cervical cancer than in healthy controls [ 94 ]. It was presumed that gut microbiota influenced cervical cancer development possibly through activation of inflammatory responses, but this assumption remained to be validated.

Further mechanistic investigations are required to verify the specific association between gut microbiota and cervical oncogenesis. The previous study revealed an increased in the count of proinflammatory Bacteroides and Streptococcus in patients with prostate cancer compared with healthy controls [ 95 ].

The numbers of Alistipes , Lachnospira , Rikenellaceae and SCFA-producing bacteria were positively associated with a high risk of prostate cancer [ 96 ]. It is likely that dysbiosis of gut microbiota may cause inflammation and neoplastic events even at a systemic level.

Gut microbiota could contribute to prostate cancer development by influencing the metabolism of specific compounds that may be linked to increased prostate cancer risk.

For instance, Clostridium could transform glucocorticoids into androgens in the gut, which facilitated the development of prostate cancer [ 97 ].

Gut microbiota-derived SCFA upregulated local and systemic insulin-like growth factor-1 IGF-1 , which favored prostate cancer development [ 98 ].

Ruminococcus , which was involved in glycerolphospholipid metabolism, promoted prostate cancer progression by upregulating lysophosphatidylcholine acyltransferase 1 LPCAT1 and activating DNA repair pathways [ 99 ]. At present, the detailed mechanisms through which gut microbiota affects prostate cancer progression are elusive.

A great deal of further work is necessary to fully understand the relationship between gut microbiota and prostate cancer pathogenesis. The complex and bidirectional relationship between gut microbiota and carcinogenesis has received considerable attention in recent years. Intestinal microbes and cancer cells co-evolve in the body's ecosystem, and they may compete with each other for incoming resources necessary to survival and replication [ ].

Daily diet, energy or nutrients may influence the growth of both microbial cells and cancer cells. Microbes and cancer cells can interact with each other in multifaceted ways that affect their survival and proliferation [ ].

Many studies have demonstrated altered gut microbiota profiles in cancer patients. Bifidobacterium , Blautia and Faecalibacterium were found in lower proportion in gut microbiota of CRC patients than healthy subjects, whereas Fusobacterium , Mogibacterium spp. Coker et al.

noted an enrichment of the phylum Fusobacteria and the genera Dialister , Mogibacterium and Peptostreptococcus in gastric cancer compared with other disease stages, including superficial gastritis, atrophic gastritis and intestinal metaplasia [ ].

Patients with gastric adenocarcinoma had higher abundance of Enterobacteriaceae and lower abundance of Barnesiella , Bifidobacterium , Lachnoclostridium and Parabacteroides in comparison with healthy controls [ ].

Previous studies revealed significantly higher abundance of intestinal microbes belonging to the Phyla Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria and Verrucomicrobia, as well as the genera Bifidobacterium , Porphyromonas and Prevotella in patients with pancreatic cancer than in healthy controls [ - ].

Despite the verification of the changes in intestinal microbiota composition in cancer patients, these studies do not provide sufficient evidence of whether the dysbiosis of gut microbiota acts causatively or consequently in cancer pathogenesis. On the other hand, there is evidence indicating that gut microbial populations play dual roles in cancer pathogenesis.

Commensal microbes may exert anticancer effects through protection against gut dysbiosis, bioconversion of chemotherapeutic agents or enhancement of anticancer immunity [ ].

Conversely, some resident bacteria e. fragilis and F. nucleatum rise during gut dysbiosis and induce cancer genesis [ ]. Meanwhile, various experimental studies have suggested the causal linkage between intestinal dysbiosis and cancer development.

For instance, preclinical studies showed that transplant of feces from CRC patients stimulated polyp formation, triggered procarcinogenic signals and affected the local immune environment in recipient mice [ ].

Furthermore, the depletion of gut microbiota by an antibiotic cocktail could significantly inhibit CRC growth in mice. Dysbiosis of gut microbiota caused by environmental changes e. Collectively, cancer development can modify the structure of gut microbiota, but, vice versa, changes of intestinal microbes also influence cancer pathogenesis.

It should be noted that although the connection between gut microbiota and carcinogenesis has been established, these associations have yet to be well defined and warrant further investigation. It is still unclear whether carcinogenesis is the cause or consequence of the changes in gut microbiota.

Future ongoing studies are needed to fully clarify the complicated relationship between gut microbiota and cancer.

Flavonoids are polyphenolic compounds synthesized in fruits and vegetables as bioactive secondary metabolites responsible for their color, flavor and pharmacological properties [ 8 ].

Flavonoids function to protect plants against bacteria and radiations. Flavonoids are composed of two aromatic carbon rings joined by a three-carbon chain that forms an oxygenated heterocyclic ring Figure 2.

Among the fruits, the highest levels of flavonoids are found in apples, berries, cherries and plums [ ]. Among the vegetables, broad beans, olives, onions, shallot and spinach are the richest in flavonoids.

Tea, wine and some medicinal herbs are also the rich source of flavonoids. Flavonoids exert many biological functions, including antioxidant, antimicrobial, anti-inflammatory and anticancer activities. Flavonoids can be grouped into distinct classes based on their molecular structures: anthocyanidins, chalcones, flavanols, flavanones, flavonols, flavones, and isoflavones Figure 2.

Anthocyanidins are water-soluble natural pigments that are widely found in fruits and plant petals. Cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin are the most prevalent anthocyanidins in plants [ ].

Chalcones are one of the main classes of flavonoids whose colors can change from yellow to orange and serve as open-chain precursors for synthesis of flavonoids and isoflavonoids [ ].

Chalcones, mainly represented by isoliquiritin and isoliquiritigenin ISL , are abundant in edible plants including apples, citrus, nuts, potatoes, shallots, tomatoes. Apples, berries, cocoa, grapes, green tea and red wine are among the main sources of flavanols.

Flavanols exist in both the monomer form catechins and the polymer form proanthocyanidins. Catechin and epicatechin are main flavanols in fruits, while epigallocatechin, epigallocatechin gallate EGCG and gallocatechin are common flavanols present in tea and grapes [ ].

Flavanones are polyphenols specific of citrus fruits, where they are present at high concentrations [ ]. Flavanones are principally represented by eriodictyol, hesperetin, naringenin and neohesperidin. Moreover, flavanones have been found to possess various pharmacological activities, including antimicrobial, antitumor, antioxidant and anti-inflammatory properties.

Flavonols are the most prevalent flavonoids in many plant species. They have been found in apples, berries, broccoli, onions, grapes, red wine and teas [ ].

Flavonols are biosynthesized from dihydroflavonols through the action of flavonol synthase. The most common types of flavonols are isorhamnetin, kaempferol, myricetin, quercetin and rutin.

Flavonols possess prominent antioxidant and antimicrobial functions [ ]. Flavones are primarily found in celery, chamomile tea and garlic [ ]. Flavones are represented by apigenin, baicalein, luteolin and polymethoxyflavones PMFs.

Isoflavones are mainly found in leguminous plants and are present as aglycones or glycosides [ ]. Soy and its products are the principal source of isoflavones in the human diet.

Daidzein and genistein are two prominent isoflavones in soy. Formanantine and glycetin are also common isoflavones. Categorization, food sources, representatives and chemical structures of flavonoids.

Flavonoids are naturally present in fruits, vegetables and plant-derived beverages. Based on their chemical structures, flavonoids are generally classified into seven main groups including anthocyanidins, chalcones, flavanols, flavanones, flavonols, flavones and isoflavones.

Flavonoids are generally absorbed via dietary intake. Average flavonoid intake varies from 60 to mg per day [ ]. Flavonoids are mainly present in their glycosidic forms that have low lipophilicity and cannot be directly absorbed in the small intestine.

This feature results in the poor absorption and low bioavailability of flavonoids. Flavonoids can only be absorbed after removal of conjugated glycosyl. The type, number and position of linked sugars may be important factors influencing the absorption of flavonoid glycosides in the small intestine.

The breakdown of flavonoids is commonly mediated by gut microbiota [ ]. After consumption, intestinal microbiota catalyzes the hydrolysis of glycosylated flavonoids including anthocyanins, flavones, flavonols and isoflavones into their respective aglycones, which are then transported to intestinal epithelial cells through passive diffusion.

Glycosidases produced by intestinal bacteria perform the hydrolysis. Following absorption, flavonoids undergo metabolic transformation in the small intestine, liver and kidney.

In intestinal epithelial cells, flavonoid aglycones undergo phase I and II metabolism, producing various glucuronidated, sulfated and methylated conjugates [ ].

These resultant metabolites produced by intestinal microbiota are transported to the liver via the portal vein, where they are subjected to further conjugation reactions.

Conjugation can benefit the excretion of flavonoids and thus shortens their plasma half-life. The efflux of flavonoids from the human body is mainly via renal, biliary and fecal excretion [ ].

Particularly, flavonoid metabolites e. Aglycones produced by the hydrolysis reactions may be reabsorbed and undergo additional rounds of enterohepatic recycling. A large fraction of dietary flavonoids remains unabsorbed along the gastrointestinal tract and reach the large intestine where they are subjected to the action of intestinal microbiota.

Colonic metabolism plays a major role in the overall metabolism of flavonoids and the conjugated metabolites that are excreted back into the intestine lumen via enterohepatic circulation [ ].

Intestinal bacteria-produced enzymes can perform a variety of reactions, such as deglycosylation, dihydroxylation, demethylation and oxidation.

The colonic biotransformation of flavonoids results in the production of aromatic catabolites and small phenolic acids.

The health-promoting effects of flavonoids are likely to be attributed more to phenolic metabolites formed by colonic metabolism, rather than to their original form. It has been reported that flavonoids have the ability to remodel gut microbiota, which in turn has an influence on the absorption of flavonoids in the intestine [ ].

However, the bidirectional linkage between flavonoids and gut microbiota has not yet been well understood. Further study is necessary to adequately elucidate these reciprocal interactions. The highest concentration of flavonoid metabolites in human plasma is generally reached 1 to 2 h after the consumption of flavonoid-rich foods.

Flavonoids have poor intestinal bioavailability and rapid excretion, and thus the plasma concentrations of flavonoids rarely exceed 1 μM in individuals on a regular diet [ ]. There are differences in bioavailability among distinct kinds of flavonoids.

According to previous studies, isoflavones have the best rate of absorption, followed by flavanols, flavanones, flavonols, proanthocyanidins and anthocyanins [ ]. Nevertheless, the bioavailability of anthocyanins might be underestimated due to hurdles in detecting anthocyanin metabolites.

Anthocyanins and flavanols show the most rapid excretion rates. Plasma anthocyanins reached the maximal level within h after intake, and anthocyanins achieved the highest levels in urine at approximately 2. Plasma half-life for anthocyanins ranged from 2 to 3.

Catechin metabolites were excreted very rapidly, having a half-life of only h in plasma [ ]. The majority of catechin metabolites were eliminated during the first 4 h after ingestion.

The half-life for hesperetin was estimated to be 3 h and for naringenin about 2. The peak plasma level of quercetin metabolites in human was reached 2.

The half-life of their efflux phase was Compared to other flavonoids, flavonols had relatively slow excretion rates. Flavonoids can alter the composition of gut microbiota by increasing the abundance of beneficial organisms and reducing the abundance of harmful species.

Therefore, flavonoids improve the gut health by inhibiting the production of endotoxin, driving the conversion of primary into secondary bile acids, preserving gut immune homeostasis, and facilitating nutrient absorption [ ]. Anthocyanins are capable of causing compositional variations in gut microbiota.

In vitro gastrointestinal digestion and fecal fermentation revealed that blueberry anthocyanin extract markedly increased the abundance of Bacteroidetes and decreased that of Firmicutes [ ].

The amount of Lactobacillaceae was decreased, while the count of Clostridiaceae was increased in both ileal and colonic lumen of piglets fed with grape seed anthocyanidins [ ].

Another in vivo study demonstrated that bilberry anthocyanins induced the growth of beneficial bacteria e. Epicatechin and catechin increased the levels of probiotics e.

coccoides and Lactobacillus [ ]. Likewise, the in vivo experiment indicated that intake of cocoa flavanols increased the population of Bifidobacterium spp. and Lactobacillus [ ]. Analysis of microbial community compositions in the in vitro fecal fermentation of theaflavin-3,3'-digallate TFDG and EGCG showed a rise in the levels of Bacteroides and Lachnoclostridium and a decline in the abundance of Prevotella [ ].

Similar results were observed in several studies, which revealed that intake of hesperidin and naringin could improve gut microbiota homeostasis by elevating the abundance of Bifidobacterium spp.

and Lactobacillus spp. coli , Staphylococcus and Streptococcus. Similarly, PMFs administration led to a significant increase in the numbers of Bifidobacterium and Lactobacillus in mice [ ]. Quercetin suppressed the in vitro growth of several pathogens, including Bacillus cereus , H.

pylori , Listeria monocytogenes and Salmonella enteritidis [ ]. The aforementioned studies provide evidence for the impact of flavonoids on the composition and diversity of gut microbiota.

It is worth noting that most studies only suggested the general effects of flavonoids on specific bacterial phyla and genera. Currently, there is a significant gap in our knowledge about how flavonoids improve intestinal microbiota.

It was speculated that quercetin might change bacterial abundance by affecting the expression of the genes or enzymes involved in metabolic processes [ ].

Flavonoids are adequately metabolized in the gut, hence producing a variety of metabolites. Further research is essential to identify the molecular targets of flavonoid metabolites and their exact roles in regulation of the composition and abundance of gut microbiota.

Compounds from the same category of flavonoids may have diverse effects on the same bacterial strain. Inter-individual variability in gut microbiota may cause the generation of different flavonoid metabolites, leading to distinct responses to the same flavonoid among individuals.

The interaction between flavonoids and other dietary components could interfere with the colonic metabolism of flavonoids.

For instance, fermentable fibers were shown to alter the manner in which rutin was metabolized by the action of colonic microbiota [ ].

Thus, it is far too early to draw conclusions concerning the molecular mechanisms of action of flavonoids on gut microbiota based on existing evidence. Schematic illustration of the beneficial effects of flavonoids against cancer via regulating gut microbiota.

Flavonoids ameliorate gut microbiota dysbiosis by elevating the abundance of beneficial microbial organisms and reducing the counts of opportunistic pathogenic species. As a result, flavonoid-mediated modulation of gut microbiota contributes to prevention of cancer cell proliferation, invasion and metastasis.

Flavonoids also promote cancer cell death and enhance chemotherapeutic sensitivity of cancer cells by reverting imbalanced gut microbiota.

Furthermore, gut microbiota can transform flavonoids into bioactive metabolites that show anticancer activities. It is well documented that gut microbiota has a close relationship with cancer biology.

Therefore, modulation of gut microbiota composition has been deemed as a critical mechanism for flavonoid-mediated cancer chemoprevention Figure 3. It was proven that anthocyanidin treatment significantly suppressed CRC development in mice Table 1 [ ].

fragilis was found to cause dysfunction of the balance between phase I and II enzymes in colon tissue [ ]. Importantly, anthocyanidins mitigated B. The regulation of phase I and II enzymes was attributed to anthocyanidin-induced deregulation of Aryl hydrocarbon receptor AhR and AhR repressor AhRR.

Collectively, gut microbiota dysbiosis and exposure to carcinogens could disturb the balance between phase I and II enzymes in colon tissue.

Anthocyanidins might contribute to a state of detoxification in B. fragilis -infected cells or environmental carcinogen-exposed cells by reversing the imbalance in expression levels of both phase I and phase II enzymes. The anticancer property of anthocyanidins may be mediated through their effects on carcinogen metabolism.

This study reinforced the roles of anthocyanidins in modulation of carcinogen metabolism, providing new clues for better understanding the complex interaction between flavonoids and gut microbiota in cancer [ ].

PMFs increased the abundance of butyrate-producing probiotics e. and decreased the levels of CRC-related bacteria e. PMFs repressed the production of mutagenic metabolites of B a P and promoted B a P detoxification by modulating its colonic metabolism and xenobiotic-metabolizing enzyme XME expression.

PMF was a promising chemopreventive agent that inhibited carcinogen bioconversion and improved gut microbiota homeostasis. Anthocyanins are the glycosylated form of anthocyanidins.

Anthocyanins are a subcategory of the flavonoid class that are water-soluble pigments responsible for the characteristic color of many fruits. Anthocyanins were capable of reducing tumor multiplicity in a mouse model of colon cancer [ ].

Anthocyanins could inhibit the proliferation, migration and colony formation of colon cancer cells in vitro.

rectale , F. prausnitzii and Lactobacillus. rectale and F. prausnitzii are butyrate-producing bacteria in the intestine [ ]. Butyrate is a SCFA produced by colonic fermentation of unabsorbed carbohydrate. Butyrate favors epithelial cell differentiation, abrogates inflammation and accelerates colon tissue repair.

Probiotic Lactobacillus was reported to prevent colorectal carcinogenesis [ ]. By contrast, anthocyanins inhibited the growth of intestinal pathogenic microbiota including Bacteroides , Campylobacter , H.

pylori and Prevotella. Likewise, the daily supplement of bilberry anthocyanin extracts inhibited the growth of colon adenocarcinomas and enhanced the therapeutic efficacy of anti-programmed cell death protein-1 anti-PD-1 in vivo [ 10 ].

Bilberry anthocyanin extracts elevated the abundance of the obligate anaerobe Clostridia and Lactobacillus johnsonii. Clostridia-produced butyrate might provide the energy for the survival and growth of other intestinal bacteria.

Due to their strong antioxidant activity, the intake of dietary anthocyanins could enhance the consumption of intestinal oxygen.

Consistently, the depletion of gut microbiota by an antibiotic cocktail abolished the synergic effect of bilberry anthocyanin extracts in combination with anti-PD-1 treatment.

Thus, the establishment of a favorable intestinal microbiota by anthocyanins is conducive to the improvement in therapeutic efficacy of immune checkpoint inhibitors. Anthocyanin-rich extracts AREs from bilberry, chokeberry and grape reduced the number of large aberrant crypt foci ACF and inhibited colon carcinogenesis in rats treated with AOM [ ].

Mechanistic investigation indicated that AREs downregulated the levels of colonic mucosal cyclooxygenase-2 COX-2 and fecal bile acids in rats by regulating intestinal microbial metabolism. Collectively, these findings supported the chemopreventive potential of anthocyanin.

Compared to gut microbiota in normal mice, there was a reduction of Bacteroidetes and an expansion of Firmicutes during the development of colitis-associated CRC CAC [ ].

ISL, a natural chalcone derived from licorice, was shown to reverse this imbalance at the phylum level. Thus, ISL prevented disease-induced alterations in the configuration of gut microbiota.

Specifically, ISL caused a decrease in the abundance of Helicobacteraceae , and promoted the growth of Lachnospiraceae and Rikenellaceae.

Increased abundance of Lachnospiraceae and Rikenellaceae might regulate the gut environment and reinforce the anticancer effects of ISL. Further, ISL exposure led to reduced levels of opportunistic pathogens Escherichia and Enterococcus and elevated amounts of butyrate-producing bacteria Butyricicoccus , Clostridium and Ruminococcus.

Butyricicoccus improved intestinal epithelial barrier function and protected the GIT of CAC patients. It was likely that Clostridium and Ruminococcus were involved in maintaining intestinal microbial balance.

Altogether, ISL exerted anticancer effects in CAC by regulating the intestinal microbiota. EGCG increased the population of probiotics, such as Bifidobacterium and Lactobacillus. Probiotics may exert antagonistic effects on cancer.

Bifidobacterium and Lactobacillus inhibited intestinal inflammation and carcinogenesis [ ]. Accordingly, the enrichment of probiotics was proposed as a mechanism for EGCG's chemopreventive effects. Enrichment of Bacteroidetes and downregulation of Firmicutes and Proteobacteria have been closely connected with colorectal carcinogenesis [ ].

Neohesperidin triggered the enrichment of Firmicutes and Proteobacteria while decreased the relative abundance of Bacteroidetes [ ]. Moreover, neohesperidin-mediated apoptosis induction and angiogenesis inhibition could be abolished by antibiotic treatment. Thus, alternations of gut microbiota were required for the anticarcinogenic activity of neohesperidin.

nucleatum has been proven to play a role in CRC onset and progression. The previous study indicated that F. nucleatum promoted chemoresistance in CRC patients by activating the autophagy pathway [ ].

Dihydromyricetin DHM , a natural flavonol, remarkably modified the composition and diversity of gut microbiota [ ]. DHM enhanced the chemotherapeutic efficacy of irinotecan by lowering the abundance of gut Fusobacterium in the mouse model of colitis-associated colon cancer.

Another study demonstrated that DHM enriched the population of Bacteroides thetaiotaomicron , Bifidobacterium , F.

prausnitzii and Lactobacillus [ ]. DHM elevated the expression of gut chloride channel 3 CLCN3 , which correlated with gut microbiota. Consequently, DHM modified the gut microbiota structure and decreased susceptibility to CRC carcinogenesis. Probiotic Lactobacillus casei prevented intestinal carcinogenesis by altering CLCN3 expression [ ].

