Resveratrol: from grapevines to mammalian biology.

With the rapid advances made over the last two decades in biomedical research, there has been an unprecedented interest in unraveling the magical properties of some commonly used natural products. Consequently, a wide variety of natural products are under scrutiny for their clinical potential, both in terms of disease prevention and treatment. Among the compounds under investigation is a family of polymers given the name viniferin. These compounds elicit strong anti-fungal properties and are therefore included under the broad class of plant antibiotics known as phytoalexins (1). One remarkable compound in this list is resveratrol (RSV), a major active ingredient of stilbene phytoalexins, first isolated from the roots of the oriental medicinal plant Polygonum Capsidatum (Kojo-kon in Japanese) (2). Observations that this compound was an active ingredient of a folk plant known for its remedial effects against a host of human afflictions (2, 3) and that it was synthesized by leaf tissue in response to fungal infection of grapevines (Vitis vinifera) (4) provided the impetus for the increase in activity surrounding RSV in the field of biomedical research. The relatively high concentration of RSV in wine (5) and its documented cardioprotective effect (6) form the basis for the so-called “French paradox” (7). Most of the initial work on RSV was centered around its effects on metabolic pathways regulating cardiovascular biology, such as lipid metabolism and platelet function; however, since the reported cancer chemopreventive activity of RSV in animal models of carcinogenesis (8), recent investigations have been directed at understanding the molecular mechanism(s) of its diverse biological effects. As a result, the positive or negative effects of RSV on some important physiological pathways have been proposed as possible mechanisms for its observed cancer chemopreventive, cardioprotective, and neuroprotective activities. These include suppression of cellular proliferation via inhibition of key steps in the signal transduction pathways (9–12) and cyclin-dependent kinases (cdks) (13), promotion of cellular differentiation (14), scavenging/suppression of intracellular reactive oxygen intermediates (ROI) (15), induction of apoptotic cell death through activation of mitochondria-dependent or -independent pathways (16–18), anti-inflammatory activity via down-regulation of proinflammatory cytokines (19, 20), and inhibition of androgen receptor function and estrogenic activity (21, 22). This review is intended to provide the reader with an appreciation of the diverse biological effects of this remarkable compound, which could have tremendous potential as a chemopreventive and/or chemotherapeutic agent in clinical medicine.