Mini-review
Multitargeted cancer prevention by quercetin
Introduction
Quercetin (3,3′,4′,5,7-pentahydroxylflavone) is a typical flavonoid present in the plant kingdom as a secondary metabolite. Flavonoids are polyphenolic compounds containing a basic skeleton of diphenylpropane (C6–C3–C6). More than 4000 types of flavonoids exist and are categorized into the subclasses of flavones, flavonols, flavan-3-ols (catechins), isoflavones, flavanones, anthocyanins and chalcones. Quercetin and related flavonoids are present in fruit and vegetables and have attracted much attention as potential anti-carcinogens. Their cancer-preventive effects have been attributed to various mechanisms including their anti-oxidative activity, the inhibition of enzymes that activate carcinogens, the modification of signal transduction pathways, and interactions with receptors and other proteins [1], [2], [3]. In this review, we firstly discuss the chemical reactivity of quercetin and its metabolic conversion, which underlies its anti-carcinogenic mechanism. Secondly, we focus on the interactions of quercetin with cellular receptors and the modification of signal transduction pathways as potential targets for the chemopreventive effects of quercetin in cancer. Finally, we discuss recent epidemiological studies on quercetin intake and cancer incidence.
Section snippets
Chemistry of quercetin and related compounds
Quercetin is a flavonol-type flavonoid ubiquitously present in plant-derived foods and medicines. Flavonoids, including quercetin, are commonly found as O-glycosides in which at least one hydroxyl group is substituted by various types of sugars (Fig. 1). The sugar group is frequently bound at the 3-position such as in quercitrin, isoquercitrin, hyperoside and rutin. Onion is a major vegetable source of quercetin glycosides, and the 4′-position-substituted glycosides, quercetin-4′-O-β-d
Bioavailability and metabolism
The bioavailability of quercetin, including its intestinal absorption and metabolic conversion, needs to be understood in order to estimate the efficacy of its anti-carcinogenic effect. It has long been known that quercetin disappears immediately from the plasma when administered intravenously to rodents. This suggests that quercetin is metabolized rapidly and excreted into the urine with no accumulation in tissues and biological fluids. It has previously also been believed that dietary
Interactions with cellular receptors
Various cellular receptors have been reported to be involved in the cancer-preventive activities of quercetin, but there are few studies demonstrating direct interactions between quercetin and these cellular receptors. In the case of (−)-epigallocatechin-3-gallate (EGCg), a major tea catechin, Tachibana et al. [17] identified a 67-kDa cell surface laminin receptor (67LR) which acted as an EGCg receptor and was involved in the anti-cancer action of EGCg. Recently, Li et al. [18] reported that
Anti-cancer properties of quercetin
Numerous reports on the chemopreventive and anti-genotoxic effects of quercetin have been published. For example, administration of a diet containing 2% quercetin to Swiss albino mice for four weeks led to marked suppression of 7,12-dimethylbenz[a]anthracene (DMBA)-induced chromosomal aberrations in the bone marrow, a predictor of future cancer risk [52]. There is also abundant evidence the colon could be one of the target sites for quercetin (Table 1). This may be due to the fact that
Epidemiological studies
There are numerous studies suggesting that a high intake of fruit and vegetables is associated with a decreased risk of human malignancies, including colon, breast, lung, laryngeal, pancreatic, bladder, stomach, esophageal, and oral cancers [61], [62], [63]. Although it is not yet known which bioactive compound(s) in food plants provide the chemoprotective effects, one class of compounds that has been well investigated is the flavonoids. Many cohort and case-control studies have been performed
Conclusion
Quercetin is an attractive natural compound for cancer prevention due to its beneficial anti-mutagenic and anti-proliferative effects, its strong anti-oxidative capacity, and its role in the regulation of cell signaling, cell cycle and apoptosis, all demonstrated in animal and in vitro studies. However, metabolic conversion must be taken into account when estimating the bioavailability and efficacy of quercetin for pharmacological use. The conjugation of xenobiotics attenuates their reactivity,
Acknowledgements
The data described here were generated from a study supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan (A.M.). We thank Prof. Takuji Tanaka of Kanazawa Medical University, Japan, and Prof. Ki Won Lee of Konkuk University, Korea, for valuable comments.
References (80)
- et al.
Comparative effects of flavonoids and model inducers on drug-metabolizing enzymes in rat liver
Toxicology
(1996) - et al.
Differential effects of flavonoid compounds on tumor promoter-induced activation of the human CYP1A2 enhancer
Arch. Biochem. Biophys.