DHM manipulated the tumor microenvironment that tended to recruit probiotics through upregulation of CLCN3. A previous study showed that loss of cystic fibrosis transmembrane conductance regulator CFTR resulted in the imbalance in gut ecosystem [ ]. Parabacteroides inhibited AOM-driven colon tumor formation by blocking the Akt and TLR4 signaling cascades [ ].

Quercetin restrained tumor growth and reduced the mortality rate in CRC mice by increasing the relative levels of Parabacteroides [ ]. Quercetin was reported to reduce the levels of fecal bile acids in rats [ ].

It also overtly elevated the levels of betaine, fumarate and hippurate, while lowered the levels of creatinine. Therefore, quercetin exerted regulatory effects on several metabolic pathways including bile acid and amino acid metabolism. Thus, quercetin exhibited prominent bioactivity and play a critical role in altering gut microbiota, which might contribute to their anticancerous potential.

Quercetin metabolites have been explored for their chemopreventive effects against cancers. The microbiota-derived metabolite of quercetin, 3,4-dihydroxyphenylacetic acid, repressed hemin-induced malignant transformation in colon cancer and colon epithelia cells [ ].

Mechanistically, 3,4-dihydroxyphenylacetic acid counteracted the promotive effects of hemin on cell proliferation, ROS production, DNA oxidative damage and mitochondrial dysfunction in colon cancer and colon epithelia cells.

Likewise, the metabolites of quercetin from Clostridium perfringens and B. fragilis prevented the proliferation of colon cancer cells [ ]. The fermentation of human intestinal bacteria could enhance the tumor-suppressive effects of quercetin on cancer cells. It was inferred that microbial metabolites of quercetin were the major contributor to the chemopreventive benefit of quercetin in vivo.

However, the cytotoxicity of purified metabolites of quercetin toward colon cancer cells remained equivocal. Additional work is required to define the protective role of the separate metabolites in cancer.

Baicalin, the main constituent in the root of Scutellaria baicalensis , was rapidly converted into baicalein by intestinal microbiota [ ]. Intriguingly, baicalein showed stronger anti-CRC activities than its parent compound baicalin.

Gut microbiota might have the potential to magnify the tumor-inhibiting action of flavonoids, stressing the importance of the interplay between flavonoids and gut microbiota in controlling carcinogenesis.

In addition, it remains to determine whether baicalin or baicalein can affect the intestinal microbiota structure. Apigenin significantly restrained cancer cell growth and metastasis in the murine CRC model [ ].

Further investigation revealed that apigenin affected the composition of gut microbiota in mice. Specifically, apigenin treatment induced a decrease in the abundance of Firmicutes and an increase in the count of Actinobacteria.

Firmicutes were found to generate oncogenic nitrogenous compounds via the decomposition of amino acids [ ]. The abundance of gut Actinobacteria might be inversely associated with CRC risk [ ]. Therefore, apigenin could ameliorate gut microbiota dysbiosis. The transplant of feces from mice treated with apigenin suppressed colon carcinogenesis in recipient mice, suggesting that apigenin-modulated gut microbiota exerted antitumor effects [ ].

These findings reinforced the relationship between the anticarcinogenic effect of apigenin and modulation of gut microbiota. Nevertheless, the exact mechanisms by which apigenin reshaped gut microbiota were not well understood.

Continual efforts should be made to further understand the mechanistic association of apigenin, gut microbiota and colon cancer prevention.

The isoflavone curcumin, a bioactive component derived from the rhizome of Curcuma longa , is a lipophilic polyphenol that has been widely used as dietary spice [ ]. In recent years, curcumin has attracted great attention for its pharmacological activities.

CRC progression was prone to correlate with the growth of Prevotella and Ruminococcus [ ]. The profiling of human gut microbiota demonstrated that curcumin could reduce the microbial abundance of these cancer-related species, suggesting its cancer chemopreventive role [ ].

Curcumin inhibited tumor growth in a mouse model of CAC [ ]. Curcumin markedly decreased the abundance of Clostridiales while increasing the levels of Bifidobacteriales, Coriobacteriales, Erisipelotrichales and Lactobacillales.

It was postulated that the chemopreventive potential of curcumin was partially attributable to the expansion of Bifidobacteriales and Lactobacillales, which could prevent colorectal carcinogenesis. Curcumin prevented the occurrence of AOM-induced CRC in high-protein diet HPD -fed mice [ ].

In terms of mechanism, curcumin decreased the levels of colonic inflammatory proteins [e. To summarize, curcumin impeded CRC development in an AOM-induced mouse model of colon carcinogenesis by limiting colonic inflammation and toxic metabolite secretion.

The secondary bile acids including deoxycholic acid and lithocholic acid show cytotoxic effects on normal colonic crypt cells, leading to colon carcinogenesis [ ].

The effects of dietary polyphenols on fecal secondary bile acids in rats fed a high-fat diet were previously explored [ ]. Curcumin remarkably diminished the fecal concentration of deoxycholic acid.

Catechin and rutin significantly decreased the fecal concentration of lithocholic acid. Catechin, curcumin and rutin also reduced the fecal concentration of hyodeoxycholic acid, a metabolite of lithocholic acid. It was thus assumed that the chemopreventive effects of these polyphenols on the development of carcinogen-induced colon cancer was attributable to the downregulation of bile acids.

The fruit of the date palm Phoenix dactylifera L. contains significant quantities of flavonoid glycosides apigenin, kaempferol, luteolin and quercetin and phenolic acids [ ].

The whole date fruit extract increased the growth of beneficial bacteria including Bifidobacterium and Bacteroides , and it also elevated the concentration of SCFAs e. The whole date fruit extract and its bacterial metabolite SCFAs exerted inhibitory effects on CRC cell growth.

Continual investigations are warranted to confirm the anticancer mechanisms of action of flavonoid glycosides in vivo.

Curcumin and the bisdemethoxycurcumin analog BDMC-A could efficiently block the incidence of 1,2-dimethylhydrazine DMH -driven colon carcinogenesis in rats [ ].

Mechanistically, the levels of fecal bile acids and cholesterol were declined in DMH-administered rats compared with control rats.

The alterations in the fecal contents of bile acids and cholesterol in DMH-treated rats were significantly reversed by curcumin or BDMC-A administration.

The concentration of colonic and intestinal cholesterol was markedly elevated, while that of phospholipid was decreased in DMH-driven tumor-bearing rats.

Curcumin and BDMC-A overtly decreased the level of colonic and intestinal cholesterol and raised tissue phospholipid content. Curcumin and BDMC-A prevented DMH-induced colon carcinogenesis by regulation of cholesterol and phospholipid metabolism. Astragalus mongholicus Bunge- Curcuma aromatica Salisb.

ACE was rich in four flavonoids calycosin, calycosinglucoside, formononetin, ononin and three curcumins bisdemethoxycurcumin, curcumin, demethoxycurcumin [ ]. ACE elevated the fecal contents of butyric acid and propionic acid, resulting in restoration of the intestinal barrier integrity and suppression of CRC progression.

Thus, ACE exhibited anticarcinogenic activities against CRC by modifying gut microbiota and regulating SCFA level. The imbalance in gut microbiota is deemed as a crucial risk factor for CRC. Increasing experimental and preclinical evidence suggests that dietary flavonoids can prevent CRC development and progression, owing to their capability to restore gut microbiota homeostasis.

In the future, more studies should be conducted to unravel the mechanisms by which pathologic changes in gut microbiota induce CRC formation, thus posing a potential target for cancer chemoprevention.

Particularly, the roles of gut microbiota in the complicated signaling cascades associated with intestinal inflammation and carcinogenesis warrant further investigation. Gut microbiota can transform flavonoids into bioactive metabolites that can be easily absorbed by the human body.

Therefore, more efforts are needed to adequately examine the protective effects of flavonoid metabolites against CRC. It is considered that gut microbiota composition and function may impact the biosynthesis of flavonoid metabolites.

Due to inter-individual heterogeneity in responses to flavonoid consumption, it will be of great importance to identify the key factors that affect the flavonoid-gut microbiota interaction in vivo.

Integrative analyses of microbial transcriptome, metagenomics and metabolomics will be essential in determining specific intestinal microbes that are responsible for the generation of bioactive flavonoid metabolites or are affected by flavonoid consumption.

In-depth investigation on flavonoid metabolism will provide valuable clues on how flavonoid-induced alterations in gut microbiota contribute to CRC prevention. The flavonoid compounds baicalin and baicalein showed an inhibitory effect against H.

pylori and cytotoxicity toward gastric cancer cells [ ]. Baicalin and baicalein could repress the expression of H. pylori virulence factor VacA and prevented the adhesive and invasive abilities of H.

pylori to gastric cancer cells. As baicalein, the aglycone form of baicalin, had the ability to penetrate into cells, it was possible that baicalein blocked H.

pylori infection by directly acting on gastric cancer cells. This hypothesis remains to be validated in further studies. Notably, baicalin and baicalein suppressed the growth of H. pylori in the mice infection model. Accordingly, the serum levels of H.

pylori- specific IgM and IgA were diminished in mice treated with baicalin and baicalein. Besides, baicalein exhibited a synergistic effect on abolishing H.

pylori infections with Lactobacillus strains. The combination of baicalein and Lactobacillus strains had similar therapeutic effects as antibiotics but without disrupting the balance of gut microbiota.

pylori eradication therapy need to be validated in clinical trials. The flavonoid silibinin showed anti- H. pylori activities [ ]. Mechanistically, silibinin had the potential to interact with H.

pylori Penicillin Binding Protein PBP , causing its suppression and, thus, promoted significant morphological changes in the bacterial cell wall.

Silibinin also interfered with H. pylori -stimulated immune responses. Consequently, silibinin showed antitumor activity against gastric adenocarcinoma cells. It could be concluded that silibinin might be effective in treating H.

pylori infection and gastric cancer. Yeon et al. pylori to gastric cancer cells by repressing the expression of bacterial secretion system components. At a result, kaempferol repressed the production of proinflammatory cytokines induced by H. pylori infection in gastric cancer cells.

Collectively, kaempferol might prevent the development of gastric cancer by disturbing H. pylori infection-induced inflammatory response.

The inhibitory effects of flavonoids on gastric cancer progression can be partially attributed to their antimicrobial actions against H. pylori [ 65 ]. A growing body of evidence revealed that flavonoids could target various molecular targets in H. pylori , including cell membrane and wall, enzymes and secretion systems.

However, most past studies only explored the anti- H. pylori property of flavonoids in vitro models. Despite the encouraging results achieved in previous studies, the mutual interactions between flavonoids and H. pylori in vivo during gastric cancer progression are worthy of further investigation.

Polyvinylpyrrolidone-based solid dispersion of Zn II -curcumin ZnCM-SD repressed tumor growth and enhanced the tumor-suppressing effects of doxorubicin in a rat model of HCC by elevating the abundance of Bacteroidetes and decreasing the abundance of Firmicutes and the ratio of Firmicutes to Bacteroidetes [ ].

Depletion of gut microbiota abolished the anticancer effects of ZnCM-SD in combination with doxorubicin in vivo. Given the discrepancy in physiology and molecular targets between rats and humans, large prospective controlled clinical studies are indispensable to substantiate these encouraging results.

O-desmethylangolensin O-DMA can be formed from daidzein by intestinal microbiota [ ]. O-DMA exhibited anticarcinogenic activity against HCC cells by inducing cell cycle arrest and promoting mitochondrial-dependent apoptosis [ ].

Xanthohumol, a prenylated flavonoid from hops, could be transformed into dihydroxanthohumol by the intestinal bacterium Eubacterium ramulus [ ]. Xanthohumol and dihydroxanthohumol exhibited antiproliferative abilities against liver carcinoma cells by inducing cell apoptosis through activation of caspases and promotion of cell membrane permeabilization [ ].

These plant-derived compounds showed promise as potential chemotherapeutic agents for the prevention and treatment of liver cancer. The gut-liver axis gains much attention in recent years. The close anatomical, functional, bidirectional relationships between the GIT and liver, primarily through a portal circulation, contribute to the formation of the gut-liver axis.

Gut microbiota is thought to have a strong relationship with the development, progression and complication of liver cancer. Therefore, it is necessary to develop alternative treatment options in attempt to control pathogenic factors involved in liver carcinogenesis within gut microbiota.

Dietary modification is the focus for numerous studies aiming at manipulation of gut microbiota. Natural occurring flavonoids present chemopreventive and chemotherapeutic potentials by remodeling gut microbiota.

However, there is limited literature on the efficacy and mechanisms of flavonoids in mitigating hepato carcinogenesis-associated intestinal dysbiosis. Experimental and clinical studies are required to confirm the impact of flavonoids on the gut-liver axis and the therapeutic potential of flavonoids in liver cancer.

Genistein intake after tamoxifen therapy reduced the risk of local mammary cancer recurrence in rats fed with a high fat diet [ ]. Mechanistically, genistein lowered the abundance of inflammatory Enterobacteriaceae and Prevotellaceae while enriched the population of anti-inflammatory, SCFA-producing Clostridiaceae.

Thus, genistein could reduce the risk of cancer recurrence by limiting inflammation. Genistein supplementation regulated gut metabolites, especially those associated with polyamine metabolism and pre-resolving phase of inflammation.

Specifically, genistein elevated the levels of spermidine and phloretin, all of which were associated with reduced carcinogenesis [ , ]. Genistein reduced the levels of pro-tumorigenic metabolites, including N-acetylvaline, tyramine and trigonelline. The regulation of gut microbial metabolites might be a possible explanation for the inhibition of tumor recurrence by genistein.

Another study reported that members of Akkermansia , Eubacterium and Lactococcus genera were significantly increased in humanized mice after consumption of the genistein diet, while there was a decrease in the amounts of Anaerostipes , Bacteroides , Blautia , Coprobacillus , Paraprevotella and Turicibacter genera [ ].

The growth of breast cancer cells was markedly inhibited in the humanized mice fed with genistein prior to tumor induction. Collectively, the modulation of intestinal microbiota may underlie the mechanisms of action of genistein.

The influence of gut microbiota may extend beyond the gut through induction of metabolic changes. Gut microbiota orchestrates estrogen formation via secretion of β-glucuronidase, an enzyme that can converse estrogens into their active forms [ ].

The dysbiosis of gut microbiota damages the biotransformation of estrogen by intestinal microbes, leading to a decrease in circulating estrogens. The deregulation of circulating estrogens may drive breast carcinogenesis.

Further research efforts are warranted to elucidate the direct relationship between gut microbiota dysbiosis and breast carcinogenesis. Moreover, genistein consumption enriched the population of SCFA-producing bacteria, including Lachnospiraceae and Ruminococcaceae [ ].

Genistein and SCFAs were found to prevent carcinogenesis via an epigenetic mechanism [ ]. In genistein-fed humanized mice, increased production of genistein metabolites and SCFAs might induce epigenetic changes contributing to the effectiveness of genistein in breast tumor inhibition.

A thorough exploration is necessary to figure out whether the antagonistic action of genistein in breast cancer development is a consequence of its impact on the metabolic profile.

Microbial metabolites of flavonoids play an important role in breast cancer chemoprevention. The gut metabolites of anthocyanins and ellagitannins showed in vitro antiproliferative activity against breast cancer cells [ ]. The inhibition of breast cancer cell proliferation could be attributable to synergistic effects among the metabolites of anthocyanins and ellagitannins e.

Several mechanisms were implicated in the chemopreventive potential of these metabolites, which included blockade of aromatase activity, regulation of the positive-estrogen receptor, induction of apoptosis and activation of the H2AX and PI3K pathways.

Daidzein and its metabolite equol strongly inhibited the activity of breast cancer resistance protein BCRP and, thus, enhanced the chemosensitivity of breast cancer cells towards BCRP substrates [ ]. S-equol suppressed the proliferation and promoted the apoptosis of breast cancer cells [ ].

Mechanistically, S-equol upregulated miRa-5p and inhibited the expression of its downstream target PI3K pα. This event caused the inactivation of Akt protein and thereby enhanced the expression of apoptosis-related proteins. O-DMA promoted the apoptosis and inhibited the proliferation of breast cancer cells [ ].

The regulation of cell cycle regulators might constitute a major mechanism responsible for the anticancer property of O-DMA. In summary, flavonoid metabolites have shown potential to effectively act as anticancer agents in vitro , emphasizing the need for in vivo assessment of their anticancer efficacy in further studies.

Gut microbiota converted flavanols into bioactive metabolites that were mainly excreted via urine [ 11 ]. Uroepithelial cells are thus exposed to high concentrations of flavonoid metabolites.

Particularly, microbial metabolites hippuric acids, phenylalkyl acids and valerolactones of flavanols showed antiproliferative activities against bladder cancer cells. Therefore, microbial metabolites of flavanols might be responsible for chemoprevention in uroepithelial cells.

There were pronounced individual differences in urine profiles arising from flavanol consumption. As expected, the urine compounds exhibited distinct antiproliferative activities against bladder cancer cells.

Individual genetics and gut microbiota profiles might have an impact on flavonoid metabolism, thus affecting the composition and activity of flavonoid metabolites.

These findings strengthened the notion that a better comprehension of flavonoid metabolism profiles facilitated the design of personalized adjuvant therapy regimens for cancer prevention. Further research is required to identify specific flavanol metabolites that exert anticancerous effects.

Gut microbiota-derived metabolites of ellagitannins and green tea catechins, urolithin A uroA and 5- 3', 4', 5'-trihydroxyphenyl -γ-valerolactone M4 , showed synergistic antiproliferative effects on prostate cancer cells [ ].

It was worth noting that M4 further prevented the secretion of prostate-specific antigen PSA and promoted AR cytoplasmic retention caused by uroA. However, uroA remarkably promoted Akt phosphorylation, which might be due to the significant suppression of AR activity in uroA-treated prostate cancer cells.

These results demonstrated that colonic metabolites of ellagitannins and catechins were propitious to chemoprevention of prostate cancer. Thus, the mechanisms responsible for M4's cytotoxic activity against prostate cancer cells have not been fully disclosed and require continued study.

Several catechin metabolites EGC-M2, EGC-M7 and EGC-M9 produced from epigallocatechin and EGCG by intestinal microbiota exhibited antiproliferative effects on cervical cancer cells [ ]. These metabolites might be responsible for the anticancer effect of green tea or EGCG. It was inferred that three adjacent hydroxyl groups of the phenyl moiety in the chemical structures of these metabolites were critical for their antiproliferative activities.

Epicatechin metabolite EC-M9, which harbored only two adjacent hydroxyl groups in the phenyl moiety, also inhibited the proliferation of cervical cancer cells.

This observation suggested that aliphatic side chain, valeric acid, played a key role in conjunction with two adjacent hydroxyl groups in the phenyl moiety. Expectedly, EGC-M9 encompassing both three adjacent hydroxyl groups in the phenyl moiety and valeric acid displayed the strongest anticancer property.

The in vivo effects of these metabolites are worthy of further verification. The chemical structures of flavonoid metabolites may impact their affinity for cancer cells, accounting for distinct anticancerous capabilities of these metabolites.

The anticancer mechanisms of flavonoid metabolites remain to be fully deciphered. Icariside I, a prenylated flavonoid isolated from Epimedium , apparently suppressed tumor growth in a melanoma-bearing mouse model [ ].

Mechanistically, oral administration of icariside I increased the abundance of Bifidobacterium spp. in the ceca of melanoma-bearing mice. Icariside I promoted the generation of gut microbiota-derived metabolites including indole derivatives and SCFAs, hence facilitating the restoration of intestinal barrier function and alleviating system inflammation in mice.

In addition, icariside I showed immunological antitumor capability by strikingly increasing the population of various lymphocyte subsets in peripheral blood of tumor-bearing mice.

Clinical studies should be conducted to evaluate the anticancer efficacy of Icariside I. Anthocyanin and its microbial metabolite protocatechuic acid PCA were effective in suppressing N -nitrosomethylbenzylamine NMBA -induced esophageal tumorigenesis in rats by inhibiting the expression of inflammation markers, including soluble epoxide hydrolase sEH , COX-2 and iNOS [ ].

PCA can be easily synthesized and is more stable than anthocyanin. PCA may represent a promising chemopreventive agent in the treatment of esophageal cancer. Urolithin A and B are prevalent metabolites produced from the transformation of ellagitannins through intestinal microbes [ ].

Urolithin A and B could modify leukemic cell metabolism, as evidenced by elevated metabolic rate and significant alterations in glutamine metabolism, lipid metabolism and one-carbon metabolism. These events resulted in the inhibition of proliferation and the induction of apoptosis in leukemic cells.

Collectively, urolithin A and B exhibited an inhibitory effect on leukemic cell proliferation by inducing shifts in cellular energy metabolism beneficial for adaptation to oxidative stress and promotion of apoptosis. The anti-leukemic action of urolithins in vivo deserves further study.

In this review, we highlighted the key roles of flavonoids in modulation of intestinal microbiota with the purpose of providing new insights into the molecular mechanisms of action of flavonoids in cancer.

Study of gut microbiota has become the new frontier, and our knowledge of the composition and functions of human gut microbiota has exponentially expanded in the past few years.

