Mini-reviewCancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives
Introduction
Despite enormous efforts to search for a cure, cancer still remains as a formidable challenge for public health. It is expected that the number of cancer-related deaths may double in the next 50 years [1]. Although chemotherapy has long been practiced to combat cancer, it can only contribute to overall patient’s survival with compromised quality of life. Moreover, an increasing trend of chemoresistance and the recurrence of secondary tumors put chemotherapy at the back foot in the fight against cancer. In this context, the practice of cancer prevention by use of non-toxic chemical entities, commonly termed ‘chemoprevention’, is considered to be an alternative, but more realistic and fundamental strategy for the management of this dread disease. A wide variety of preclinical and human intervention studies demonstrate the success of chemoprevention in reducing the burden of cancer. Accumulating evidence from population-based and laboratory studies suggests that regular consumption of fruits and vegetables is inversely associated with the risk of certain malignancies [2]. Besides anti-oxidant vitamins, numerous non-nutritive substances present in plant-based diet, collectively termed phytochemicals, have been identified as promising chemopreventive agents. Some of these dietary chemopreventive phytochemicals have been reported to have chemotherapeutic potential as well.
One of the promising dietary phytochemicals with chemopreventive and chemotherapeutic potential is resveratrol (3,5,4′-trihydroxystilbene) [3], which has first been isolated from the roots of white hellebore (Veratrum glandiflorum O. Loes), and subsequently identified in various food sources including red wine, grapes, peanuts, mulberries, etc. and in more than 70 other plant species [4]. There had been little interest in the medicinal value of resveratrol until 1990s. Due to its broad-spectrum health beneficial effects, such as anti-infective, anti-oxidant, and cardioprotective functions, resveratrol is considered as the state-of-the-art nature’s medicine [4]. This phytoalexin has attracted considerable attention from cancer researchers as well as general public since 1997, when Jang and colleagues [5] published a seminal article demonstrating its anti-carcinogenic effects. Shortly thereafter, there has been a rapid progress in uncovering the molecular mechanisms of anti-carcinogenic properties of resveratrol [6]. Fig. 1 illustrates the biochemical basis of cancer chemopreventive and therapeutic potential of resveratrol. The chemopreventive property of resveratrol has been reflected by its ability to block the activation of various carcinogens and/or to stimulate their detoxification, to prevent oxidative damage of target cell DNA, to reduce inflammatory responses and to diminish proliferation of cancer cells [3], [6], [7]. Blockade of angiogenic and metastatic processes of tumor progression, and alleviation of chemotherapy resistance indicate the chemotherapeutic potential of resveratrol [6], [8], [9]. The induction of apoptosis in various premalignant or cancerous cells by resveratrol can contribute to both chemopreventive and chemotherapeutic potential of this compound (Fig. 1). The biochemistry behind the anti-cancer property of resveratrol has been extensively studied over past ten years. Resveratrol was shown to modulate various intracellular signal transduction pathways, which often become awry during the course of carcinogenesis. This review is intended to shed light on multifarious molecular targets of resveratrol as an anti-cancer agent (Table 1).
Section snippets
Chemopreventive and chemotherapeutic potential of resveratrol
In a pioneering study, John M. Pezzuto and his colleagues [5] reported that resveratrol was effective in blocking all three stages (i.e., initiation, promotion and progression) of carcinogenesis. According to this study, topically applied resveratrol significantly reduced 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-teradecanoylphorbol-13-acetate (TPA)-promoted skin tumors in female CD-1 mice. Subsequent studies demonstrated that resveratrol exhibited strong chemopreventive effects
Upstream kinases and transcription factors as molecular targets of resveratrol
The multistage carcinogenesis involves a breaking of the ‘chain-of-command’ in the normal intracellular signaling network. A panel of receptor proteins, linkers, upstream kinases, DNA-interacting proteins, and transcriptionally regulated gene products function abnormally during the course of carcinogenesis. In response to carcinogenic insults, the microenvironment of intracellular signaling network becomes disrupted, thereby favoring premalignant and malignant transformation of damaged cells
Conclusion
Fighting cancer with naturally occurring substances, especially those derived from plant-based diet, appears to be a fascinating strategy. We are currently passing an accelerated phase of developing dietary phytochemicals as potential chemopreventive/chemotherapeutic agents. Due to extreme heterogeneity of cancer cells, it is hard to find a specific molecular target for the prevention or treatment of cancer. Thus, a cancer preventive/therapeutic agent should target multiple biochemical pathways
Acknowledgements
This work was supported by the National Research Laboratory Fund from the Ministry of Science and Technology and the Grant (B050007) from the Ministry of Health and Welfare, Republic of Korea.
