Resveratrol: Challenges in Translation to the Clinic — A Critical Discussion

Abstract

Low cancer survival rates and the serious side effects often associated with current chemotherapeutics highlight the need for new and effective nontoxic anticancer agents. Since 1997 when Jang and colleagues first described resveratrol's ability to inhibit carcinogenesis, it has consistently proven effective at tumor inhibition in diverse human cancer models. This finding has raised the hope that resveratrol would pioneer a novel class of nontoxic chemotherapeutics. As a consequence of initial basic and preclinical studies, resveratrol is now being extensively promoted in the unregulated nutraceutical sector. However, some fundamental aspects of resveratrol's action need to be understood before it can be developed into a clinically viable anticancer drug. These areas pertain to the key mechanism(s) by which resveratrol potentiates its antitumor effects. Current research suggests that these mechanisms might be through novel pathways, requiring an understanding of cellular uptake, sentinel targets, and in vivo biological networks. The metabolism of resveratrol and its bioavailablity also warrant further consideration in light of recent in vitro and in vivo studies. Finally, we need to appreciate the sorts of information about resveratrol that may translate between different disease entities. We present a critical discussion of these issues and suggest important experiments that could pave the way to the successful translation of resveratrol to the clinic.

Sulfate Metabolites Provide an Intracellular Pool for Resveratrol Generation and Induce Autophagy with Senescence

“…In recent years resveratrol has received considerable scientific and public attention for its numerous potential health benefits, but doubts persist over whether the promising preclinical data can translate to humans because of its rapid metabolism and resulting poor bioavailability (8). Whether the major products of this transformation, sulfate and glucuronide conjugates, can contribute to activity in vivo has important implications for the future clinical development of resveratrol, particularly whether the development of alternative prodrugs or drug-delivery systems that resist metabolism is indicated.…”

“…However, a perceived major limitation in translating these observations to efficacy in humans is the fact that resveratrol is poorly bioavailable, due to rapid and extensive phase II metabolism, and toxicity concerns prohibit simply increasing the dose to overcome this issue (8). This is exemplified by our previous pharmacokinetic study in healthy volunteers, which revealed the prominent plasma and urinary species to be resveratrol-3-O-sulfate, resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide, after a single dose of resveratrol (0.5-5.0 g) (9).…”

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

“…Resveratrol is rapidly metabolized by the liver and intestines into glucuronidated and sulfated compounds and these metabolites have not been shown to inhibit tumor cell growth (Subramanian et al, 2010). Since resveratrol is primarily metabolized in the liver, the gastrointestinal bioavailability would be significantly thus explaining the demonstrated efficacy of resveratrol in gastrointestinal cancers, including liver cancer (reviewed by Bishayee, 2009).…”

Tristetraprolin: a novel mediator of the anticancer properties of resveratrol

“…Therefore, finding less toxic, safer, and more effective anticancer drugs is the current research focus (Tan et al, 2008). Resveratrol, a natural polyphenolic compound present in many plants, can extend life and inhibit inflammation and oxidation (Subramanian et al, 2010). More interestingly, several research groups have proven the prominent anti-cancer effects of resveratrol.…”