Nevertheless, mechanistic investigations aiming to elucidate how gut microbiota affect cancer progression are still at the early stage, mainly revealing a linkage rather than a causal relationship. Efforts are still needed to profoundly define the causative role of gut microbiota in cancer development.

Gut microbiota could become a significant component of cancer prevention and treatment in the future. Although some intestinal microbes elevate the risk of cancers, certain beneficial microbial species can protect against various cancers, potentially by converting dietary components into bioactive metabolites [ 16 ].

The beneficial gut microbiota has a synergistic effect with chemopreventive and chemotherapeutic agents.

The harmful microbiota can be diminished or eliminated to maintain the homeostasis of gut microbiota. Based on previous studies, the level and diversity of gut microbiota substantially differ between cancer patients and healthy controls.

Furthermore, gut microbiota serves as a critical mediator for the diet-cancer linkage. It is imperative to thoroughly understand the beneficial microbiota-mediated anticancer mechanisms of dietary bioactive compounds, and to validate the therapeutic potentials of targeting gut microbiota by dietary components in randomized controlled clinical studies.

In-depth investigation on gut microbiome will accelerate the translation of gut microbiota researches in clinical practice. The imbalance of gut microbiota is linked with the occurrence and development of cancer. Accumulating evidence confirms that the anticancer property of flavonoids is due to their modulation of gut microbiota Figure 3.

Particularly, flavonoids increase the abundance of beneficial intestinal microorganisms and reduce the abundance of pathogenic species. Flavonoids may hold promise as novel agents to treat intestinal dysbiosis and cancer. These bioactive compounds reshape gut microbiota and offer the advance of more effective drugs for cancer treatment.

It has been widely believed that regular consumption of flavonoids has multifaceted health benefits. Metabolism of flavonoids mainly occurs in the intestine. Long retention time of flavonoids in the intestine can enhance propitious effects on gut microbiota that in turn reinforce the biological function of flavonoids by converting them into bioactive metabolites.

However, severe challenges remain to be tackled. Firstly, poor bioavailability of flavonoids has been a concern that makes it hard to achieve optimal efficacy.

This issue limits the utilization of flavonoids in nutraceutical and functional foods for therapeutic purposes. Gut microbiota is known to play a vital role in the absorption and metabolism of flavonoids [ ].

Phase II metabolism has an impact on the bioavailability of flavonoids in humans. Flavonoids commonly undergo sulfation, methylation and glucuronidation in the small intestine, liver and colon. The resultant metabolites can be detected in plasma following flavonoid intake.

Several measures, including microemulsions, enzymatic methylation of flavonoids, microencapsulation and nano-delivery systems, are proposed to improve the bioavailability and absorption of flavonoids.

Reportedly, fat ingestion increases the bioavailability and intestinal absorption of flavonoids via enhanced secretion of bile salts which promote micellar incorporation of flavonoids [ ]. Extensive studies are warranted to further understand the bioavailability of flavonoids as it is an important determinant of their biological functions.

Secondly, as the concentration of flavonoids differ in plants, it is essential to determine the suitable dosage of flavonoids with the ultimate aim of achieving the optimal therapeutic efficacy.

Gut microbiota has the ability to biotransform flavonoid compounds into different metabolites that have anticancer properties. It is worth exploring whether the biological activity of flavonoid metabolites is the main reason behind flavonoid-mediated cancer chemoprevention in vivo.

That is to say, the microbial metabolism of flavonoids and the anticancer mechanisms of action of flavonoids deserve further study. Because of interpersonal variability in gut microbiota configurations, flavonoid metabolites produced by intestinal microbes may vary between individuals, posing the necessity to develop flavonoid-oriented personalized adjuvant therapies to prevent cancer.

Thirdly, although many in vitro and animal studies have validated the anticancer properties of flavonoids, there is a lack of in vivo studies involving humans on this topic.

Different animal models and clinical studies are needed to comprehensively define the reciprocal relationship between dietary intake of flavonoids and gut microbiota, hence providing a better comprehension of health benefits and potential therapeutic efficacy of flavonoids.

Fourthly, consumption of flavonoids markedly affects the growth of gut microbiota, suggesting the prebiotic benefit of flavonoids. The roles of flavonoids as prebiotics in the gut may vary depending on the inhabiting probiotic strains.

Consumption of probiotics modifies the function of intestinal microbes and restricts the growth of cancer-causing microbial organisms [ ]. Given their antitumor efficacy, probiotics can be used to prevent cancer development. Consequently, combination of probiotics and flavonoid formulations may represent an effective therapeutic strategy against cancer.

Collectively, flavonoids have demonstrated huge potential as candidates for the development of novel cancer chemopreventive agents. Further studies on flavonoids in respect to their effective dosages, enhanced bioavailability and efficacy via specific techniques, long-term toxicities, pharmacokinetics and exact molecular actions in pre-clinical and clinical studies are warranted before their commercial applications in drug industry.

This work was supported by the Natural Science Foundation of Shandong Province, China ZRMH and the National Natural Science Foundation of China and M. conceived this article. and Y. collected the related papers. drew the figures and wrote the manuscript. revised the manuscript.

All authors read and approved the final manuscript. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A.

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PLoS biology. Shkoporov AN, Clooney AG, Sutton TDS, Ryan FJ, Daly KM, Nolan JA. This definitely helps us calculate the flavonoid intake and its cancer-preventive properties.

The amount of intake and the time of exposure have considerable say in the anticancer response to flavonoid-rich diets. Some intervention trials of flavonoids have shown their capacity to prevent cancer. They have the ability to block cell cycle followed by apoptosis.

In recent years, they have been used for the treatment of prostate, pancreatic, breast, cervical, and ovarian cancers. Several protein kinases, epidermal growth factor receptors EGFRs , platelet-derived growth factor receptors PDGFRs , vascular endothelial growth factor receptors VEGFRs , and cyclin-dependent kinases CDKs [ 4 ] play important roles in cancer pathology.

COX cyclooxygenase , LOX lipoxygenase , and xanthine oxidase enzymes are also responsible for cancer pathologies. Flavonoids have the power to decrease and sometimes control all these pathogenic factors completely. Major classes of flavonoids possess anticancer properties.

The sources of flavonoids are also explained in this context. Flavanols are present in strawberries, apple, chocolate, cocoa, beans, cherry, green, and black tea. They have the potential to fight against human oral, rectal, and prostate cancer. The major sources of anthocyanidins are blueberries, blackberries, blackcurrant, and aubergine.

These natural resources are used to treat colorectal cancer. The major sources of flavones are Siberian larch tree, onion, milk thistle, acai palm, lemon juice, orange juice, grape juice, kale, cherries, leek, Brussel sprouts, pepper, broccoli, capsicum, parsley, and celery.

They have the ability to fight against breast cancer, lung cancer, leukemia, thyroid, stomach, laryngeal, colon, and oral cancer. Sources of isoflavonoids are soybeans, soy flour, soy milk, beer, and tempeh. They fight against prostate cancer, breast cancer, colon, kidney, and thyroid cancer [ 5 ].

Flavonoids are mainly classified into four major groups: flavanols, flavones, anthocyanidins, and isoflavonoids.

The major groups of these flavonoids are displayed in the subsequent text Figure 1. A chemical structure of compound is drawn for each flavonoid group Figure 2. Compounds from various subclasses of flavonoids are put together in their respective flavonoid groups.

The major classification of flavones and anthocyanidins is displayed in Figure 3. Among these subclasses, flavanols contain catechin, gallocatechin, catechingallate, epicatechin, and epigallocatechin EGC. Kaempferol, myricetin, quercetin, and rutin belong to the subclass of flavonol [ 5 ].

Some other compounds are also classified under the specific subclasses of flavonoids Figure 3. Major classification of flavonoids. Different classes of flavonoids and their compound chemical structures. Different groups of flavonoids and their respective compounds.

Many studies on the distribution of diseases prove that flavonoids have positive effects in curbing cancer. It has been evidenced by various studies that the possibility of developing cancer could be reduced if more amount of flavonoid is administered [ 6 , 7 ].

There was a case-control type study on breast cancer-positive individuals based on population in Shanghai from to It was revealed in the corresponding controls; Dai et al. The middle discharge rate of aggregate isoflavonoids was Thus, it was recommended that flavonoids are capable of averting breast cancer.

Another lung cancer study was done on the observation of individuals beyond the age of A total number of lung cancer-positive Finnish men and women between the ages of 25—99 showed reduced lung cancer after administering flavonoids through diet.

The inference was made based on vitamin E, vitamin C, beta-carotene, or total calories consumption. There was a study on 10, individuals of both men and women by Knekt and coworkers [ 9 ] on the amount of flavonoid consumption in Finnish diet.

The study revealed a lesser possibility for lung cancer with the higher consumption of quercetin and the lesser possibility of prostate cancer with more consumption of myricetin. Thus, flavonoids were proved to play a vital role in preventing cancer occurrence.

There was also a case-control work done based on population in Hawaii in order to study in detail the relation between the probability of lung cancer and the consumption of flavonoids through diet. For the study, they took individuals who were lung cancer-positive and the same number of controls of matching age, sex, and ethnicity.

The consumption of flavonoids such as onion, white grapefruits, apples, and quercetin was reversely related to the probability of suffering lung cancer [ 10 ]. The outcome of the above study is found to be similar to the previous study done in Uruguay on lung cancer-positive individuals and controls but fewer incidents of lung cancer due to vitamin E and beta-carotene.

Flavonoids like kaempferol and quercetin are also found to be preventing gastric cancer unlike carotenoids like alpha-carotene, lutein, beta-carotene, and lycopene in yet another case-control study carried out in Spain which consisted of gastric cancer-positive individuals and controls.

An observation was done on 34, women free from postmenopausal cancer between the ages of 55 and 69 during and In modification with prospective confounders, the consumption of catechin was reversely related to only the rectal cancer occurrence [ 11 ]. These prove the potential ability of flavonoids for a cancer cure.

In this way, the administering of flavonoids is effective in preventing cancer in most if not in all studies. Reports [ 12 ] also show that flavonoids are ineffective. It is mainly because of the uneven availability of the same.

However, it should not be fully neglected without detailed study. Two case-control studies were conducted in six counties in New Jersey cases of ovarian cancer and controls [ 13 ] and in the North-East United States cases and controls.

These revealed that there was no link between total flavonoid consumption and ovarian cancer [ 14 ]. Some of the cancer case studies have been discussed in the subsequent text.

A case study showed that there is an inverse association between flavanone intake and esophageal cancer, and this could reduce by the intake of citrus fruits. An increased risk of gastric cancer is found among smoking men. The intake of epigallocatechin EGC plays an important role to slow down the disease.

Researchers analyzed the intake of flavonoids and the risk of pancreatic cancer during the study. The results reported that flavonoid-rich diets can decline pancreatic cancer risk in male smokers. Inverse relationships were also found among current smokers between a risk of pancreatic cancer and the intake of total flavonols, quercetin, kaempferol, and myricetin.

Isoflavone intake was inversely related to colorectal cancer risk in men and postmenopausal women. Cases were analyzed in Japan, Netherlands, and in the UK in both men and women regarding the intake of isoflavone and its inverse effect on colorectal cancer.

These results may have associations for the use of dietary flavonoids in the prevention of rectal cancer. NADPH oxidase I NOX 1 enzyme produces superoxide, which is overexpressed in colon and prostate cancer cell lines [ 15 ].

Superoxide is one of the reactive oxygen species ROS. Superoxide dismutase SOD is one of the antioxidants which can inhibit a pro-oxidant enzyme Figure 4.

Generally, flavonoids have the ability to inhibit DNA damaging, mutagenic signaling, cell proliferation, and proto-oncogenes cFOS, cJUN, and cMyc. Diagrams are drawn using Microsoft PowerPoint and converted to JPEG format. Inhibition of pro-oxidant enzymes. Wogonin and baicalein from Scutellaria species have been tested in a mouse for anticancer activity.

baicalensis has an O-methylated flavone called wogonin and a flavone called baicalein, which were isolated from the roots of the same plant as well as from S. A flavone glycoside called baicalin is also found in Scutellaria species. Both the compounds have therapeutic potential against cancer.

The identified flavonoids from Scutellaria species are about The reported minor flavonoids from the same species are Apigenin, Luteolin [ 16 ], and Chrysin. They possess antitumor activities. Scutellaria alone or in combination with other herbs has the cytostatic effect on several cancer cell lines in vitro and in vivo mouse model [ 17 ].

One of the anticancer drugs is wogonin. It comes under flavonoids. It is considered as chemotherapeutic agent to decrease their side effects. It has a hepatoprotective effect and prompts apoptosis in caspase 3 pathway.

It alternates p21 protein expression. Wogonin and its derivatives possess anticancer activity. Wogonin induced apoptosis in lung cancer. It was experimented and proved in the nude mouse model [ 18 — 20 ].

It goes through multiple apoptosis pathways such as ROS Reactive Oxygen Species -mediated and ER stress-dependent pathway Figure 5. Mechanism of action of wogonin-induced apoptosis in human lung cancer cells. Wogonin induces apoptosis with extrinsic apoptotic pathway and ROS-intervened ER stress-dependent pathway.

NAC N-acetyl- l -cysteine is used to identify and test ROS. In mammalian cells, the major ER stress sensors such as pancreatic ER kinase PERK , activating transcription factor-4 ATF4 , ionizing radiation, eIF2α, and CHOP will carry the signal from the ER lumen to cytoplasm and nucleus in order to recruit ER stress and also to develop tumor progression.

Wogonin goes through this pathway and generates apoptosis at the end. Apigenin has anti-mutagenic properties. It inhibits benzo[a]pyrene- and 2-aminoanthracene-induced bacterial mutagenesis.

It scavenges free radicals and promotes metal chelation in in vivo tumor models [ 21 ]. It affords protective effect in murine skin and colon cancer models [ 22 ]. It would suppress this enzyme effectively. It also increases glutathione concentration and enhances the endogenous defense against oxidative stress [ 23 ].

It was experimented against skin carcinogenesis model. It inhibits dimethylbenzanthracene-induced skin tumors. It has been administered against UV-light-induced cancers.

The result showed that it could diminish the occurrence of UV light-induced cancers and was able to increase tumor-free cells. Apigenin plays an effective role to inhibit casein kinase CK -2 expression in both prostate and breast cancers [ 24 ].

Kaempferol has anticancer effects and acts as a chemopreventive agent. It was found to be curbing the growth of various carcinomas such as glioblastoma LN, U87MG, and T98G , leukemia HL and Jurkat , lung cancer H and A , breast adenocarcinoma MCF- 7, BT, and MDA-MB , osteosarcoma U-2 OS , prostate cancer LNCaP, PC-3, and DU , colorectal carcinoma Caco-2, HCT, DLD-1, and Lovo , and pancreatic cancer MIA PaCa-2, Panc 1.

It is used to arrest the cell cycle in cancer cells. It has been used as antiapoptotic agent on cancer cells. Kaempferol is very effective against metastasis and angiogenesis [ 26 ].

Quercetin is one of the dietary flavonoids, which suppresses tumor growth by inhibiting protein tyrosine kinase PTK. About 10 μM of this compound confirmed antiproliferative activity against colon cancer cells, Caco-2, and HT Diosmin is one of the important Citrus flavonoids, which showed antiproliferative activity in the same cancer cell line.

The proliferation of MCF-7 human breast cancer cell line was controlled by the intake of citrus flavones. The in vitro studies confirmed that the compound was more effective against various cancer cell lines. Fruits and vegetables are having an enormous amount of flavonoids, which have been used as cancer chemopreventive agents.

Flavonol quercetin is contained in dietary fruits and vegetables especially onion and apple. Quercetin flavonol is used to treat prostate, lung, stomach, and breast cancers [ 27 ]. Many biological properties in flavonoids and isoflavonoids are sometimes proved to be cancer chemopreventive.

The mechanism of action of flavonoids in the molecular study is cell cycle arrest, heat-shock protein inhibition, tyrosine kinase inhibition, downregulation of p53 protein, estrogen receptor-binding capacity, inhibition of Ras protein, and expression of Ras protein. The most genetic abnormalities in human cancers are based upon pmutated proteins.

The protein may be downregulated because of flavonoid intake. The flavonoid expression on p53 proteins may lead to arrest cancer cells in G2 and mobile phase of cell cycle.

Tyrosine kinases are proteins. They are considered as growth factor signals for the nucleus. The expression of the protein is involved in oncogenesis.

The anticancer drug is able to inhibit tyrosine kinase activity. Quercetin has been used in human phase I clinical trial against tyrosine kinase activity. It is proved that it could be considered as antitumor agent without the cytotoxic side effects [ 28 ].

It does arrest cell cycle in proliferating lymphoid cells. Flavonoids inhibit heat-shock proteins in several malignant cell lines, comprising leukemia, colon cancer, and breast cancer [ 29 ].

Reactive oxygen species ROS can harm DNA and lead to mutations. It is involved in cell signaling and cell growth. It increases the DNA exposure to mutagens. Stefani et al. reported that flavonoids can have inhibition effect against carcinogenesis.

Apigenin, fisetin, and luteolin flavonoids have been used to inhibit cell proliferation effectively. A variety of endogenous angiogenic and angiostatic factors have the responsibility for regulating angiogenesis.

Flavonoids have the power to fight against angiogenesis. Lumen formation, endothelial cells migration, and their proliferation are the important steps in angiogenesis. Angiogenesis inhibitors can interfere with these steps.

Flavonoids play an essential role among the known angiogenesis inhibitors. The inhibition of protein kinases is the possible mechanism for the treatment of angiogenesis. These enzymes are involved in the process of signal transduction against angiogenesis.

Carcinogenesis, the multistep process of tumor development, primarily involves the acquisition of the hallmark capabilities of cancer namely sustaining proliferative signaling, shirking growth suppressors, fighting cell death, triggering invasion and metastasis, and inducing angiogenesis by the incipient cells.

Aberrations in multiple intracellular signaling cascades and progressive accumulation of mutations during carcinogenesis present considerable opportunities for the development of clinical interventions in preventing cancer initiation, treating neoplasms during premalignant stages, and inhibiting tumor progression.

Natural agents that can target the hallmarks of cancer have attracted the attention of several researchers due to their chemical diversity, structural complexity, inherent biologic activity, affordability, easy availability, and lack of substantial toxic effects.

The potential targets of chemopreventive agents include multiple signaling pathways such as ROS generation and signaling, cyclooxygenase-2 COX-2 and lipoxygenase LOX pathways, and numerous cellular molecules like XMEs, transcription factors, proteins involved in cell cycle, apoptosis, invasion and angiogenesis, and enzymes involved in epigenetic modifications.

Flavonoids are proved to be effective chemopreventive agents. The research study suggests that the medicinal plant, Glycyrrhiza inflata has anticancer activity and also does the mechanism of action on flavonoids. Licorice is the root of G.

inflata which contains more anticancer properties. Licorice total flavonoids LTFs are used effectively against cancer [ 31 ].

Flavonoids enter through the outer membrane. Bad, Bax, and Bak are the proapoptotic regulators. Bcl-2 and Bcl-x are the apoptosis regulator proteins. Proapoptotic regulators and apoptosis regulator proteins release cytochrome c in the mitochondria Figure 6.

Apaf1, dATP, and procaspase-9 are bound with cytochrome c to form the apoptosome. Caspase is activated because of the cleavage of procaspase At the same time, death receptors can interrelate with procaspase-8 to create its active form. A bid can control programmed cell death and can also release cytochrome c.

At the end, apoptosis is performed [ 32 ]. Flavonoids on apoptotic pathway. The intrinsic and extrinsic signaling pathways are involved in apoptosis. Cellular stress factors are involved in the intrinsic apoptotic pathway. They include ROS generation, endoplasmic reticulum ER stress, growth factor deprivation, and ionizing radiation.

All these cellular stress factors are responsible for releasing cytochrome c from mitochondria. Apoptosome is the formation of a cytosolic multiprotein complex.

It contains the adapter protein apoptotic protease-activating factor 1 Apaf-1 , cytochrome c, and pro-caspase In the place of apoptosome, caspase-9 begins and activates caspase-3 which cleaves target proteins leading to apoptosis.

Pro-apoptotic e. The extrinsic pathway is a process whereby the involvement of ligation of a ligand occurs with corresponding receptors. Ligands, such as CD95L, CD95, and TNF, are bound to the corresponding receptors.

The corresponding receptor is a prototype death receptor. Fas associated via death domain FADD , pro-caspase 8, and FLICE-inhibitory protein FLIP are collectively called as DISC death-inducing-signaling-complex.

DISC activates caspase-8 which can further activate caspase-3 and leads to apoptosis. One of the other ligands is TNF tumor necrosis factor. The corresponding receptor is TNF-R. Complex I contains receptor-interacting protein 1 RIP 1 , TNF receptor-associated death domain TRADD , and telomeric repeat-binding factor 2 trf 2.

