From the studies described in this review, it is clear that resveratrol holds great potential not only in the prevention but also in the therapy of a wide variety of cancers. Tumor cells use multiple survival pathways to prevail over normal cells. Therefore, agents such as resveratrol that can suppress multiple cellular pathways may have a strong potential for cancer prevention and treatment. It may be speculated that the anticancer effects of resveratrol cannot be explained by a unique mechanism of action but likely stem from various complementary actions of several molecular, biochemical, and physiologic pathways involved in carcinogenesis.
Several reports suggest that resveratrol could be ineffective in inhibiting tumor growth in certain animal models despite its in vitro antitumor action in related cells. For example, resveratrol had no effect on the in vivo growth and metastasis of transplanted 4T1 breast cancer cells in mice, whereas it inhibited the in vitro growth of the same cancer cells (30). Again, based on reports presented here, resveratrol could be more effective in inhibiting the growth of established tumors in a particular organ (e.g., the lung) than in preventing tumors in the same site. However, an opposite trend has also been observed (e.g., for skin and breast tumors). There is an obvious need for further studies to address the tissue specificity of resveratrol so as to determine where resveratrol may have the strongest preventive potential.
The conundrum posed by the undeniable efficacy of resveratrol in preclinical models in spite of its low bioavailability has not been resolved yet. Likewise, the question of whether resveratrol itself can accumulate to bioactive levels in target organs remains unanswered. To enhance the bioavailability of resveratrol, active research should examine resveratrol delivery routes and formulations and modulation of resveratrol metabolism, as well as possible interactions of resveratrol with other food components.
Developing novel resveratrol derivatives is another possible approach for enhancing bioavailability. A series of cis-stilbenes and trans-stilbenes related to resveratrol with varying functional groups have been synthesized, and some of these compounds are more potent than is resveratrol in suppressing the growth of human cancer cells in vitro (reviewed in ref. 2). Researchers have started to explore the anticancer effects of resveratrol derivatives in vivo (40, 55, 73–75), and at least one study indicated that a tetramer of resveratrol (heyneanol) had comparable or better anticancer efficacy than did resveratrol in a mouse lung cancer model (55). However, more in vivo studies of head-to-head comparisons between resveratrol and its analogues are ongoing and no doubt will help elucidate the anticancer potential of specific compounds.
Since the first report on the biological activity of resveratrol, an enormous body of work has revealed many important biological properties (e.g., anti-inflammatory, antioxidant, caloric restriction mimetic, and antiaging effects) of this naturally occurring polyphenol. Much more study is needed, however, including studies to identify resveratrol-binding proteins and the pathways through which resveratrol functions and thus may exert clinical effects and to develop mechanism-based markers for evaluating clinical outcome. Long-term epidemiologic studies and controlled clinical trials are also necessary for developing resveratrol to become a standard clinical agent. The preclinical and clinical data examined in this review strongly suggest that resveratrol is a promising candidate in chemopreventive and chemotherapeutic strategies and a potential weapon in the effort to alleviate the burden of human cancer.