Cancer Letters

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 243-261
Cancer Letters

Mini-review
Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives

https://doi.org/10.1016/j.canlet.2008.03.057Get rights and content

Abstract

A plant kingdom is considered as a gold mine for the discovery of many biologically active substances with therapeutic values. Resveratrol (3,5,4′-trihydroxystilbene), a naturally occurring polyphenol, exhibits pleiotropic health beneficial effects including anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. Currently, numerous preclinical findings suggest resveratrol as a promising nature’s arsenal for cancer prevention and treatment. A remarkable progress in dissecting the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the past decade. As a potential anti-cancer agent, resveratrol has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compound significantly inhibits experimental tumorigenesis in a wide range of animal models. Resveratrol targets many components of intracellular signaling pathways including pro-inflammatory mediators, regulators of cell survival and apoptosis, and tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. This review summarizes the diverse molecular targets of resveratrol with a special focus on those involved in fine-tuning of orchestrated intracellular signal transduction.

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.

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