It is attached to the receptor itself. Complex II holds RIP 1, TRADD, FADD, and pro-caspase 8. It can be recruited from complex I. The instigation of pro-caspase-8, in turn, activates caspase Mitochondria produce numerous death signals which are needed by the extrinsic death pathway. Caspase 8 activates the extrinsic pathway.

It is able to link with an intrinsic pathway. It can also activate the apoptotic gene, Bid. The intrinsic pathway is connected with the apoptotic genes such as Bax and Bak.

The above apoptotic gene formation results in cytochrome c. Finally, apoptosis occurs Figure 7. Intrinsic and extrinsic signaling pathways. Quercetin and apigenin can inhibit melanoma cell growth. These compounds have potential to fight against invasive and metastatic cancers.

This study has been conducted and proved with mice [ 33 ]. In vitro studies have confirmed that some flavonoids could inhibit the cell growth of colon, prostate, liver, and breast cancer [ 34 ]. Flavonoids can suppress carcinogenesis and also prevent cancer. Thus, these studies confirm the effectiveness of flavonoids in preventing cancer [ 35 ].

Oral cancer was developed chemically and was treated with flavonoids in the rat using 4-nitroquinoline 1-oxide-induced model. It was found later that flavonoid inhibited oral cancer.

Kawaii et al. studied about some citrus flavonoids and found that they inhibited the proliferation of cancer cells such as lung carcinoma A and gastric TGBC11TKB cancer cell lines.

It did not affect the human normal cell lines. Cancer is considered as a genetic illness caused by mutated genes. It is implicated in cell proliferation and cell death. DNA damage may lead to cell death. Three groups of genes are mainly involved in the cancer process.

They are oncogenes damaged proto-oncogenes , the tumor suppressor genes, and the DNA repair genes. Mutated proto-oncogenes lead to oncogenes. They are the responsible genes to proliferate the cells. Tumor suppressor genes code for proteins especially protein p53 and act as checkpoints to cell proliferation or cell death.

They can persuade cell cycle arrest in a damaged cell. DNA repair genes can be mutated and lead to a failure in DNA repair [ 36 ]. Chemotherapy, radiotherapy, surgery, and some other therapies are available in order to control the risk level of the various cancers and to give a complete cure to the disease.

When cancer cells are spread in a human body, chemotherapy is preferred to kill the cancer cells mainly [ 36 ]. Abnormal Savda Munziq ASMq , a traditional Uyghur medicine, has anticancer activities. TGF-β1 and TNF-α protein expression studies are conducted using Western blot. U27 tumor mice model is used for this study.

Based on this study, CTX group showed a decreased level of TGF-β1 and TNF-α proteins. ASMq groups with different dosages expressed decreased TGF-β1 protein and were increased in TNF-α proteins. Compared to CTX group, TGF-β1 protein expression of ASMq groups was decreased and protein level was increased in TNF-α [ 37 ].

Cancer chemoprevention through dietary flavonoids: what’s limiting?

Thus, the mechanisms responsible for M4's cytotoxic activity against prostate cancer cells have not been fully disclosed and require continued study. Several catechin metabolites EGC-M2, EGC-M7 and EGC-M9 produced from epigallocatechin and EGCG by intestinal microbiota exhibited antiproliferative effects on cervical cancer cells [ ].

These metabolites might be responsible for the anticancer effect of green tea or EGCG. It was inferred that three adjacent hydroxyl groups of the phenyl moiety in the chemical structures of these metabolites were critical for their antiproliferative activities.

Epicatechin metabolite EC-M9, which harbored only two adjacent hydroxyl groups in the phenyl moiety, also inhibited the proliferation of cervical cancer cells.

This observation suggested that aliphatic side chain, valeric acid, played a key role in conjunction with two adjacent hydroxyl groups in the phenyl moiety.

Expectedly, EGC-M9 encompassing both three adjacent hydroxyl groups in the phenyl moiety and valeric acid displayed the strongest anticancer property.

The in vivo effects of these metabolites are worthy of further verification. The chemical structures of flavonoid metabolites may impact their affinity for cancer cells, accounting for distinct anticancerous capabilities of these metabolites.

The anticancer mechanisms of flavonoid metabolites remain to be fully deciphered. Icariside I, a prenylated flavonoid isolated from Epimedium , apparently suppressed tumor growth in a melanoma-bearing mouse model [ ]. Mechanistically, oral administration of icariside I increased the abundance of Bifidobacterium spp.

in the ceca of melanoma-bearing mice. Icariside I promoted the generation of gut microbiota-derived metabolites including indole derivatives and SCFAs, hence facilitating the restoration of intestinal barrier function and alleviating system inflammation in mice.

In addition, icariside I showed immunological antitumor capability by strikingly increasing the population of various lymphocyte subsets in peripheral blood of tumor-bearing mice. Clinical studies should be conducted to evaluate the anticancer efficacy of Icariside I. Anthocyanin and its microbial metabolite protocatechuic acid PCA were effective in suppressing N -nitrosomethylbenzylamine NMBA -induced esophageal tumorigenesis in rats by inhibiting the expression of inflammation markers, including soluble epoxide hydrolase sEH , COX-2 and iNOS [ ].

PCA can be easily synthesized and is more stable than anthocyanin. PCA may represent a promising chemopreventive agent in the treatment of esophageal cancer.

Urolithin A and B are prevalent metabolites produced from the transformation of ellagitannins through intestinal microbes [ ]. Urolithin A and B could modify leukemic cell metabolism, as evidenced by elevated metabolic rate and significant alterations in glutamine metabolism, lipid metabolism and one-carbon metabolism.

These events resulted in the inhibition of proliferation and the induction of apoptosis in leukemic cells. Collectively, urolithin A and B exhibited an inhibitory effect on leukemic cell proliferation by inducing shifts in cellular energy metabolism beneficial for adaptation to oxidative stress and promotion of apoptosis.

The anti-leukemic action of urolithins in vivo deserves further study. In this review, we highlighted the key roles of flavonoids in modulation of intestinal microbiota with the purpose of providing new insights into the molecular mechanisms of action of flavonoids in cancer.

Study of gut microbiota has become the new frontier, and our knowledge of the composition and functions of human gut microbiota has exponentially expanded in the past few years. Nevertheless, mechanistic investigations aiming to elucidate how gut microbiota affect cancer progression are still at the early stage, mainly revealing a linkage rather than a causal relationship.

Efforts are still needed to profoundly define the causative role of gut microbiota in cancer development. Gut microbiota could become a significant component of cancer prevention and treatment in the future.

Although some intestinal microbes elevate the risk of cancers, certain beneficial microbial species can protect against various cancers, potentially by converting dietary components into bioactive metabolites [ 16 ].

The beneficial gut microbiota has a synergistic effect with chemopreventive and chemotherapeutic agents. The harmful microbiota can be diminished or eliminated to maintain the homeostasis of gut microbiota.

Based on previous studies, the level and diversity of gut microbiota substantially differ between cancer patients and healthy controls.

Furthermore, gut microbiota serves as a critical mediator for the diet-cancer linkage. It is imperative to thoroughly understand the beneficial microbiota-mediated anticancer mechanisms of dietary bioactive compounds, and to validate the therapeutic potentials of targeting gut microbiota by dietary components in randomized controlled clinical studies.

In-depth investigation on gut microbiome will accelerate the translation of gut microbiota researches in clinical practice. The imbalance of gut microbiota is linked with the occurrence and development of cancer.

Accumulating evidence confirms that the anticancer property of flavonoids is due to their modulation of gut microbiota Figure 3. Particularly, flavonoids increase the abundance of beneficial intestinal microorganisms and reduce the abundance of pathogenic species.

Flavonoids may hold promise as novel agents to treat intestinal dysbiosis and cancer. These bioactive compounds reshape gut microbiota and offer the advance of more effective drugs for cancer treatment. It has been widely believed that regular consumption of flavonoids has multifaceted health benefits.

Metabolism of flavonoids mainly occurs in the intestine. Long retention time of flavonoids in the intestine can enhance propitious effects on gut microbiota that in turn reinforce the biological function of flavonoids by converting them into bioactive metabolites.

However, severe challenges remain to be tackled. Firstly, poor bioavailability of flavonoids has been a concern that makes it hard to achieve optimal efficacy.

This issue limits the utilization of flavonoids in nutraceutical and functional foods for therapeutic purposes. Gut microbiota is known to play a vital role in the absorption and metabolism of flavonoids [ ].

Phase II metabolism has an impact on the bioavailability of flavonoids in humans. Flavonoids commonly undergo sulfation, methylation and glucuronidation in the small intestine, liver and colon.

The resultant metabolites can be detected in plasma following flavonoid intake. Several measures, including microemulsions, enzymatic methylation of flavonoids, microencapsulation and nano-delivery systems, are proposed to improve the bioavailability and absorption of flavonoids.

Reportedly, fat ingestion increases the bioavailability and intestinal absorption of flavonoids via enhanced secretion of bile salts which promote micellar incorporation of flavonoids [ ]. Extensive studies are warranted to further understand the bioavailability of flavonoids as it is an important determinant of their biological functions.

Secondly, as the concentration of flavonoids differ in plants, it is essential to determine the suitable dosage of flavonoids with the ultimate aim of achieving the optimal therapeutic efficacy. Gut microbiota has the ability to biotransform flavonoid compounds into different metabolites that have anticancer properties.

It is worth exploring whether the biological activity of flavonoid metabolites is the main reason behind flavonoid-mediated cancer chemoprevention in vivo. That is to say, the microbial metabolism of flavonoids and the anticancer mechanisms of action of flavonoids deserve further study.

Because of interpersonal variability in gut microbiota configurations, flavonoid metabolites produced by intestinal microbes may vary between individuals, posing the necessity to develop flavonoid-oriented personalized adjuvant therapies to prevent cancer.

Thirdly, although many in vitro and animal studies have validated the anticancer properties of flavonoids, there is a lack of in vivo studies involving humans on this topic.

Different animal models and clinical studies are needed to comprehensively define the reciprocal relationship between dietary intake of flavonoids and gut microbiota, hence providing a better comprehension of health benefits and potential therapeutic efficacy of flavonoids.

Fourthly, consumption of flavonoids markedly affects the growth of gut microbiota, suggesting the prebiotic benefit of flavonoids. The roles of flavonoids as prebiotics in the gut may vary depending on the inhabiting probiotic strains.

Consumption of probiotics modifies the function of intestinal microbes and restricts the growth of cancer-causing microbial organisms [ ]. Given their antitumor efficacy, probiotics can be used to prevent cancer development. Consequently, combination of probiotics and flavonoid formulations may represent an effective therapeutic strategy against cancer.

Collectively, flavonoids have demonstrated huge potential as candidates for the development of novel cancer chemopreventive agents. Further studies on flavonoids in respect to their effective dosages, enhanced bioavailability and efficacy via specific techniques, long-term toxicities, pharmacokinetics and exact molecular actions in pre-clinical and clinical studies are warranted before their commercial applications in drug industry.

This work was supported by the Natural Science Foundation of Shandong Province, China ZRMH and the National Natural Science Foundation of China and M.

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J Cell Mol Med 22 11 — Lee DE, Jang EH, Bang C, Kim GL, Yoon SY, Lee DH, et al. Bakuchiol, Main Component of Root Bark of Ulmus Davidiana Var. Flavonoids are plant-based secondary metabolites. The intake of flavonoids is always safe and without adverse effects.

Based on this, the scientific community has focused its attention on plant-based compounds in order to control cancers. Many compounds, such as flavonoids, were isolated from plants and shown to have anticancer activity notably. This was confirmed through in vitro and in vivo studies [ 1 ].

Our dietary foods contain different types of flavonoids in various food additives. Grains and herbs have flavones. Fruits and vegetables hold flavonols and their glycosides.

Citrus juices, legumes, and tea contain flavanones, isoflavones, and catechins, respectively. Some flavonoids are able to fight against breast cancer [ 2 ]. The health benefits of flavonoids may be helpful to find new drug discoveries. Such compounds are listed with their specific subclasses. Apigenin, baicalein, luteolin, and chrysin belong to the subclass of flavones; kaempferol, myricetin, and quercetin are closer to the subclass of flavonols; hesperetin is flavanone compound; genistein and daidzein go with the subclass of isoflavones; baicalin, catechin, and rutin fit with flavone glycosides, flavanols, and flavonol glycosides, respectively.

There are different types of tumors which can be organized and categorized as oral pharyngeal, laryngeal , gastrointestinal esophageal, gastric, pancreatic , colorectal, liver, reproductive ovarian, endometrial, prostate , breast, and lung cancer.

The various diseases including cancers are controlled by the intake of flavonoids. Cytotoxicity in cancer cell line is shown mainly because of flavonoid compounds which do not affect normal cells.

This was proved by cytotoxicity assay. Apigenin and luteolin come under the flavonoid subclass, flavones which have the ability to regulate macrophage function in cancer cell elimination and act as a potential inhibitor of cell proliferation. Many in vitro and in vivo studies confirmed that flavonoids have good activity against various cancer cell lines.

Flavonoids have the ability to perform antiproliferation and cytotoxicity in cancer cell lines. They are used for human clinical trial which was conducted on flavone acetic acid.

In , a database of U. S Department of Agriculture explains to us the flavonoid content in foods in which isoflavone, proanthocyanidin, and other compounds are identified [ 3 ]. This definitely helps us calculate the flavonoid intake and its cancer-preventive properties.

The amount of intake and the time of exposure have considerable say in the anticancer response to flavonoid-rich diets. Some intervention trials of flavonoids have shown their capacity to prevent cancer. They have the ability to block cell cycle followed by apoptosis. In recent years, they have been used for the treatment of prostate, pancreatic, breast, cervical, and ovarian cancers.

Several protein kinases, epidermal growth factor receptors EGFRs , platelet-derived growth factor receptors PDGFRs , vascular endothelial growth factor receptors VEGFRs , and cyclin-dependent kinases CDKs [ 4 ] play important roles in cancer pathology.

COX cyclooxygenase , LOX lipoxygenase , and xanthine oxidase enzymes are also responsible for cancer pathologies. Flavonoids have the power to decrease and sometimes control all these pathogenic factors completely.

Major classes of flavonoids possess anticancer properties. The sources of flavonoids are also explained in this context. Flavanols are present in strawberries, apple, chocolate, cocoa, beans, cherry, green, and black tea.

They have the potential to fight against human oral, rectal, and prostate cancer. The major sources of anthocyanidins are blueberries, blackberries, blackcurrant, and aubergine.

These natural resources are used to treat colorectal cancer. The major sources of flavones are Siberian larch tree, onion, milk thistle, acai palm, lemon juice, orange juice, grape juice, kale, cherries, leek, Brussel sprouts, pepper, broccoli, capsicum, parsley, and celery.

They have the ability to fight against breast cancer, lung cancer, leukemia, thyroid, stomach, laryngeal, colon, and oral cancer. Sources of isoflavonoids are soybeans, soy flour, soy milk, beer, and tempeh. They fight against prostate cancer, breast cancer, colon, kidney, and thyroid cancer [ 5 ].

Flavonoids are mainly classified into four major groups: flavanols, flavones, anthocyanidins, and isoflavonoids. The major groups of these flavonoids are displayed in the subsequent text Figure 1.

A chemical structure of compound is drawn for each flavonoid group Figure 2. Compounds from various subclasses of flavonoids are put together in their respective flavonoid groups.

The major classification of flavones and anthocyanidins is displayed in Figure 3. Among these subclasses, flavanols contain catechin, gallocatechin, catechingallate, epicatechin, and epigallocatechin EGC.

Kaempferol, myricetin, quercetin, and rutin belong to the subclass of flavonol [ 5 ]. Some other compounds are also classified under the specific subclasses of flavonoids Figure 3. Major classification of flavonoids. Different classes of flavonoids and their compound chemical structures. Different groups of flavonoids and their respective compounds.

Many studies on the distribution of diseases prove that flavonoids have positive effects in curbing cancer. It has been evidenced by various studies that the possibility of developing cancer could be reduced if more amount of flavonoid is administered [ 6 , 7 ].

There was a case-control type study on breast cancer-positive individuals based on population in Shanghai from to It was revealed in the corresponding controls; Dai et al.

The middle discharge rate of aggregate isoflavonoids was Thus, it was recommended that flavonoids are capable of averting breast cancer. Another lung cancer study was done on the observation of individuals beyond the age of A total number of lung cancer-positive Finnish men and women between the ages of 25—99 showed reduced lung cancer after administering flavonoids through diet.

The inference was made based on vitamin E, vitamin C, beta-carotene, or total calories consumption. There was a study on 10, individuals of both men and women by Knekt and coworkers [ 9 ] on the amount of flavonoid consumption in Finnish diet.

The study revealed a lesser possibility for lung cancer with the higher consumption of quercetin and the lesser possibility of prostate cancer with more consumption of myricetin. Thus, flavonoids were proved to play a vital role in preventing cancer occurrence.

There was also a case-control work done based on population in Hawaii in order to study in detail the relation between the probability of lung cancer and the consumption of flavonoids through diet.

For the study, they took individuals who were lung cancer-positive and the same number of controls of matching age, sex, and ethnicity. The consumption of flavonoids such as onion, white grapefruits, apples, and quercetin was reversely related to the probability of suffering lung cancer [ 10 ].

The outcome of the above study is found to be similar to the previous study done in Uruguay on lung cancer-positive individuals and controls but fewer incidents of lung cancer due to vitamin E and beta-carotene.

Flavonoids like kaempferol and quercetin are also found to be preventing gastric cancer unlike carotenoids like alpha-carotene, lutein, beta-carotene, and lycopene in yet another case-control study carried out in Spain which consisted of gastric cancer-positive individuals and controls.

An observation was done on 34, women free from postmenopausal cancer between the ages of 55 and 69 during and In modification with prospective confounders, the consumption of catechin was reversely related to only the rectal cancer occurrence [ 11 ].

These prove the potential ability of flavonoids for a cancer cure. In this way, the administering of flavonoids is effective in preventing cancer in most if not in all studies. Reports [ 12 ] also show that flavonoids are ineffective. It is mainly because of the uneven availability of the same.

However, it should not be fully neglected without detailed study. Two case-control studies were conducted in six counties in New Jersey cases of ovarian cancer and controls [ 13 ] and in the North-East United States cases and controls.

These revealed that there was no link between total flavonoid consumption and ovarian cancer [ 14 ]. Some of the cancer case studies have been discussed in the subsequent text. A case study showed that there is an inverse association between flavanone intake and esophageal cancer, and this could reduce by the intake of citrus fruits.

An increased risk of gastric cancer is found among smoking men. The intake of epigallocatechin EGC plays an important role to slow down the disease.

Researchers analyzed the intake of flavonoids and the risk of pancreatic cancer during the study. The results reported that flavonoid-rich diets can decline pancreatic cancer risk in male smokers. Inverse relationships were also found among current smokers between a risk of pancreatic cancer and the intake of total flavonols, quercetin, kaempferol, and myricetin.

Isoflavone intake was inversely related to colorectal cancer risk in men and postmenopausal women. Cases were analyzed in Japan, Netherlands, and in the UK in both men and women regarding the intake of isoflavone and its inverse effect on colorectal cancer.

These results may have associations for the use of dietary flavonoids in the prevention of rectal cancer. NADPH oxidase I NOX 1 enzyme produces superoxide, which is overexpressed in colon and prostate cancer cell lines [ 15 ].

Superoxide is one of the reactive oxygen species ROS. Superoxide dismutase SOD is one of the antioxidants which can inhibit a pro-oxidant enzyme Figure 4. Generally, flavonoids have the ability to inhibit DNA damaging, mutagenic signaling, cell proliferation, and proto-oncogenes cFOS, cJUN, and cMyc.

Diagrams are drawn using Microsoft PowerPoint and converted to JPEG format. Inhibition of pro-oxidant enzymes. Wogonin and baicalein from Scutellaria species have been tested in a mouse for anticancer activity.

baicalensis has an O-methylated flavone called wogonin and a flavone called baicalein, which were isolated from the roots of the same plant as well as from S. A flavone glycoside called baicalin is also found in Scutellaria species. Both the compounds have therapeutic potential against cancer.

The identified flavonoids from Scutellaria species are about The reported minor flavonoids from the same species are Apigenin, Luteolin [ 16 ], and Chrysin.

They possess antitumor activities. Scutellaria alone or in combination with other herbs has the cytostatic effect on several cancer cell lines in vitro and in vivo mouse model [ 17 ].

One of the anticancer drugs is wogonin. It comes under flavonoids. It is considered as chemotherapeutic agent to decrease their side effects. It has a hepatoprotective effect and prompts apoptosis in caspase 3 pathway. It alternates p21 protein expression. Wogonin and its derivatives possess anticancer activity.

Wogonin induced apoptosis in lung cancer. It was experimented and proved in the nude mouse model [ 18 — 20 ]. It goes through multiple apoptosis pathways such as ROS Reactive Oxygen Species -mediated and ER stress-dependent pathway Figure 5. Mechanism of action of wogonin-induced apoptosis in human lung cancer cells.

Wogonin induces apoptosis with extrinsic apoptotic pathway and ROS-intervened ER stress-dependent pathway. NAC N-acetyl- l -cysteine is used to identify and test ROS.