References (157)
- et al.
Molecular basis of chemoprevention by resveratrol: NF-κB and AP-1 as potential targets
Mutat. Res.
(2004) - et al.
Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review
Cancer Detect. Prev.
(2006) - et al.
Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway
Carcinogenesis
(1999) - et al.
Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo
Cancer Lett.
(2006) - et al.
Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice
J. Nutr.
(2004) - et al.
Evaluation of butylated hydroxyanisole, myo-inositol, curcumin, esculetin, resveratrol and lycopene as inhibitors of benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice
Cancer Lett.
(1999) - et al.
Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth
J. Nutr.
(2006) - et al.
Effect of resveratrol on growth of 4T1 breast cancer cells in vitro and in vivo
Biochem. Biophys. Res. Commun.
(2002) - et al.
Mechanism-based in vitro screening of potential cancer chemopreventive agents
Mutat. Res.
(2003) - et al.
Phytoalexin resveratrol attenuates the mutagenicity of the heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
J. Chromatogr. B Anal. Technol. Biomed. Life Sci.
(2004)
Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells
Biochem. Biophys. Res. Commun.
Toxicogenomics of resveratrol in rat liver
Life Sci.
Mechanism of concentration-dependent induction of heme oxygenase-1 by resveratrol in human aortic smooth muscle cells
Biochem. Pharmacol.
Modulation of pregnane X receptor- and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds
Free Radic. Biol. Med.
Breaking the relay in deregulated cellular signal transduction as a rationale for chemoprevention with anti-inflammatory phytochemicals
Mutat. Res.
Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production
Biochem. Pharmacol.
Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferon-gamma-induced IκB degradation in RAW264.7 macrophages
Cancer Lett.
Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells
J. Biol. Chem.
Resveratrol blocks interleukin-1β-induced activation of the nuclear transcription factor NF-κB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells
Blood
Resveratrol induces apoptosis, influences IL-6 and exerts immunomodulatory effect on mouse lymphocytic leukemia both in vitro and in vivo
Int. Immunopharmacol.
Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells
Cancer Lett.
De novo ceramide biosynthesis is associated with resveratrol-induced inhibition of ornithine decarboxylase activity
Biochem. Pharmacol.
Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors
Curr. Opin. Pharmacol.
Resveratrol, a remarkable inhibitor of ribonucleotide reductase
FEBS Lett.
Involvement of the retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) cells
Biochem. Biophys. Res. Commun.
Downregulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell cycle arrest in colon cancer cell lines
J. Nutr.
Resveratrol induces apoptosis involving mitochondrial pathways in mouse skin tumorigenesis
Life Sci.
Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells
Blood
Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells
J. Biol. Chem.
Resveratrol-mediated sensitisation to TRAIL-induced apoptosis depends on death receptor and mitochondrial signalling
Eur. J. Cancer
Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells
J. Biol. Chem.
Resveratrol-induced apoptosis is mediated by p53-dependent pathway in Hep G2 cells
Life Sci.
Caspase-2 triggers Bax-Bak-dependent and -independent cell death in colon cancer cells treated with resveratrol
J. Biol. Chem.
Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells
Biochem. Pharmacol.
Regulation of angiogenesis by hypoxia and hypoxia-inducible factors
Curr. Top. Dev. Biol.
Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors
Cancer Lett.
Mechanisms of disease: inflammatory mediators and cancer prevention
Nat. Clin. Pract. Oncol.
Cancer chemoprevention with dietary phytochemicals
Nat. Rev. Cancer
Therapeutic potential of resveratrol: the in vivo evidence
Nat. Rev. Drug Discov.
Cancer chemopreventive activity of resveratrol, a natural product derived from grapes
Science
Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies
Anticancer Res.
Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential
Front. Biosci.
Chemosensitization and radiosensitization of tumors by plant polyphenols
Antioxid. Redox Signal.
Inhibition of cell transformation by resveratrol and its derivatives: differential effects and mechanisms involved
Oncogene
Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice
World J. Gastroenterol.
Dietary supplementation of resveratrol suppresses colonic tumour incidence in 1,2-dimethylhydrazine-treated rats by modulating biotransforming enzymes and aberrant crypt foci development
Br. J. Nutr.
Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis
Nutr. Cancer
Resveratrol suppresses prostate cancer progression in transgenic mice
Carcinogenesis
Inflammation and cancer: an ancient link with novel potentials
Int. J. Cancer
Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells
Carcinogenesis
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