(2000) - et al.
Dietary flavonoids: effects on xenobiotic and carcinogen metabolism
Toxicol. In Vitro
(2006) - et al.
Flavonoids as antioxidant; determination of radical-scavenging efficiencies
Methods Enzymol.
(1990) - et al.
Inhibitory effect of quercetin metabolites and their related derivatives on copper-induced lipid peroxidation in human low-density lipoprotein
Arch. Biochem. Biophys.
(1999) - et al.
Conjugation position of quercetin glucuronides and effect on biological activity
Free Radic. Biol Med.
(2000) - et al.
Efficiency of absorption and metabolic conversion of quercetin and its glucosides in human intestinal cell line Caco-2
Arch. Biochem. Biophys.
(2000) - et al.
Quercetin appears in the lymph of unsaturated rats at its phase II metabolites after administered into the stomach
FEBS Lett.
(2005) - et al.
Tissue distribution of quercetin in rats and pigs
J. Nutr.
(2005) - et al.
Mjacrophase as a target of quercetin glucuronides in human atherosclerotic arteries: implication in the anti-atherosclerotic melanism of dietary flavonoids
J. Biol. Chem.
(2008)
The intermediate filament protein vimentin is a new target for epigallocatechin gallate
J. Biol. Chem.
Ligand binding and activation of the Ah receptor
Chem. Biol. Interact.
Flavones and flavonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin
FEBS Lett.
Interaction between the aryl hydrocarbon receptor and its antagonists, flavonoids
Biochem. Biophys. Res. Commun.
Overexpression of c-Jun induced by quercetin and resverol inhibits the expression and function of the androgen receptor in human prostate cancer cells
Cancer Lett.
Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells
J. Nutr. Biochem.
Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2)
J. Nutr.
Anti-apoptotic effect of quercetin: intervention in the JNK- and ERK-mediated apoptotic pathways
Kidney Int.
Quercetin abrogates taxol-mediated signaling by inhibiting multiple kinases
Exp. Cell Res.
Antioxidative and prooxidative effects of quercetin on A549 cells
Cell Biol. Int.
Quercetin decreases oxidative stress, NF-kappaB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats
J. Nutr.
Nrf2 as a novel molecular target for chemoprevention
Cancer Lett.
Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways
J. Hepatol.
Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin
Free Radic. Biol. Med.
Quercetin, but not its glycosylated conjugate rutin, inhibits azoxymethane-induced colorectal carcinogenesis in F344 rats
J. Nutr.
Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodium-induced experimental colitis in mice: attenuation of pro-inflammatory gene expression
Biochem. Pharmacol.
Glucuronidase deconjugation in inflammation
Methods Enzymol.
Polyphenols and disease risk in epidemiologic studies
Am. J. Clin. Nutr.
Flavonoid intake and risk of chronic diseases
Am. J. Clin. Nutr.
Prevention of N-nitrosodiethylamine-induced lung tumorigenesis by ellagic acid and quercetin in mice
Food Chem. Toxicol.
Effect of storage and domestic processing on the contents and composition of flavonol glucosides in onion (Allium capa L.)
J. Agric. Food Chem.
Evaluation for safety of antioxidant chemopreventive agents
Antioxid. Redox Signal.
Human metabolism of dietary flavonoids; identification of plasma metabolites of quercetin
Free Radic. Res.
In vitro biological properties of flavonoid conjugates found in vivo
Free Radic. Res.
Accumulation of quercetin conjugates in blood plasma after the short-term ingestion of onion by women
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Deconjugation of a flavonoid, luteolin monoglucuronide, during inflammation
Drug Metab. Dispos.
A receptor for green tea polyphenol EGCG
Nat. Struct. Mol. Biol.
Direct inhibition of insulin-like growth factor-I receptor kinase activity by (−)-epigallocatechin-3-gallate regulates cell transformation
Cancer Epidemiol. Biomarkers Prev.
(−)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78
Cancer Res.
Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine
Cancer Res.
Cited by (599)
-
A pH/ROS dual-responsive system for effective chemoimmunotherapy against melanoma via remodeling tumor immune microenvironment
2024, Acta Pharmaceutica Sinica B -
Flavonoids as receptor tyrosine kinase inhibitors in lung cancer
2023, Journal of Functional Foods -
Advances in CD73 inhibitors for immunotherapy: Antibodies, synthetic small molecule compounds, and natural compounds
2023, European Journal of Medicinal Chemistry
- 1
-
These authors contributed equally to this review article.