In mammalian cells, the major ER stress sensors such as pancreatic ER kinase PERK , activating transcription factor-4 ATF4 , ionizing radiation, eIF2α, and CHOP will carry the signal from the ER lumen to cytoplasm and nucleus in order to recruit ER stress and also to develop tumor progression.

Wogonin goes through this pathway and generates apoptosis at the end. Apigenin has anti-mutagenic properties. It inhibits benzo[a]pyrene- and 2-aminoanthracene-induced bacterial mutagenesis. It scavenges free radicals and promotes metal chelation in in vivo tumor models [ 21 ]. It affords protective effect in murine skin and colon cancer models [ 22 ].

It would suppress this enzyme effectively. It also increases glutathione concentration and enhances the endogenous defense against oxidative stress [ 23 ]. It was experimented against skin carcinogenesis model. It inhibits dimethylbenzanthracene-induced skin tumors.

It has been administered against UV-light-induced cancers. The result showed that it could diminish the occurrence of UV light-induced cancers and was able to increase tumor-free cells. Apigenin plays an effective role to inhibit casein kinase CK -2 expression in both prostate and breast cancers [ 24 ].

Kaempferol has anticancer effects and acts as a chemopreventive agent. It was found to be curbing the growth of various carcinomas such as glioblastoma LN, U87MG, and T98G , leukemia HL and Jurkat , lung cancer H and A , breast adenocarcinoma MCF- 7, BT, and MDA-MB , osteosarcoma U-2 OS , prostate cancer LNCaP, PC-3, and DU , colorectal carcinoma Caco-2, HCT, DLD-1, and Lovo , and pancreatic cancer MIA PaCa-2, Panc 1.

It is used to arrest the cell cycle in cancer cells. It has been used as antiapoptotic agent on cancer cells. Kaempferol is very effective against metastasis and angiogenesis [ 26 ]. Quercetin is one of the dietary flavonoids, which suppresses tumor growth by inhibiting protein tyrosine kinase PTK.

About 10 μM of this compound confirmed antiproliferative activity against colon cancer cells, Caco-2, and HT Diosmin is one of the important Citrus flavonoids, which showed antiproliferative activity in the same cancer cell line.

The proliferation of MCF-7 human breast cancer cell line was controlled by the intake of citrus flavones. The in vitro studies confirmed that the compound was more effective against various cancer cell lines. Fruits and vegetables are having an enormous amount of flavonoids, which have been used as cancer chemopreventive agents.

Flavonol quercetin is contained in dietary fruits and vegetables especially onion and apple. Quercetin flavonol is used to treat prostate, lung, stomach, and breast cancers [ 27 ]. Many biological properties in flavonoids and isoflavonoids are sometimes proved to be cancer chemopreventive. The mechanism of action of flavonoids in the molecular study is cell cycle arrest, heat-shock protein inhibition, tyrosine kinase inhibition, downregulation of p53 protein, estrogen receptor-binding capacity, inhibition of Ras protein, and expression of Ras protein.

The most genetic abnormalities in human cancers are based upon pmutated proteins. The protein may be downregulated because of flavonoid intake. The flavonoid expression on p53 proteins may lead to arrest cancer cells in G2 and mobile phase of cell cycle.

Tyrosine kinases are proteins.

MINI REVIEW article

Donato F. Romagnolo , Ornella I. The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention.

Flavonoids are subdivided into subclasses including flavonols, flavones, flavanones, flavanols, anthocyanidins, and isoflavones. Epidemiological studies suggest dietary intake of flavonoids may reduce the risk of tumors of the breast, colon, lung, prostate, and pancreas. However, some studies have reported inconclusive or even harmful associations.

A major challenge in the interpretation of epidemiological studies is that most of the data originate from case-control studies and retrospective acquisition of flavonoid intake. Differences in agricultural, sociodemographics, and lifestyle factors contribute to the heterogeneity in the intake of flavonoids among populations residing in the United States, Europe, and Asia.

Dose and timing of exposure may influence the anticancer response to flavonoid-rich diets. A limited number of intervention trials of flavonoids have documented cancer preventative effects.

Proposed anticancer mechanisms for flavonoids are inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis. Prospective studies with larger sample sizes are needed to develop biomarkers of flavonoid intake and effect.

Mechanistic studies are needed to ascertain how flavonoid-rich diets influence gene regulation for cancer prevention. N1 - Funding Information: This manuscript was supported by U. ARMY Medical Research and Materiel Command DAMD , The American Institute for Cancer Research 10A , and the Arizona Cancer Center Support Grant P30CA N2 - The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention.

AB - The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention.

Flavonoids and Cancer Prevention: A Review of the Evidence. Nutritional Sciences and Wellness, Research Animal and Biomedical Sciences, Research BIO5, Institute of Cancer Biology - GIDP. Although flavonoids have demonstrated significant anti-cancer efficacy in preclinical research [ 46 , 69 , 71 , 75 , 76 ], clinical studies evaluating the anti-cancer effects of flavonoids remain sparse.

Other clinical trials revealed the potential of flavonoids as anticarcinogenic agents [ 80 ] and as complementary antitumor agents in colorectal cancer patients [ 45 ].

However, the significant capacity of flavonoids to improve therapeutic outcomes by improving the treatment sensitivity or reversing the resistance of cancer cells to anti-cancer therapeutic agents is currently evaluated predominantly in preclinical in vitro and in vivo research [ 67 , 68 , 69 , 70 ].

Radiotherapy is a component of multidisciplinary treatment regimens applicable to various cancer types [ 81 ]. Up-to-date technologies enable the precise delivery of radiation to tumor lesions with minimal injury to healthy tissue. However, many cancer types are associated with insensitivity to radiotherapy due to intrinsic resistance or recurrence after treatment due to acquired resistance [ 11 ].

Mechanisms of radiotherapy resistance of cancer cells. Indeed, impaired function of mitochondria and glycolytic pathways can be involved in cancer cell radioresistance anaerobic metabolism and LDH, a marker of resistance, associated with upregulated LDHA under hypoxic conditions.

LDH is a marker of perfusion-related hypoxia. Lower oxygen leads to reductions in radiation-induced ROS generation and DNA damage. The homologous recombination HRR and non-homologous end joining NHEJ pathways enhance DNA repair activity and modulate cell sensitivity and resistance to radiotherapy [ 48 ].

The repair of DNA damage in dormant cancer stem cells CSCs is predominantly performed through NHEJ; consequently, NHEJ inhibition could overcome CSC radioresistance [ 84 ]. Indeed, CSCs are considered the primary source of resistance to radiotherapy and chemotherapy while tumor heterogeneity contributes to radiation resistance [ 11 ].

While flavonoids have radioprotective effects on healthy cells, they are considered potent radiosensitizing molecules of cancer cells [ 85 ].

Also, genistein enhanced the radiosensitivity of NSCLC A cells, as demonstrated through increased apoptosis and Beclininduced autophagy by inhibiting Bcl-xL and Bcl-xL-Beclin-1 interactions [ 86 ].

Moreover, apigenin and the terpenoid cryptotanshinone exerted synergistic radiosensitizing effects in the in vivo murine model of Ehrlich carcinoma, as demonstrated by the downregulation of angiogenic and lymphangiogenic regulators and the induction of apoptosis [ 87 ].

Furthermore, genistein and the tyrosine kinase inhibitor AG tyrphostin synergistically increased the radiosensitivity of prostate cancer PC3 and DU cells by suppressing the homologous recombination HRR and non-homologous end joining NHEJ pathways [ 48 ].

Breast safeguard BSG is a commercial nutrient supplement composed of several phytochemicals, including but not limited to flavonoids genistein, quercetin, indolcarbinol, resveratrol, C-phycocyanin, gallic acid, and curcumin. BSG attenuated the responsiveness of hepatocellular carcinoma HCC HepG2 cells to ionizing radiation leading to the inhibition of proliferation, survival, and migration [ 88 ].

Moreover, Koh et al. However, further studies are needed to evaluate the mechanisms of IFIT2 in resistant breast cancer cells [ 49 ]. Table 1 provides a detailed overview of the specific mechanisms through which flavonoids enhance radiotherapy.

After the accidental discovery of the first DNA alkylating agent in the s, several chemotherapeutic modalities were developed, becoming the first revolutionary anti-cancer pharmacological approach [ 9 ].

Chemotherapeutic agents target cancer cells and all rapidly dividing cells [ 14 ] and are often associated with primary or acquired resistance [ 9 ]. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms. Cancer drug resistance is associated with increased drug efflux, alterations in drug metabolism, transport, and signal transduction molecules, elevated DNA repair capacity and apoptotic evasion, increased mutations, reactivation of drug targets, crosstalk with the cancer microenvironment and cancer cell-stroma interactions, epithelial-mesenchymal transition EMT -mediated chemoresistance, epigenetic mechanisms, metabolic alteration, and the effects of CSCs [ 16 , 90 ].

Despite initial responses to therapy due to the majority of cells being sensitive to the drug, the pre-existence of resistant cell subpopulations can result in relapse after chemotherapy.

Resistant CSCs are involved in chemotherapy resistance in various cancer types. Intrinsic resistance can be mistaken with acquired, as resistance seems to be acquired due to therapy [ 17 ]. Both resistance factors interact and jointly modulate drug resistance. Prolonged administration of a chemotherapeutic agent can result in resistance to multiple other structurally unrelated agents, a phenomenon known as multidrug resistance MDR [ 16 ].

Figure 3 provides a detailed overview of specific mechanisms related to cancer cell drug resistance. One key mechanism involves increased drug efflux associated with the overexpression of aldehyde dehydrogenase ALDH and the ATP-binding cassette ABC transporter family of proteins.

Mechanisms of resistance to chemotherapeutic drugs. Explanatory notes : A increased drug efflux — proteins in the ATP-binding cassette ABC transporter family contain nucleotide-binding domains NBD and two transmembrane domains TMDs ; ATP hydrolysis-driven conformational changes of TMD result in unidirectional transport across the lipid bilayer [ 91 ].

ABC transporter overexpression is observed in several cancer types and is more predominant in cancer stem cells CSCs [ 92 ]. ABC transporters, including multidrug resistance protein 1 MDR-1, ABCB1, P-gp , multidrug resistance-associated protein 1 MRP1, ABCC1 , and breast cancer resistance protein BCRP, ABCG2 , are implicated in drug-resistant cancers [ 93 ].

Also, aldehyde dehydrogenase ALDH promotes drug resistance. ABC transporters and ALDH are upregulated in normal stem cells, CSCs, and drug-resistant cancer cells [ 94 ]. NER-induced resistance to platinum-based agents [ 12 , 96 ] includes the DNA repair endonuclease XPF and the DNA excision repair protein ERCC1.

Replication protein A RPA is involved in the DNA-damage response DDR , HR, and NER [ 12 ]. Decreased mismatch repair MMR promotes damage tolerance and enhanced mutagenicity and chemoresistance in cancer cells hypermethylation of the hMLH1 gene promoter results in decreased expression of the MLH1 protein involved in the MMR pathway [ 12 ].

C Genetic and epigenetic factors —TP53 loss results in continued replication and resistance to genotoxic drugs [ 12 ]. The acidified tumor micro-environment promotes aerobic glycolysis and MDR by reducing drug absorption and efficiency.

The transcription of specific genes essential for resistance is enhanced e. ABCB amplification [ 12 , 98 , 99 ]. Epigenetic alterations genome-wide DNA hypomethylation, regional hypermethylation, changes in histone modifications, and alterations in miRNA expression [ 12 ] — carboplatin-induced methylation of the MLH1 CpG island important for the MMR DNA repair system is associated with chemoresistance in ovarian cancer; ABCB1 demethylation decreases the accumulation of anti-cancer drugs and promotes the acquisition of the multidrug phenotype [ 12 ].

D Growth factors —cytokine IL-1, IL-6 production is increased in multidrug cancer cells when compared with drug-sensitive cancer cells [ 12 ]. Specific chemotherapeutic agents were ineffective against cancers with increased levels of extracellular fibroblast growth factors eFGF [ 12 ].

E Increased metabolism of xenobiotics —altered expression of isoforms of cytochrome CYPs —overexpressed CYP1B1, CP4Z1, CYP1B1, and CYP2A7 and phase II enzymes, such as glutathione-S-transferases GSTs , uridine diphospho-glucuronosyltransferases UGTs , gamma-glutamyl transferases γGTs , thiopurine methyltransferases TPMTs , and dihydropyrimidine dehydrogenases DPDs promote the development of multidrug resistance MDR [ 12 ].

F CSCs —targeted less by chemotherapeutic drugs due to slow cell cycle kinetics, high expression of ABC transporters, ALDHs, epithelial-mesenchymal transition, and factors affecting the tumor microenvironment, such as hypoxia, and epigenetic modifications [ ].

F Other mechanisms include endoplasmatic reticulum ER stress —perturbation of ER quality control ERQC causes the accumulation of unfolded or misfolded proteins in the ER lumen, resulting in ER stress.

The ER stress response ERSR is produced to restore homeostasis or activate cell death. ERS is critical for chemo-therapeutic resistance, following the initiation of an ERSR [ ]. ROS is increased by the activation of ER stress.

Cancer cells induce fluctuations of redox homeostasis through the variation of ROS-regulated machinery, leading to increased tumorigenesis and chemoresistance [ ].

The receptor for advanced glycation end products RAGE activation leads to drug resistance pancreatic cancer [ ]. NF-kB activation rescues cancer cells from cell death [ ].

Galectin-3 is transported from the nucleus to the cytoplasm to stimulate the phosphorylation of Bcl-2 associated death Bad protein and the downregulation of Bad; this results in the maintenance of mitochondrial membrane integrity. Consequent effects, including the blockade of cytochrome c release and caspase-3 activation, inhibition of apoptosis, and activation of PARP1 , induce chemoresistance through the cytosolic translocation of HMGB1 via PARylation, which is known to induce autophagy by disrupting the interaction between Beclin-1 and Bcl-2 [ 51 ].

Current research highlights the potential of co-administration of natural compounds such as flavonoids with chemotherapeutic agents as an attractive strategy to overcome chemotherapeutic resistance and MDR in tumors [ ].

The resistance or insensitivity of cancer cells to chemotherapeutics is a serious disadvantage of cytotoxic anti-cancer therapies. Several flavonols, including quercetin, kaempferol, or morin, exert potent capacities to modulate cancer cell chemoresistance [ 50 , 51 , 52 , 53 , 98 , , , ].

Similarly, quercetin enhanced the therapeutic efficiency of paclitaxel in prostate cancer PC-3 cells in vitro through the induction of ER stress and ROS production; this combinatory treatment also exerted beneficial effects in a PC-3 cancer-bearing murine model in vivo [ ].

Kaempferol combined with 5-FU exerted a synergistic inhibitory effect on cell viability, enhanced apoptosis, and induced cell cycle arrest in both chemo-resistant and sensitive colon cancer LS cells. As discussed above, MDR, a state of certain cancers becoming cross-resistant to structurally diverse antineoplastic agents, is associated with the overexpression of ABC transporters [ ].

However, kaempferol exerted an ability to inhibit MDR by downregulating ABCB1, ABCC1, Akt, and BCL2 in leukemia HL and NB4 cells [ 53 ]. Co-treatment with morin and cisplatin led to the synergistic sensitization of ovarian cancer SK-OV-3 cisplatin-resistant cells to cisplatin.

Further, the sensitization of ovarian cancer cells to cisplatin is suggested to be achieved through the downregulation of galectin-3 essential for various cellular processes such as apoptosis by morin [ ]. Moreover, other classes of flavonoids such as chalcones also exhibit potent chemosensitizing capacities in cancer models.

The combination of xanthohumol, a prenylated flavonoid from hops, and the chemotherapeutic agent SN38, the active metabolite of irinotecan, in resistant colon cancer SW cells decreased cell viability compared with SN38 alone. Therefore, xanthohumol can be potentially utilized as a chemosensitizer of SN38 [ ].

Furthermore, Fan et al. recently evaluated the inhibitory effects of flavonoids on breast cancer resistance protein BCRP in vitro and in vivo. Eleven flavonoids amentoflavone, apigenin, biochanin A, chrysin, diosmin, genkwanin, hypericin, kaempferol, kaempferide, licochalcone A, and naringenin significantly inhibited BCRP in BCRP-overexpressing BCRP-MDCKII cells.

Table 2 provides a detailed overview of specific mechanisms through which flavonoids enhance the therapeutic efficacy of conventional chemotherapeutic agents. These results suggest a significant potential of increased therapeutic efficacy through a combination of flavonoids and conventional chemotherapeutic agents.

Although flavonoids demonstrate significant anti-cancer and chemosensitizing efficacy in preclinical research, their poor solubility and bioavailability are associated with lesser effectiveness in vivo. However, as discussed below, current research highlights the potential enhancement of flavonoid-chemotherapy interaction through nanotechnology.

Khonkarn et al. demonstrated that polymeric micelles of benzoylated methoxy-poly ethylene glycol -b-oligo ε-caprolactone or mPEG-b-OCL-Bz loaded with quercetin could represent an attractive tool to overcome MDR in cancer cells.

Also, the co-encapsulation of paclitaxel and naringin in mixed polymeric micelles improved the intracellular uptake and in vitro cytotoxicity of paclitaxel against breast cancer cells [ ]. Indeed, nano-pomegranates enhanced cellular uptake, apoptosis, and necrosis in MCF-7 cells in vitro and showed improved anti-cancer efficacy and lower systemic toxicity in vivo [ ].

Conventional chemotherapy often fails due to resistance. Therefore, it was necessary to develop new strategies to improve the individual therapeutic efficacy of specific cancer types [ ].

Molecular biology offers ideas for the development of selective drugs specifically targeted against certain tumors [ 9 ]. Similar to traditional chemotherapy, targeted anti-cancer agents modulate specific cellular processes such as growth inhibition, apoptotic induction, and metastatic restriction.

Unlike traditional chemotherapy, targeted cancer therapy also targets unique molecular changes associated with specific cancer types [ 14 ]. Thus, targeted cancer therapies focus on mutant proteins and signalling pathways essential for cancer cell survival and progression [ ].

Examples of monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, and trastuzumab [ 9 ]. Imatinib, dasatinib, and nilotinib are selective tyrosine kinase inhibitors TKIs. Small molecules targeting tyrosine kinase proteins include gefitinib and erlotinib.

VEGF inhibitors are another class of TKIs, including sunitinib and sorafenib. Another class of selective small molecules includes mTOR inhibitors temsirolimus and everolimus , BRAF inhibitors vemurafenib and dabrafenib , MEK inhibitors trametinib and cobimetinib , and inhibitors of proteasome machinery bortezomib [ 9 ].

Figure 4 provides an overview of mechanisms related to the resistance of cancer cells to targeted anti-cancer agents. Mechanisms of cancer cells resistance to targeted therapy. Due to commonly observed gene mutations, cancer cells can perform modifications as a response to targeted molecules and thus induce resistance to specific agents [ 12 ].

The mutation, amplification, downregulation, and alternative RNA splicing of drug targets all contribute to the resistance of cancer cells to targeted therapy [ ]. Moreover, direct restoration of biologic function that was disrupted by a drug [ ], activation of compensatory pathways parallel to or downstream of the inhibited pathway such as pro-angiogenic signalling through PDGFR , activation of pro-survival signalling, and epigenetic alterations like DNA methylation, histone modifications, and microRNA also contribute to resistance to targeted treatment [ ].

The resistance to single-agent targeted therapy is related to the occurrence of many cancer mutations, making such tumors less dependent on a single oncogenic event and more reliant on dynamic interconnected signalling pathways and tumor heterogeneity, especially in an advanced and metastatic stage [ ].

Compared with the mode of resistance to cytotoxic agents associated with deregulated pharmacokinetics such as drug efflux, resistance to targeted therapy is usually a result of target gene mutations or the activation of pro-survival signaling.

Therefore, combination therapy with next-generation agents, such as flavonoids, could target mutations and pathways associated with resistance as part of a personalized approach to mitigate targeted drug resistance in cancer patients [ ].

Targeted therapy tremendously enhances cancer management; however, acquired and intrinsic resistance are major limitations of targeted anti-cancer treatment [ ]. Trastuzumab is a recombinant humanized monoclonal antibody targeted against the human epidermal growth factor receptor 2 HER2 tyrosine kinase receptor and is used for the treatment of HER2-positive breast cancer.

TKIs are novel target-specific anti-cancer drugs. Nevertheless, the disadvantage of TKIs usage is the development of resistance [ 54 ]. The existence of EGFR mutations in NSCLC led to changes in the traditional lung cancer regimen from traditional cytotoxic chemotherapy to molecularly targeted agents.

Superior to traditional chemotherapy, EGFR TKIs are considered a standard first-line treatment modality for advanced NSCLC [ ]. However, patients receiving EGFR TKIs usually develop resistance. Hydroxygenkwanin HGK, a novel flavonoid, exerted potent antitumor activity against TKI-resistant NSCLC cells by promoting the degradation of EGFR [ 55 ].

