Resveratrol inhibits cell cycle progression in U937 cells

Resveratrol, a naturally occurring stylbene present in grapes, is proposed to be responsible for the positive effects of red wine consumption on cardiovascular diseases (French paradox). In recent years this molecule has also been proposed as a cancer chemopreventive agent. The aim of the present study was to investigate the mechanisms by which resveratrol inhibits tumor growth. For this purpose, U937 cells were exposed to resveratrol at concentrations usually present in red wine, and the effects on proliferation, death and cell cycle machinery were assessed. The U937 cell growth was impaired due to reduced cell proliferation, without significant induction of apoptosis. This anti-proliferative effect is associated with modulations in the pattern of DNA distribution, with a reduction of G₀/G₁, particularly G₂-M peaks and accumulation in the S phase of the cell cycle. This result was confirmed by the observation that the rate of [³H]- thymidine incorporation into DNA was significantly reduced in resveratrol-treated U937 cells. Consistent with this observation, in the same experimental conditions, the activity of ribonucleotide reductase, an enzyme critically involved in the process of DNA duplication, decreased. The altered progression in the cell cycle could depend on modulations in the activity of cyclin dependent kinases and their inhibitors. After exposure of U937 cultures to resveratrol, the expression of cyclins A and E, as well as that of CDK2 increased, while that of p21^CIP was significantly reduced. The data shown in this report suggests that the prevention of cancer development exerted by resveratrol may result from modulations of molecules involved in the regulation of cell cycle progression, which block the cells at the S phase checkpoint.