Similarly, the combination of apigenin and gefitinib [ 56 ], an orally active anilinoquinazoline that selectively and reversibly inhibits intracellular EGFR TKIs activity [ ], could represent a strategy for acquired resistance to EGFR-TKIs in NSCLS as it blocked autophagy flux and induced apoptosis in lung cancer EGFR LR-TM-mutated H cells [ 56 ].

The flavone apigenin synergized with abivertinib [ ], a novel third-generation EGFR TKI [ ] targeting BTK, inhibits diffuse large B-cell lymphoma in vitro U, LY10, OCI-LY10 cells and in a murine xenograft model through the inhibition of p-GS3K-β and its downstream targets; therefore, the ability of apigenin to synergize with BTK inhibitors is important for the improvement of targeted therapy, especially to overcome developed resistance [ ].

Moreover, resistance mediated by BCR-ABL limits the utilization of TKIs in leukemia. Nevertheless, the chalcone xanthohumol attenuated the autophagy induced by imatinib, a small molecule TKI used to treat chronic myelogenous leukemia and enhanced its therapeutic efficacy in myelogenous leukemia K cells [ ].

Further, Trifolium flavonoids showed a capacity to overcome resistance to gefitinib, EGFR-TKI, through suppressing ERK and STAT3 signaling in NSCLC cell line PC-9R [ ]. Sorafenib is a multikinase angiogenesis inhibitor [ 9 ] used as first-line therapy in HCC. However, patients who initially benefit from sorafenib usually develop resistance within 6 months [ ].

A proposed mechanism of this resistance is the expression of the pregnane X receptor PXR or MDR-1, which is related to the elimination of sorafenib in HCC cells. Therefore, rhamentin decelerated the metabolic clearance of sorafenib and also sensitized HCC cells to the drug [ ].

Similarly, the combinatory treatment with apigenin potentiated the cytotoxicity of sorafenib in HCC HepG2 cells, as demonstrated through decreased cell viability, decreased migration and invasion, and increased apoptosis compared with single treatment groups [ ].

Also, Saraswati et al. As stated above, the disadvantage of TKIs usage is resistance; important mechanisms of the development of resistance include enhanced TKI efflux through efflux transporters such as BCRP [ 54 ].

Further, the flavonol kaempferol enhanced the chemotherapeutic efficacy of sorafenib against HCC demonstrated in silico and in vitro liver cancer HepG2 and N1S1 cells ; also, kaempferol reversed MDR by decreasing P-gp overexpression [ ].

Moreover, the flavonoid derivative WYC is a potential adjuvant agent against CDdriven urothelial carcinoma UC CSCs and could serve as a potent strategy against UC therapeutic resistance; among others, WYC declined EMT-CSCs markers such as MDR-1 or ABCG2 in vitro [ ].

HDACi is a novel class of small-molecular therapeutics that target the regulation of histone and non-histone proteins [ ]. The flavonol fisetin is a potential complementary agent in HDACi resistance, as it improves the chemosensitivity of HA22T, apicidin-resistant, and suberoylanilide hydroxamic acid-resistant SAHA-R HCC cells.

Fisetin synergistically interacted with HDACi in parental cells and also resistant cell lines. Fisetin also promoted therapeutic potential in the xenograft model generated from HDAC inhibitor-resistant cells [ ]. Further, TRAIL is an immune cytokine of the TNF family that received attention as a targeted anti-cancer agent through the selective induction of apoptosis in cancer cells [ , ].

Mutations in DR4 and DR5, domains of death receptors associated with TRAIL-induced apoptosis, induce cancer cell resistance to TRAIL.

Table 3 provides a summary of the mechanisms through which flavonoids enhance the therapeutic efficacy of targeted anti-cancer agents.

Combinatorial and nanoparticulate approaches are suggested to overcome the challenges of resistance and severe side effects posed by monotherapies. Currently, the combinatory therapy of a chemotherapeutic agent and phytochemicals or chemotherapy and targeted therapy is an important tool to improved cancer patient management.

Chemotherapy combined with targeted therapy is suggested to be effective especially for advanced NSCLC while EGFR is an essential target in NSCLC patients.

Cetuximab, a monoclonal antibody targeting EGFR, is a first-line treatment for NSCLC, advanced colorectal cancer, and head and neck cancers. Indeed, cetuximab-functionalized nanostructured lipid carriers were developed for the co-delivery of paclitaxel and 5-demethylnobiletin a hydroxylated polymethoxyflavone from citrus and to avert dose-related adverse effects of anti-cancer agents.

These nanostructured lipid carriers effectively inhibited tumor growth in a model of A paclitaxel-resistant cell-bearing mice [ ].

In conclusion, flavonoids represent an effective tool to improve the therapeutic outcomes of targeted anti-cancer strategies facing evident disadvantages such as insensitivity and resistance. After , cancer immunotherapy research introduced new monoclonal antibodies targeting tumor antigens and T-cell protein receptors to downregulate the immune response, specifically the immune checkpoint inhibitor monoclonal antibodies anti-cytotoxic T-lymphocyte-associated antigen 4 anti-CTLA4 and anti-programmed cell death protein 1 antibody anti-PD1.

Monoclonal antibodies directed against immune checkpoint inhibitors include ipilimumab, nivolumab, and pembrolizumab [ 9 ]. Immunotherapy is a promising tool for cancer management, as it restores the anti-tumor immune response [ 15 ]. Not all patients respond to immunotherapy; thus, it is necessary to improve its efficacy [ 15 ].

Some level of immune escape and resistance is intrinsic to malignancies due to the development of most human tumors in an immune-competent environment.

However, acquired resistance to immunotherapy can result from pre-existing genetic and epigenetic traits or de novo alterations of cancer cells or other tumor microenvironmental components. Thus, cancer cells can evade the immune response intrinsically loss or downregulation of target antigen expression, defective antigen presentation, insensitivity to immune effector molecules, upregulation of alternative immune checkpoints, and epigenetic alterations or via extrinsic mechanisms, which are mediated by non-cancer cells of the tumor microenvironment including tumor-associated macrophages TAMs , regulatory T cells Tregs , and myeloid-derived suppressor cells MDSCs [ ].

Programmed death ligand 1 PD-L1 is an essential immune checkpoint protein that binds to programmed death 1 PD-1 on T lymphocytes. Indeed, T cells exert an essential role in the eradication of cancer cells.

However, cancer cells escape the immune response through PD-L1 expression. The binding of PD-L1 to PD-1 results in the inhibition of T-cell proliferation and activity, leading to tumor immunosuppression [ ].

Due to the ineffectiveness of immunotherapy and the experience of resistance in some cases, the antitumor efficacy of cancer immunotherapy needs to be increased. Thus, immunotherapeutic agents are often administered in combination with each other or with chemotherapeutic agents, radiotherapy, or surgery.

Also, the combination of immunotherapy with antiangiogenic drugs yields promising outcomes [ 9 , ]. It is also essential to emphasize the potential of phytochemicals and their derivatives to improve cancer immunotherapy responses in the development of novel immunotherapeutic strategies [ , ].

As discussed below, the anti-cancer effects of flavonoids are also applicable in cancer immunotherapy either in combination with other agents or single agents [ 57 , 59 , , , , ].

Due to the frequent development of resistance to sorafenib, the first-line therapy for HCC, immune checkpoint inhibitors ICI such as nivolumab are studied as alternatives. However, due to the often unsuccessful outcomes of immunotherapy, the combinatorial approach seems to be a better choice to improve the treatment and to block immunosuppressive signals in the tumor microenvironment.

Although the co-administration of VEGF inhibitors and ICI is associated with synergistic anti-cancer effects, it exerts several adverse effects. However, phytochemicals including flavonoids could improve the plant-based antiangiogenic-immunotherapy combination in HCC when compared with single compounds that are often associated with therapeutic failure [ ].

Furthermore, flavopiridol is a synthetic flavonoid that inhibits cyclin-dependent kinases [ ]. Although most chronic lymphocytic leukemia CLL patients receiving chemoimmunotherapy achieve complete remission, patients with significantly shortened progression-free intervals still represent an important obstacle.

Also, minimal residual disease MRD occurs in a majority of CLL patients who relapse. Moreover, a phase I clinical trial demonstrated flavopiridol to be safe and efficient as consolidation therapy after chemoimmunotherapy in CLL patients [ ]. As discussed above, the immune escape of cancer cells is associated with PD-L1 expression [ ].

Also, the chemoresistance of nasopharyngeal carcinoma is associated with the upregulation of checkpoint inhibitor PD-L1, which is linked to enhanced aerobic glycolysis promoted by HIF1-α deregulation and LDH-A activity.

Moreover, checkpoint blockade is an effective treatment of lung cancer; however, it often leads to resistance. Therefore, Tang et al. aimed to develop a new strategy to improve checkpoint blockade therapy.

Eventually, dual inhibition of COX-2 and EGFR by melafolone improved PD-1 immunotherapy against Lewis lung carcinoma and CMT tumors; these results highlight its important role as a combinatory strategy against lung cancer by affecting vessels and immune cells [ 59 ]. Further, the prenylated flavonoid icaritin exerts potent anti-cancer activity by modulating multiple biochemical and cellular responses [ 58 ].

Advanced HCC is associated with limited treatment options. As the authors demonstrated in a phase I trial, the preliminary durable survival benefits of icaritin in advanced HCC patients correlated with its immuno-modulatory activities and immune biomarkers [ ].

Similarly, apigenin also suppressed PD-L1 in vitro in melanoma cells and in host dendritic cells; this potentiated the cytotoxicity of cocultured cytokine-induced killer cells against melanoma cells [ ].

In conclusion, flavonoids improve cancer immunotherapeutic effects either through increased efficacy of other anti-cancer agents or as potent single molecules modulating immune responses of cancer cells.

Consequently, complex treatment models presenting concepts of predictive diagnostics followed by the targeted prevention and treatments tailored to the individualized patient profiles earn global appreciation as benefitting the patient, healthcare economy, and the society at large.

In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and tertiary prevention.

Conventional anti-cancer strategies demonstrate evident deficits. Despite recent progress in anti-cancer strategies, the development of a therapy resistance remains the leading cause of the cancer-related mortality.

An improved understanding of carcinogenic processes allows for the technological innovation creating more efficient therapeutic modalities. Targeted anti-cancer therapies leverage unique molecular changes associated with specific cancer types.

Anti-cancer protective application of flavonoids in the context of 3P medicine should follow principles of the evidence-based therapeutic effects, individualized prediction, targeted prevention and personalization of the treatment algorithms.

To this end, application of specialized analytical approaches is strongly recommended such as liquid biopsy analysis, risk assessment tools, predictive and companion diagnostics, multi-omics and multi-parametric analysis, and application of artificial intelligence in medicine.

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Citation: Li C, Li X, Jiang Z, Wang D, Sun L, Li J and Han Y Flavonoids Inhibit Cancer by Regulating the Competing Endogenous RNA Network. Received: 24 December ; Accepted: 22 February ; Published: 18 March Copyright © Li, Li, Jiang, Wang, Sun, Li and Han.

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MINI REVIEW article Front. Mechanistic studies are needed to ascertain how flavonoid-rich diets influence gene regulation for cancer prevention. N1 - Funding Information: This manuscript was supported by U.

ARMY Medical Research and Materiel Command DAMD , The American Institute for Cancer Research 10A , and the Arizona Cancer Center Support Grant P30CA N2 - The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention.

AB - The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention. Flavonoids and Cancer Prevention: A Review of the Evidence.

Nutritional Sciences and Wellness, Research Animal and Biomedical Sciences, Research BIO5, Institute of Cancer Biology - GIDP. Overview Fingerprint.

Abstract The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention. Keywords cancer diet epidemiology flavonoids mechanisms of action prevention. ASJC Scopus subject areas Nutrition and Dietetics Geriatrics and Gerontology.

Access to Document Anti-oxidant action could also contribute to anti-cancer ability because ROS could initiate signal transduction through the mitogen-activated protein MAP kinases Wiseman and Halliwell There have been a number of reports relating to the possible anti-oxidant effects of isoflavone consumption.

It is of considerable interest that widely differing effects in relation to the potential benefits to human health are frequently reported for isoflavones consumed within the food matrix in soy foods, compared to those consumed in capsule or tablet form as dietary supplements.

Angiogenesis, the formation of new blood vessels, is an important process which is regulated by endogenous angiogenic and angiostatic factors. Any alteration in this tightly regulated process can lead to a persistent and uncontrolled growth and metastasis of tumors.

Flavanoids have been reported as angiogenesis inhibitors Tosetti et al. These inhibitors can cause lack of diffusion of nutrients and oxygen to rapidly growing cancerous cells due to anti-angiogenic properties and hence lead to cell death. Angiogenesis inhibitors can interfere with various steps in angiogenesis, such as the proliferation and migration of endothelial cells and lumen formation.

A possible mechanism could be inhibition of protein kinases Oikawa et al. These enzymes are implicated to play an important role in signal transduction and are known for their effects on angiogenesis. Genistein is a potent inhibitor of angiogenesis in vitro Fotsis et al.

Studies on the inhibition of cell proliferation and angiogenesis by flavonoids in six different cancer cell lines had been reported and noted that the IC50 of active flavonoids were in the low micromolar range, physiologically available concentrations Fotsis et al.

Isoflavonones genistein, genistin, daidzein, and biochanin A also inhibit growth of murine and human bladder cancer cell lines by inducing cell cycle arrest, apoptosis, and angiogenesis Zhou et al.

Luteolin has been found to inhibit VEGF-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositolkinase action Bagli et al.

Favot et al. During the last decade, some more novel molecular targets for the inhibition of angiogenesis by genistein have been discovered including tissue factor, endostatin, and angiostatin Su et al.

Genistein may enhance the action of transforming growth factor-β TGF-β Kim et al. This action may be a link between the effects of genistein in a variety of chronic diseases Barnes including atherosclerosis and hereditary hemorrhagic telangiectasia the Osler—Weber—Rendu syndrome in which defects in TGF-β have been characterized Johnson et al.

Schindler and Mentlein determined whether secondary plant constituents, i. It was found that the glycosylated flavonoids i. Inhibition of VEGF release by flavonoids, tocopherols, and lovastatin in models of neoplastic cells suggests a novel mechanism for mammary cancer prevention.

He et al. Apoptosis is a programed cell death to eliminate damaged or unwanted cells. It is regulated by a variety of genes that can either promote apoptosis or can favor cell survival in response to internal or external stimuli.

Dysregulation of apoptosis could play a critical role in oncogenesis. Among these genes, the tumor suppressor p53 plays a pivotal role in controlling the cell cycle, apoptosis, genomic integrity, and DNArepair Bode and Dong by acting as transactivator or as transrepressor Ho et al.

EGCG also activated p53 and BAX in breast carcinoma cells Roy et al. In addition to p53, mammalian cells contain two closely related proteins, p63 and p EGCG induces apoptosis by activating pdependent expression of a subset of p53 target genes Amin et al.

Nuclear factor-kappa B NF-кB family of transcription factors consists of five members, p50, p52, p65 Rel A , c-Rel, and Rel B, which share an N-terminal Rel homology domain responsible for DNA binding.

NF-кB is activated by free radicals, inflammatory stimuli, cytokines, carcinogens, tumor promoters, endotoxins, γ-radiation, ultraviolet UV light, and X-rays and induces NF-кB target genes important for cellular growth and transformation, suppression of apoptosis, invasion, metastasis, chemoresistance, radioresistance, and inflammation.

Flavonoids may block one or more steps in the NF-кB signaling pathway such as inhibition of the most upstream growth factor receptors that activate the NF-кB signaling cascade, translocation of NF-кB to the nucleus, DNA binding of the dimers, or interactions with the basal transcriptional machinery Ju et al.

The NF-кB target genes influenced by the flavonoids include inhibition of Bcl-2 and Bclx L , cyclin D1, matrix metalloproteinases MMP , and VEGF Hastak et al. Flavonoids have been found to suppress activator protein-1 AP-1 activation and modulate AP-1 target genes.

Some of the biologic effects of AP-1 are mediated by gene repression. APregulated genes include important modulators of invasion and metastasis, angiogenesis, proliferation, differentiation, and survival. Activation of various tyrosine kinases leads to phosphorylation, dimerization, and nuclear localization of the signal transducers and activators of transcription STAT proteins, binding to specific DNA elements and direct transcription.

Constitutive activation of STAT3 and STAT5 has been implicated in multiple myelomas, lymphomas, leukemias, and several solid tumors. Selvendiran et al. Luteolin is capable of inducing anti-cancer effects by inducing cell cycle arrest or apoptosis in oral squamous cancer cells Yang et al.

Luteolin inhibited proliferation and induced apoptosis of prostate cancer cells in vitro and in xenografts Chiu and Lin , with increased efficacy of cisplatin in gastric cancer cells Wu et al. Some characteristic changes in nuclear morphology, phosphatidylserine externalization, mitochondrial membrane depolarization, modulation of cell-cycle regulatory proteins and NF-κB family members, upregulation of proapoptotic Bcl-2 family proteins, cytochrome C, Apaf-1 and caspases, and downregulation of anti-apoptotic Bcl-2 proteins and surviving was reported.

It significantly increases the expression of p53 and p21 proteins, and decreases the levels of cyclin D1, cyclin A, CDK4 and CDK2, thereby contributing to cell cycle arrest. In addition, fisetin increased the expression of Bax and Bak but decreased the levels of Bcl-2 and Bcl-xL and subsequently triggered mitochondrial apoptotic pathway Li et al.

Pretreatment with chrysin could increase TRAIL-induced degradation of caspase 3, caspase 8, PARP protein. Z-VAD- fmk, which is a pan-cascade inhibitor, could inhibit the apoptosis enhanced by combination of chrysin and TRAIL Li et al.

Thereby, DHC and fisetin induced apoptosis, but not accelerated senescence in prostate cells Haddad Flavonoids greatly influence the cascade of immunological events associated with the development and progression of cancer. One has to understand the mechanism how these flavonoids get accumulated in cellular organelles and tissues once they enter inside.

Flavonoids have the potential of modulatng many biological events in cancer such as apoptosis, vascularization, cell differentiation, cell proliferation, etc. A strong correlation persists between flavonoid-induced modulation of kinases with apoptosis, cell proliferation and tumor cell invasive behavior in vitro.

Also, some of the dietary flavonoids have been known to display in vivo anti-tumor activity and repress in vivo angiogenesis. The cross talk between flavonoids and the key enzymes related to neoplastic cells and metastasis has to be understood in vitro and in vivo as well, providing new insights for fighting against cancer.

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RSM is a mathematical and statistical method for designing experiments [ ]. RSM significantly increased the yield of flavonoids from Chinese Huangqi when the extraction parameters were optimized as follows: ethanol concentration, However, such optimization is required for each plant source of flavonoids and can be time-consuming.

Therefore, several novel technologies can be applied to reduce the cost and the loss of extracted flavonoids from their natural sources. One of these is the use of high-speed, counter-current chromatography that has been reported to be of lower cost and produce higher yields compared with other technologies [ 63 ].

Another technology that has recently emerged is nano-harvesting, where nanoparticles are used to harvest flavonoids from their sources [ ]. The nanoparticles enter the plant structures and are released to bind to the targeted compounds and carry them outside the cells without harming the plants.

This technique eliminates the use of organic solvents, allows for continuous production of flavonoids, and has opened a new era in natural product extraction methodologies [ ]. The ultrasound-assisted extraction method has been purported to increase extraction efficiency and reduce the required time for extraction [ , , ].

As mentioned in the challenges section, the extraction of certain compounds from the plant source can significantly harm plant communities. Therefore, the microbial production of plant natural products, such as flavonoids, at an industrial scale, is currently an attractive alternative approach [ 61 , ].

This approach has the potential to preserve the environmental resources and use economical stocks associated with less energy use and waste emission. Currently used microorganisms include Escherichia coli [ , ] and Saccharomyces cerevisia e [ , ]. The engineering and synthetic biology of microorganisms encourage the return to natural compounds as promising anticancer agents [ 61 , ].

There are a number of approaches or strategies that can be used to surmount factors that lower the bioavailability of flavonoids. For example, the formulation of flavonoids as certain types of glycosides can result in enhanced bioavailability compared with the flavonoid alone or other types of glycosides [ ].

These glycosidic derivatives are substrates for certain intestinal epithelial transporters, which would increase their absorption [ ]. Therefore, the conversion of quercetin glycosides into glucosides can be considered an approach to improve flavonoid bioavailability [ ]. Another strategy involves adding piperine to the flavonoid formulations.

The use of bioenhancers, such as piperine, which is an amide alkaloid from the plants of the Piperaceae family, is another approach [ ]. Piperine significantly inhibits the conjugation of various flavonoid compounds such as quecetin [ ] and epigallocatechingallate [ ] by certain UDP-glucuronosyltransferase phase II enzymes, decreasing their metabolism and increasing bioavailability [ , , ].

The use of more specific novel ABC transporter blockers such as lapatinib, nilotinib, or specific small interfering RNA is another option, provided that they do not produce intolerable adverse effects, for flavonoids whose bioavailability is limited by certain ABC transporters [ ].

In addition, the efficiency of modulators of the intestinal microflora can be considered to improve the flavonoid bioavailability. Such modulation could be achieved by the use of antibiotics or other formulation products that can bypass the gut microbiome [ ].

These compounds would contain the basic pharmacophore of the parent compound to retain their desired effects. Methyl- and hyro-sliybin derivatives have been reported to be fold more potent than the parent compound, sylibin [ , , , ].

The introduction of hydrophobic functional groups e. It has also been shown that blocking some groups e. An epoxypropoxy flavonoid derivative MHY , by inhibiting the enzyme topoisomerase II enzyme, exhibited significant potency against the prostate cancer cell lines LNCaP, PC-3, and DU [ ].

An area that has shown significant growth is the development and use of micro- and nanodelivery systems to maximize the bioavailability of flavonoids [ , , , ]. The emulsified flavonoids are released slowly over time, allowing for a higher surface area for absorption, ultimately improving their absorption and bioavailability after oral administration [ ].

Another approach is the advanced delivery system with nano-crystal, self-stabilized pickering emulsions that has been reported to increase the delivery of some flavonoids including silybin [ ]. Formulating flavonoids as a povidone-mixed, micelle-based microparticle has been shown to significantly enhance their release and PK profile [ ].

The encapsulation of the flavonoid quercetin in Zein nanoparticles increases effectiveness in a mouse model of endotoxemia [ ]. Flavonoid complexing with protein has been shown to increase flavonoid stability in vitro [ , ]. Several studies suggest that this characteristic of flavonoids can be used to enhance their chemical stability [ , , ].

The overall stability of the grape skin-derived anthocyanine extracts was enhanced when complexed with the proteins α- and β-casein [ ]. Furthermore, studies indicate that other milk-derived proteins e. The complexation of flavonoids with phospholipids has been reported to enhance their bioavailability [ ].

The amphiphilic nature of phospholipids helps in enhancing the passage of compounds across the membranes [ ]. Indeed, the complexing of the flavonoid quercetin with phospholipid phosphatidylcholine to form a quercetin-phospholipid complex significantly improved the PK parameters maximum serum concentration that a drug achieves and area under the curve of quercetin in rats compared with quercetin alone [ ].

The preclinical anticancer effect of certain flavonoids suggests that the flavonoids may prevent certain types of cancer. However, the development of flavonoids is limited by their poor extraction yield, complicated extraction methods, the cost and difficulties of epidemiological studies, and their unfavorable PK characteristics.

Versatile strategies are being applied to overcome such limitations. Future studies are required to determine whether these strategies can be applied economically and safely. The modulation of phase II metabolism and intestinal microflora can affect the metabolism, bioavailability, and toxicity of other drugs.

It also can modulate the availability of dietary minerals and vitamins, thereby having potential impacts on health. Consequently, it may be more preferable to conduct research directed towards new delivery systems, such as nano-emulsions and nanoparticles. These delivery systems should be expected to have enhanced target specificity and safety.

However, the cost of developing natural products and applying these strategies should be considered in the light of the cost of currently available synthetic compounds.

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Oncol Rep — They are mainly classified into four major groups, such as flavanols, flavones, anthocyanidins, and isoflavonoids. Furthermore, they are divided into some subclasses. They are available in dietary foods and they cure various diseases.

Certain plants and spices contain flavonoids, which have been commonly used for thousands of years in traditional medicine. Some of the flavonoids have been clinically used in many countries. Baicalein and its glycosides are one among them to have been experimented clinically.

Flavonoids have the capability to regulate cell division and proliferation in an important pathway. They have medicinal activities including anticancer properties. The isoflavone analog rotenone is one of the flavonoid compounds, which has been revealed to be actual anticancer agent.

Scutellaria species having flavones retain cytotoxic activities against many human cancer cell lines. At the same time, they do not harm the myeloid cells, normal peripheral and normal epithelial blood cells. Epidemiological studies also confirmed that the intake of dietary flavonoids reduces a risk condition in cancer.

Flavonoids are plant-based secondary metabolites. The intake of flavonoids is always safe and without adverse effects. Based on this, the scientific community has focused its attention on plant-based compounds in order to control cancers. Many compounds, such as flavonoids, were isolated from plants and shown to have anticancer activity notably.

This was confirmed through in vitro and in vivo studies [ 1 ]. Our dietary foods contain different types of flavonoids in various food additives. Grains and herbs have flavones. Fruits and vegetables hold flavonols and their glycosides.

Citrus juices, legumes, and tea contain flavanones, isoflavones, and catechins, respectively. Some flavonoids are able to fight against breast cancer [ 2 ]. The health benefits of flavonoids may be helpful to find new drug discoveries.

Such compounds are listed with their specific subclasses. Apigenin, baicalein, luteolin, and chrysin belong to the subclass of flavones; kaempferol, myricetin, and quercetin are closer to the subclass of flavonols; hesperetin is flavanone compound; genistein and daidzein go with the subclass of isoflavones; baicalin, catechin, and rutin fit with flavone glycosides, flavanols, and flavonol glycosides, respectively.

There are different types of tumors which can be organized and categorized as oral pharyngeal, laryngeal , gastrointestinal esophageal, gastric, pancreatic , colorectal, liver, reproductive ovarian, endometrial, prostate , breast, and lung cancer.

The various diseases including cancers are controlled by the intake of flavonoids. Cytotoxicity in cancer cell line is shown mainly because of flavonoid compounds which do not affect normal cells.

This was proved by cytotoxicity assay. Apigenin and luteolin come under the flavonoid subclass, flavones which have the ability to regulate macrophage function in cancer cell elimination and act as a potential inhibitor of cell proliferation.

Many in vitro and in vivo studies confirmed that flavonoids have good activity against various cancer cell lines. Flavonoids have the ability to perform antiproliferation and cytotoxicity in cancer cell lines.

They are used for human clinical trial which was conducted on flavone acetic acid. In , a database of U. S Department of Agriculture explains to us the flavonoid content in foods in which isoflavone, proanthocyanidin, and other compounds are identified [ 3 ].

This definitely helps us calculate the flavonoid intake and its cancer-preventive properties. The amount of intake and the time of exposure have considerable say in the anticancer response to flavonoid-rich diets. Some intervention trials of flavonoids have shown their capacity to prevent cancer.

They have the ability to block cell cycle followed by apoptosis. In recent years, they have been used for the treatment of prostate, pancreatic, breast, cervical, and ovarian cancers.

Several protein kinases, epidermal growth factor receptors EGFRs , platelet-derived growth factor receptors PDGFRs , vascular endothelial growth factor receptors VEGFRs , and cyclin-dependent kinases CDKs [ 4 ] play important roles in cancer pathology. COX cyclooxygenase , LOX lipoxygenase , and xanthine oxidase enzymes are also responsible for cancer pathologies.

Flavonoids have the power to decrease and sometimes control all these pathogenic factors completely. Major classes of flavonoids possess anticancer properties. The sources of flavonoids are also explained in this context.

Flavanols are present in strawberries, apple, chocolate, cocoa, beans, cherry, green, and black tea. They have the potential to fight against human oral, rectal, and prostate cancer.

The major sources of anthocyanidins are blueberries, blackberries, blackcurrant, and aubergine. These natural resources are used to treat colorectal cancer. The major sources of flavones are Siberian larch tree, onion, milk thistle, acai palm, lemon juice, orange juice, grape juice, kale, cherries, leek, Brussel sprouts, pepper, broccoli, capsicum, parsley, and celery.

They have the ability to fight against breast cancer, lung cancer, leukemia, thyroid, stomach, laryngeal, colon, and oral cancer. Sources of isoflavonoids are soybeans, soy flour, soy milk, beer, and tempeh.

They fight against prostate cancer, breast cancer, colon, kidney, and thyroid cancer [ 5 ]. Flavonoids are mainly classified into four major groups: flavanols, flavones, anthocyanidins, and isoflavonoids. The major groups of these flavonoids are displayed in the subsequent text Figure 1.

A chemical structure of compound is drawn for each flavonoid group Figure 2. Compounds from various subclasses of flavonoids are put together in their respective flavonoid groups. The major classification of flavones and anthocyanidins is displayed in Figure 3.

Among these subclasses, flavanols contain catechin, gallocatechin, catechingallate, epicatechin, and epigallocatechin EGC. Kaempferol, myricetin, quercetin, and rutin belong to the subclass of flavonol [ 5 ]. Some other compounds are also classified under the specific subclasses of flavonoids Figure 3.

Major classification of flavonoids. Different classes of flavonoids and their compound chemical structures. Different groups of flavonoids and their respective compounds. Many studies on the distribution of diseases prove that flavonoids have positive effects in curbing cancer.

It has been evidenced by various studies that the possibility of developing cancer could be reduced if more amount of flavonoid is administered [ 6 , 7 ]. There was a case-control type study on breast cancer-positive individuals based on population in Shanghai from to It was revealed in the corresponding controls; Dai et al.

The middle discharge rate of aggregate isoflavonoids was Thus, it was recommended that flavonoids are capable of averting breast cancer. Another lung cancer study was done on the observation of individuals beyond the age of A total number of lung cancer-positive Finnish men and women between the ages of 25—99 showed reduced lung cancer after administering flavonoids through diet.

The inference was made based on vitamin E, vitamin C, beta-carotene, or total calories consumption. There was a study on 10, individuals of both men and women by Knekt and coworkers [ 9 ] on the amount of flavonoid consumption in Finnish diet. The study revealed a lesser possibility for lung cancer with the higher consumption of quercetin and the lesser possibility of prostate cancer with more consumption of myricetin.

Thus, flavonoids were proved to play a vital role in preventing cancer occurrence. There was also a case-control work done based on population in Hawaii in order to study in detail the relation between the probability of lung cancer and the consumption of flavonoids through diet.

For the study, they took individuals who were lung cancer-positive and the same number of controls of matching age, sex, and ethnicity. The consumption of flavonoids such as onion, white grapefruits, apples, and quercetin was reversely related to the probability of suffering lung cancer [ 10 ].

The outcome of the above study is found to be similar to the previous study done in Uruguay on lung cancer-positive individuals and controls but fewer incidents of lung cancer due to vitamin E and beta-carotene.

Flavonoids like kaempferol and quercetin are also found to be preventing gastric cancer unlike carotenoids like alpha-carotene, lutein, beta-carotene, and lycopene in yet another case-control study carried out in Spain which consisted of gastric cancer-positive individuals and controls.

An observation was done on 34, women free from postmenopausal cancer between the ages of 55 and 69 during and In modification with prospective confounders, the consumption of catechin was reversely related to only the rectal cancer occurrence [ 11 ].

These prove the potential ability of flavonoids for a cancer cure. In this way, the administering of flavonoids is effective in preventing cancer in most if not in all studies. Reports [ 12 ] also show that flavonoids are ineffective. It is mainly because of the uneven availability of the same.

However, it should not be fully neglected without detailed study. Two case-control studies were conducted in six counties in New Jersey cases of ovarian cancer and controls [ 13 ] and in the North-East United States cases and controls.

These revealed that there was no link between total flavonoid consumption and ovarian cancer [ 14 ]. Some of the cancer case studies have been discussed in the subsequent text. A case study showed that there is an inverse association between flavanone intake and esophageal cancer, and this could reduce by the intake of citrus fruits.

An increased risk of gastric cancer is found among smoking men. The intake of epigallocatechin EGC plays an important role to slow down the disease. Researchers analyzed the intake of flavonoids and the risk of pancreatic cancer during the study.

The results reported that flavonoid-rich diets can decline pancreatic cancer risk in male smokers. Inverse relationships were also found among current smokers between a risk of pancreatic cancer and the intake of total flavonols, quercetin, kaempferol, and myricetin.

Isoflavone intake was inversely related to colorectal cancer risk in men and postmenopausal women. Cases were analyzed in Japan, Netherlands, and in the UK in both men and women regarding the intake of isoflavone and its inverse effect on colorectal cancer.

These results may have associations for the use of dietary flavonoids in the prevention of rectal cancer. NADPH oxidase I NOX 1 enzyme produces superoxide, which is overexpressed in colon and prostate cancer cell lines [ 15 ].

Superoxide is one of the reactive oxygen species ROS. Superoxide dismutase SOD is one of the antioxidants which can inhibit a pro-oxidant enzyme Figure 4. Generally, flavonoids have the ability to inhibit DNA damaging, mutagenic signaling, cell proliferation, and proto-oncogenes cFOS, cJUN, and cMyc.

Diagrams are drawn using Microsoft PowerPoint and converted to JPEG format. Inhibition of pro-oxidant enzymes. Wogonin and baicalein from Scutellaria species have been tested in a mouse for anticancer activity. baicalensis has an O-methylated flavone called wogonin and a flavone called baicalein, which were isolated from the roots of the same plant as well as from S.

A flavone glycoside called baicalin is also found in Scutellaria species. Both the compounds have therapeutic potential against cancer. The identified flavonoids from Scutellaria species are about The reported minor flavonoids from the same species are Apigenin, Luteolin [ 16 ], and Chrysin. They possess antitumor activities.

Scutellaria alone or in combination with other herbs has the cytostatic effect on several cancer cell lines in vitro and in vivo mouse model [ 17 ].

One of the anticancer drugs is wogonin. It comes under flavonoids. It is considered as chemotherapeutic agent to decrease their side effects. It has a hepatoprotective effect and prompts apoptosis in caspase 3 pathway. It alternates p21 protein expression. Wogonin and its derivatives possess anticancer activity.

Wogonin induced apoptosis in lung cancer. It was experimented and proved in the nude mouse model [ 18 — 20 ]. It goes through multiple apoptosis pathways such as ROS Reactive Oxygen Species -mediated and ER stress-dependent pathway Figure 5.

Mechanism of action of wogonin-induced apoptosis in human lung cancer cells. Wogonin induces apoptosis with extrinsic apoptotic pathway and ROS-intervened ER stress-dependent pathway.

NAC N-acetyl- l -cysteine is used to identify and test ROS. In mammalian cells, the major ER stress sensors such as pancreatic ER kinase PERK , activating transcription factor-4 ATF4 , ionizing radiation, eIF2α, and CHOP will carry the signal from the ER lumen to cytoplasm and nucleus in order to recruit ER stress and also to develop tumor progression.

Wogonin goes through this pathway and generates apoptosis at the end. Apigenin has anti-mutagenic properties. It inhibits benzo[a]pyrene- and 2-aminoanthracene-induced bacterial mutagenesis.

It scavenges free radicals and promotes metal chelation in in vivo tumor models [ 21 ]. It affords protective effect in murine skin and colon cancer models [ 22 ].

It would suppress this enzyme effectively. It also increases glutathione concentration and enhances the endogenous defense against oxidative stress [ 23 ]. It was experimented against skin carcinogenesis model.

It inhibits dimethylbenzanthracene-induced skin tumors. It has been administered against UV-light-induced cancers. The result showed that it could diminish the occurrence of UV light-induced cancers and was able to increase tumor-free cells.

Apigenin plays an effective role to inhibit casein kinase CK -2 expression in both prostate and breast cancers [ 24 ]. Kaempferol has anticancer effects and acts as a chemopreventive agent. It was found to be curbing the growth of various carcinomas such as glioblastoma LN, U87MG, and T98G , leukemia HL and Jurkat , lung cancer H and A , breast adenocarcinoma MCF- 7, BT, and MDA-MB , osteosarcoma U-2 OS , prostate cancer LNCaP, PC-3, and DU , colorectal carcinoma Caco-2, HCT, DLD-1, and Lovo , and pancreatic cancer MIA PaCa-2, Panc 1.

It is used to arrest the cell cycle in cancer cells. It has been used as antiapoptotic agent on cancer cells. Kaempferol is very effective against metastasis and angiogenesis [ 26 ].

Quercetin is one of the dietary flavonoids, which suppresses tumor growth by inhibiting protein tyrosine kinase PTK.

About 10 μM of this compound confirmed antiproliferative activity against colon cancer cells, Caco-2, and HT

Flavonoids and cancer prevention -

DOI: Flavonoids are widely distributed in nature and a prevalent component of the human diet. Numerous biological activities have been reported. Some clinical trials or meta-analyses have suggested positive associations between flavonoid intake and human health, whereas others have not supported such a relationship.

We currently highlight some responses that may be relevant to cancer chemoprevention, including antioxidation, anti-inflammation, and effects on NK cells.

In addition, the prooxidant capacity of flavonoids may be relevant for the treatment of cancer. As is the case with other phytochemical constituents found in the diet, many questions over-shadow the results obtained with in vitro studies that do not take into account the ramifications of poor bioavailability, rapid and extensive metabolism, and physiologically relevant concentrations.

To overcome some of these difficulties, greater emphasis has been placed on the study of methoxylated flavonoids, which may demonstrate more favorable pharmacokinetic properties.

In terms of drug development, newer approaches such as nanotechnology could be useful. It is clear that flavonoids or flavonoid derivatives offer value for the chemoprevention of cancer. Many avenues of development are available and necessary for exploiting the impact on human health.

Keywords: Flavonoids , Bioavailability , Cancer prevention , Methoxylated flavonoids , phytochemical , methoxylated flavonoids , cancer chemoprevention , polyphenolic , cinnamatehydroxylase , oxygenated heterocyclic ring.

Volume: 12 Issue: 8. Abstract: Flavonoids are widely distributed in nature and a prevalent component of the human diet. Park Eun-Jung and M. Pezzuto John, Flavonoids in Cancer Prevention, Anti-Cancer Agents in Medicinal Chemistry ; 12 8. The Management of Metastatic Triple-Negative Breast Cancer: An Integrated and Expeditionary Approach.

Anti-Cancer Agents in Medicinal Chemistry Editor-in-Chief: Simone Carradori. Flavonoids in Cancer Prevention Author s : Eun-Jung Park and John M.

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Download references. HA, CRA, and AKT conceptualized the idea. HA and AKT wrote the paper. AKT and CRA proofed and revised the paper. All authors read and approved the final manuscript. We thank Ms. Charisse Montgomery, University of Toledo for critical reading of this manuscript. This work was supported by seed-fund to AKT from Department of Pharmacology and Experimental Therapeutics at UT.

Department of Pharmacology and Systems Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, , USA. Pharmaceutical Sciences, College of Pharmacy, St.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, , USA.

You can also search for this author in PubMed Google Scholar. Correspondence to Amit K. Like ART-Tf, artemisinin—peptide conjugates that are designed to target TfR also showed highly potent and selective anti-cancer activities Oh et al.

Although the generation of free radicals originating from the reaction of artemisinin with molecular iron is mentioned as one of the main mechanism for its anti-cancer activity, there are other mechanisms, crucial for cancer proliferation and survival that are affected by artemisinins.

These mechanisms have been described in a current review Firestone and Sundar ; Ferreira et al. Mammographic breast density can be used as biomarker of estrogenic or anti-estrogenic effects of a particular treatment on breast tissue Atkinson et al.

Consumption of a dietary supplement that provided red clover-derived isoflavones 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0. Honeybee propolis and its polyphenolics exerted an anti-metastatic anti-tumor effect in mice and rats and considerable cytotoxicity without cross resistance in both wild-type and chemoresistant human tumor cell lines suggesting these to be potent adjunct to chemotherapy and radiotherapy in treatment of cancers Oršolić et al.

Colon cancer risk is influenced by estrogen exposure; studies with estrogen receptor α knockout mice indicate that it may be independent of estrogen receptor α Guo et al. Furthermore, in vivo studies in male rats have shown that genistein decreases the amount of EGF receptor present in the prostate, indicating that the observed decrease in tyrosine phosphorylation may be only a secondary effect of the influence of genistein on the expression or turnover of EGF receptor Dalu et al.

Luteolin can delay or block the development of cancer cells in vitro and in vivo by protection from carcinogenic stimuli, by inhibition of tumor cell proliferation, by induction of cell cycle arrest and by induction of apoptosis via intrinsic and extrinsic signaling pathways.

Flavonoids have been very often pointed out as in vitro enzyme inhibitors and ligands of receptors involved in signal transduction Middleton and Kandaswami ; Havsteen ; Williams et al.

So these flavonoid—protein interactions together with their anti-oxidant properties are the key features for their potential health benefits. Furthermore, some effects may be a result of a combination of radical scavenging and interaction with enzyme functions.

The phenolic nucleus is a structural unit that is favorable to molecular non-covalent interactions with proteins. These interactions can be either Vander wall or electrostatic interactions. In former type, the non-polar polarizable aromatic ring can develop strong dispersion interactions with non-polar amino acid residues followed by simultaneous release of water; while in later type, H-bonding is the most important electrostatic interaction.

Flavanoid—protein redox reactions and oxidative covalent coupling may result fom one-or two-electron oxidation of the flavonoid brought about by autooxidation, scavanging of reactive oxygen species and enzymatic oxidation.

For some conformationally open proteins e. salivary proteins , binding constants are quite low with polyphenols but polymerization and condensation of these polyphenols produces an increase in affinity Kurisawa et al.

It can be due to unspecific binding along an extended protein chain or at the surface of globular proteins Haslam ; Spencer et al. Phosphorylation of proteins at OH groups of serine, threonine, and tyrosine residues is an important mechanism of intracellular signal transduction involved in various cellular responses including the regulation of cell growth and proliferation Birt et al.

The reaction makes use of ATP as a phosphate donor and is catalyzed by protein kinases. For instance, growth factor hormones bind to extracellular domains of large transmembrane receptors that display a tyrosine kinase moiety in their intracellular portion. On the other hand, each phase of the cell cycle, during which the DNA is replicated and the chromosomes built and then separated, is characterized by intense bursts of phosphorylation controlled by highly regulated kinases called cyclin-dependent kinases CDKs.

A possible mechanism for the potential anti-carcinogenic effects of flavonoids could be their ability to inhibit various PKs, thereby inhibiting signal transduction event of cell proliferation. The isoflavone genistein has been shown to inhibit the epidermal growth factor EGF receptor in the submicromolar range by competing with ATP for its binding site Rudrabhatla and Rajasekharan ; Akiyama et al.

Consistently, studies with intact cells have shown that various flavonoids can cause cell cycle arrest in correlation to their ability to inhibit CDKs Zi et al.

Flavonoids can also modulate the activity of MAPKs as a possible mechanism for their potential anti-neurodegenerative action Schroeter et al. For instance, investigations on intact antigen-presenting dendritic cells have shown that the MAP kinases involved in cell maturation ERK, p38 kinase, JNK can be activated by bacterial lipopolysaccharide and that this activation is strongly inhibited by pretreatment of the cells by EGCG.

Formation of reactive oxygen species ROS is a major step in the tumor promotion and progression stages. The involvement of ROS in tumor progression has been demonstrated in human cells.

NADPH oxidase I NOX 1 , an enzyme that produces superoxide is overexpressed in colon and prostate cancer cell lines Fukuyama et al. ROS play important role in DNA damaging and mutagenic signaling Poli et al. ROS act as secondary messenger in several pathways that lead to increase in cell proliferation, resistance to apoptosis, activation of proto-oncogenes such as cFOS, cJUN and cMyc.

In human hepatoma cells, ROS modulate the expression of cFOS and cJUN through PKB pathway Liu et al. Lipoxygenases LOX , cycloxygenases COXs , and xanthine oxidase XO are metalloenzymes whose catalytic cycle involves ROS such as lipid peroxyl radicals, superoxide, and hydrogen peroxide.

LOXs and COXs catalyze important steps in the biosynthesis of leucotrienes and prostaglandins from arachidonic acid, which is an important cascade in the development of inflammatory responses.

XO catalyzes the ultimate step in purine biosynthesis, i. XO inhibition is an important issue in the treatment of gout. Flavonoids may exert part of their anti-oxidant and anti-inflammatory activities via direct inhibition of these prooxidant enzymes LOXs, COXs, and XO.

Similarly, flavonoids can inhibit ornithine decarboxylase rate-limiting enzyme in polyamine biosynthesis induced by tumor promoters, and thereby inhibiting proliferation. Typically, interpretation of the inhibition studies is complicated because of the possible combination of distinct inhibition mechanisms: formation of non-covalent enzyme-inhibitor complexes, direct scavenging by flavonoid anti-oxidants of ROS inside or outside the catalytic pocket with simultaneous oxidation of the flavonoids , chelation of the enzyme metal centers by the flavonoids, and enzyme inactivation by reactive aryloxyl radicals, quinones, or quinonoid compounds produced upon flavonoid oxidation that may eventually form covalent adducts with the enzyme Olivier and Claire ; Sandhar et al.

Activation of a procarcinogen to carcinogen is an important step in carcinogenesis and can be modulated by flavonoids. Flavonoids can exert their effect by two possible mechanisms. Firstly, by interacting with phase 1 enzymes CyP that are involved in metabolic activation of procarcinogens.

Second mode of action can be the detoxification and elimination of carcinogens via induction of phase II enzymes such as UDP-glucuronyl transferase, quinone reductase and glutathione S -transferase. These heme-containing cytochrome P CYP monooxygenases include several isoforms CYP 1A1, 1A2, 1B1, 3A4, 3A5, etc.

with different tissue distributions and play a key role in the metabolism of endogenous substrates e. Indeed, CYPs are responsible for the conversion of some procarcinogens e. Cytochrome P enzymes are a good example of proteins whose function can be regulated by flavonoids via such diverse mechanisms Hodek et al.

CYP—flavonoid interactions are a good example of the multiple ways flavonoids can affect enzymatic activities, i. Flavonoids can induce, or eventually inhibit, the biosynthesis of CYP 1A1 via interactions with the aryl hydrocarbon receptor AhR , a cytosolic protein that, once activated by a ligand, translocates to the nucleus and, in association with the AhR translocator, forms a transcription factor for CYP 1A1.

For instance, in human breast cancer cells, quercetin binds to AhR as an agonist and stimulates gene expression for CYP 1A1 with a parallel increase in CYP 1A1-mediated O -deethylation of 7-ethoxyresorufin Ciolino et al. It is also highly dependent on the cell type since, in hepatic cells, quercetin binds to AhR as an antagonist, thereby inhibiting gene expression for CYP 1A1 and benzo[a]pyrene activation Kang et al.

This provides a possible mechanism for the anti-cancer activity of quercetin. Flavonoids, especially flavones and flavonols, also directly bind to several CYP isoforms 1A1, 1A2, 1B1, 3A4 involved in xenobiotics metabolism and inhibit enzyme activity.

Structure—activity relationships Doostdar et al. Finally, flavonoids are also able to inhibit CYP19 or aromatase, an enzyme catalyzing a three-step oxidation sequence resulting in aromatization of the A ring of male steroid hormones androgens to yield estrogens.

Together with flavonoid—estrogen receptor binding, this process could be relevant to the prevention of hormone-dependent breast cancer by flavonoids Brueggemeier et al. Interestingly, 17β-hydroxysteroid dehydrogenase, another redox enzyme involved in steroid metabolism, is also strongly inhibited by 7-hydroxyflavonoids Le Bail et al.

For instance, the flavone apigenin is more potent at inhibiting 17b-hydroxysteroid dehydrogenase IC50 ¼0. The flavonols quercetin, kaempferol, myricetin, the flavone apigenin, and the biflavone biapigenin were also reported to inhibit CYP3A4 activity at low micromolar concentrations in human liver microsomes von Moltke et al.

Xenobiotics, drugs and flavonoids follow the same course of metabolism. As these compounds are hydrophobic in nature, so the first step involving the conjugation of these drugs to increase their hydrophilicity is a key step in their metabolism.

This step is performed by the above mentioned phase-II enzymes. Flavonoids have been demonstrated to activate these enzymes and thereby increase detoxification and elimination of carcinogens from the body. UDPglucuronosyltransferases UGT use UDP-glucuronic acid as a cosubstrate and transfer glucuronic acid to available substrates thereby making them more water soluble and facilitating their excretion in the urine or bile.

Similarly, sulfotransferases SULT catalyze the transfer of a sulfonate group, glutathione S -transferases GST transfer glutathione and N -acetyltransferases transfer acetyl moiety to an appropriate substrate. It has been shown that all these phase II enzymes are affected by flavonoids in cell and animal models.

An increase in mRNA levels, protein expression and enzyme activity of UGT isoform 1A1 has been reported in human Hep G2 cells and human colon carcinoma cells by chrysin, apigenin, baicalein, diosmetin, quercetin and kaempferol Galijatovic et al.

van der Logt et al. Quercetin significantly increased UGT1A1 mRNA in shed enterocytes on in vivo perfusion of human jejunam and in Caco-2 cells Petri et al. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 or P-PST ; this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis Moon et al.

Dietary intake of citrus limonoids Perez et al. Johnson et al. They have shown that ARPE cells that overexpress HO-1 or NQO-1 were more resistant to oxidative stress-induced cell death than control cells.

Cermak reviewed flavonoids as potent inhibitors of cytosolic SULT isoforms. Quercetin inhibited sulfation of 4-nitrophenol and of several drugs including salbutamol, minoxidil, paracetamol, apomorphine in human liver cytosol De Santi et al.

Changes in GST and NAD P H quinone oxidoreductase-1 activity were partly reflected on mRNA levels Wiegand et al. Cancer cells typically overexpress P-glucoprotein Pgp or multidrug resistance associated protein MRP which is ATP-dependent transmembrane transporters capable of expelling a wide variety of chemically unrelated drugs used in cancer therapy at the expense of ATP hydrolysis.

This phenomenon is known as multidrug resistance MDR and inhibition of MDR, to prevent drug efflux has potential clinical application during cancer therapy. Quercetin was shown to efficiently inhibit the Pgp-mediated drug efflux by inhibiting the overexpression of human MDR1 gene Kioka et al.

From investigations using a soluble cytosolic portion of mouse Pgp, which includes the nucleotide- and drug-binding domains, it was possible to monitor flavonoid binding by fluorescence as well as its influence on ATP binding and the efflux of the anti-cancer steroid drug RU Conseil et al.

Flavones aglycones bearing OH groups at positions 3 and 5 come up as efficient mouse Pgp ligands with apparent dissociation constants lower than 10 mM. By contrast, the quercetin glycoside rutin, the flavanone naringenin, and the isoflavone genistein have low affinity for Pgp.

Interestingly, flavones and flavonols behave as bifunctional inhibitors whose binding site overlap the vicinal binding sites for both ATP and RU Those trends were confirmed using a cytosolic portion of Pgp from the parasite Leishmania tropica Perez-Victoria et al.

Flavonoids have been reported to inhibit ATPase activity, nucleotide hydrolysis and energy-dependent drug interaction with transporter enriched membranes Di Pietro et al. This unique property of reversal of MDR has been found to enhance doxorubin DOX -induced anti-tumor activity by increasing the DOX concentration at target site Blagosklonny To study that how epicatechin gallate, epigallocatechin gallate, genistein, genistin, naringenin, naringin, quercetin and xanthohumol will modulate cellular uptake and permeability [P e ] of multidrug-resistant substrates, cyclosporin A CSA and digoxin, across Caco-2 and MDCKII-MDR1 cell-transport models, uptake experiments were perfomed with and without flavonids.

Aglycone flavonoids reduced the P e of CSA to a greater extent than that of digoxin, suggesting that transport mechanism of CSA can be different from digoxin Rodriguez-Proteau et al. Ofer et al. Six of the investigated flavonoids reduced the secretory flux of talinolol across Caco-2 cells but none of the selected flavonoids was able to replace 3 H-talinolol from its binding to P-gp.

This might be due to an interaction with P-gp, but apparently not via competition at the talinolol binding site of P-gp. This flavonoid—ABC-transporter interaction could be beneficial for poorly absorbed drugs but could also result in severe drug intoxication, especially drugs with a narrow therapeutic window Alvarez et al.

Most of the studies have demonstrated inhibitory effects of flavonoids on the substrate efflux in cells that either endogenously expressed these transporters or that were transfected with them Morris and Zhang These ABC-transporter proteins can affect the oral availability and tissue distribution of the flavonoids also, thereby modifying their beneficial effects Brand et al.

In addition to enzymatic oxidation, flavonoid oxidation can take place via autoxidation metal-catalyzed oxidation by dioxygen and ROS scavenging.

The former process can be related to flavonoid cytotoxicity ROS production while the latter is one of the main anti-oxidant mechanisms. Both processes may be modulated by flavonoid—protein binding.

Although poorly documented so far, these points could be important and, for instance, albumin—flavonoid complexes with an affinity for LDL could act as the true plasma anti-oxidants participating in the regeneration of α-tocopherol from the α-tocopheryl radical formed upon scavenging of LDL-bound lipid peroxyl radicals.

In addition, flavonoid—protein complexation can be expected to provide protection to the protein against oxidative degradation. Since lipid peroxidation is clearly related to the onset of atherosclerosis and the impairment of membrane functions, the influence of proteins on the ability of flavonoids to inhibit lipid peroxidation deserves examination Peng and Kuo ; Liu et al.

Such investigations have been carried out with BSA and lecithin liposomes Heinonen et al. Whereas BSA alone already slows down the formation of lipid hydroperoxides and hexanal, its influence on the anti-peroxidizing activity of the selected polyphenols is highly dependent on the polyphenolic structure.

Hence, BSA lowers the inhibition of hydroperoxide formation by catechins and caffeic acid, enhances inhibition by malvidin and rutin, and leaves essentially unchanged inhibition by quercetin.

No clear interpretation based on polyphenol—BSA binding can be given. One-electron oxidation of protein-bound phenols to form reactive aryloxyl radicals is a possible pro-oxidant mechanism, since these radicals can propagate H-atom or electron transfers within the protein.

In addition to phenol—protein covalent coupling, these phenol-mediated oxidative damages to proteins could be detrimental to their function as enzymes, receptors, and membrane transporters. Anti-oxidant properties have been reported for isoflavones both in vitro and in vivo Wei et al.

Equol, in model membrane systems, was a more effective anti-oxidant than genistein or the parent compound daidzein Wiseman et al. Daidzein and geinstein showed anti-oxidant action in primary and cancer lymphocytes Jurkat cells , both isoflavones increased DNA protection against oxidative damage and decreased lipid peroxidation Foti et al.

Moreover, a protective effect was achieved at concentrations that can be achieved in plasma following soy consumption. Anti-oxidant action could also contribute to anti-cancer ability because ROS could initiate signal transduction through the mitogen-activated protein MAP kinases Wiseman and Halliwell There have been a number of reports relating to the possible anti-oxidant effects of isoflavone consumption.

It is of considerable interest that widely differing effects in relation to the potential benefits to human health are frequently reported for isoflavones consumed within the food matrix in soy foods, compared to those consumed in capsule or tablet form as dietary supplements.

Angiogenesis, the formation of new blood vessels, is an important process which is regulated by endogenous angiogenic and angiostatic factors. Any alteration in this tightly regulated process can lead to a persistent and uncontrolled growth and metastasis of tumors.

Flavanoids have been reported as angiogenesis inhibitors Tosetti et al. These inhibitors can cause lack of diffusion of nutrients and oxygen to rapidly growing cancerous cells due to anti-angiogenic properties and hence lead to cell death.

Angiogenesis inhibitors can interfere with various steps in angiogenesis, such as the proliferation and migration of endothelial cells and lumen formation. A possible mechanism could be inhibition of protein kinases Oikawa et al.

These enzymes are implicated to play an important role in signal transduction and are known for their effects on angiogenesis. Genistein is a potent inhibitor of angiogenesis in vitro Fotsis et al. Studies on the inhibition of cell proliferation and angiogenesis by flavonoids in six different cancer cell lines had been reported and noted that the IC50 of active flavonoids were in the low micromolar range, physiologically available concentrations Fotsis et al.

Isoflavonones genistein, genistin, daidzein, and biochanin A also inhibit growth of murine and human bladder cancer cell lines by inducing cell cycle arrest, apoptosis, and angiogenesis Zhou et al. Luteolin has been found to inhibit VEGF-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositolkinase action Bagli et al.

Favot et al. During the last decade, some more novel molecular targets for the inhibition of angiogenesis by genistein have been discovered including tissue factor, endostatin, and angiostatin Su et al. Genistein may enhance the action of transforming growth factor-β TGF-β Kim et al.

This action may be a link between the effects of genistein in a variety of chronic diseases Barnes including atherosclerosis and hereditary hemorrhagic telangiectasia the Osler—Weber—Rendu syndrome in which defects in TGF-β have been characterized Johnson et al. Schindler and Mentlein determined whether secondary plant constituents, i.

It was found that the glycosylated flavonoids i. Inhibition of VEGF release by flavonoids, tocopherols, and lovastatin in models of neoplastic cells suggests a novel mechanism for mammary cancer prevention.

He et al. Apoptosis is a programed cell death to eliminate damaged or unwanted cells. It is regulated by a variety of genes that can either promote apoptosis or can favor cell survival in response to internal or external stimuli. Dysregulation of apoptosis could play a critical role in oncogenesis.

Among these genes, the tumor suppressor p53 plays a pivotal role in controlling the cell cycle, apoptosis, genomic integrity, and DNArepair Bode and Dong by acting as transactivator or as transrepressor Ho et al.

EGCG also activated p53 and BAX in breast carcinoma cells Roy et al. In addition to p53, mammalian cells contain two closely related proteins, p63 and p EGCG induces apoptosis by activating pdependent expression of a subset of p53 target genes Amin et al.

Nuclear factor-kappa B NF-кB family of transcription factors consists of five members, p50, p52, p65 Rel A , c-Rel, and Rel B, which share an N-terminal Rel homology domain responsible for DNA binding. NF-кB is activated by free radicals, inflammatory stimuli, cytokines, carcinogens, tumor promoters, endotoxins, γ-radiation, ultraviolet UV light, and X-rays and induces NF-кB target genes important for cellular growth and transformation, suppression of apoptosis, invasion, metastasis, chemoresistance, radioresistance, and inflammation.

Flavonoids may block one or more steps in the NF-кB signaling pathway such as inhibition of the most upstream growth factor receptors that activate the NF-кB signaling cascade, translocation of NF-кB to the nucleus, DNA binding of the dimers, or interactions with the basal transcriptional machinery Ju et al.

The NF-кB target genes influenced by the flavonoids include inhibition of Bcl-2 and Bclx L , cyclin D1, matrix metalloproteinases MMP , and VEGF Hastak et al. Flavonoids have been found to suppress activator protein-1 AP-1 activation and modulate AP-1 target genes.

Some of the biologic effects of AP-1 are mediated by gene repression. APregulated genes include important modulators of invasion and metastasis, angiogenesis, proliferation, differentiation, and survival.

Activation of various tyrosine kinases leads to phosphorylation, dimerization, and nuclear localization of the signal transducers and activators of transcription STAT proteins, binding to specific DNA elements and direct transcription. Constitutive activation of STAT3 and STAT5 has been implicated in multiple myelomas, lymphomas, leukemias, and several solid tumors.

Selvendiran et al. Luteolin is capable of inducing anti-cancer effects by inducing cell cycle arrest or apoptosis in oral squamous cancer cells Yang et al. Luteolin inhibited proliferation and induced apoptosis of prostate cancer cells in vitro and in xenografts Chiu and Lin , with increased efficacy of cisplatin in gastric cancer cells Wu et al.

Some characteristic changes in nuclear morphology, phosphatidylserine externalization, mitochondrial membrane depolarization, modulation of cell-cycle regulatory proteins and NF-κB family members, upregulation of proapoptotic Bcl-2 family proteins, cytochrome C, Apaf-1 and caspases, and downregulation of anti-apoptotic Bcl-2 proteins and surviving was reported.

It significantly increases the expression of p53 and p21 proteins, and decreases the levels of cyclin D1, cyclin A, CDK4 and CDK2, thereby contributing to cell cycle arrest. In addition, fisetin increased the expression of Bax and Bak but decreased the levels of Bcl-2 and Bcl-xL and subsequently triggered mitochondrial apoptotic pathway Li et al.

Pretreatment with chrysin could increase TRAIL-induced degradation of caspase 3, caspase 8, PARP protein. Z-VAD- fmk, which is a pan-cascade inhibitor, could inhibit the apoptosis enhanced by combination of chrysin and TRAIL Li et al.

Thereby, DHC and fisetin induced apoptosis, but not accelerated senescence in prostate cells Haddad Flavonoids greatly influence the cascade of immunological events associated with the development and progression of cancer.

One has to understand the mechanism how these flavonoids get accumulated in cellular organelles and tissues once they enter inside.

Flavonoids have the potential of modulatng many biological events in cancer such as apoptosis, vascularization, cell differentiation, cell proliferation, etc. A strong correlation persists between flavonoid-induced modulation of kinases with apoptosis, cell proliferation and tumor cell invasive behavior in vitro.

Also, some of the dietary flavonoids have been known to display in vivo anti-tumor activity and repress in vivo angiogenesis. The cross talk between flavonoids and the key enzymes related to neoplastic cells and metastasis has to be understood in vitro and in vivo as well, providing new insights for fighting against cancer.

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Cancer is a major Flavonoids and cancer prevention health Cabcer in both developed and developing countries. Several Flagonoids anti-cancer acncer including taxol, vinblastine, vincristine, the campothecin derivatives, Flavonojds, irinotecan and etoposide are in clinical use all over the preventkon. Other Green tea extract and muscle recovery anti-cancer prevetnion include flavopiridol, roscovitine, combretastatin A-4, prevnetion Flavonoids and cancer prevention and silvestrol. From this list one can well imagine the predominance of polyphenols, flavonoids and their synthetic analogs in the treatment of ovarian, breast, cervical, pancreatic and prostate cancer. Flavonoids present in human diet comprise many polyphenolic secondary metabolites with broad-spectrum pharmacological activities including their potential role as anti-cancer agents. A positive correlation between flavonoids-rich diet from vegetables and fruits and lower risk of colon, prostate and breast cancers lead to a question that whether flavonoids mediate the protective effects as chemopreventive agents or can interact with different genes and proteins to play role in chemotherapy. Flavonoids and cancer prevention

Author: Arashinos

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