Resveratrol, a tumor-suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl-2.

We report that resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other plant food, induced a breakdown of the mitochondrial transmembrane potential (∆Ψm) in T-acute lymphoblastic leukemia cells and swelling of isolated rat mitochondria. The breakdown of ∆Ψm was accompanied by the production of reactive oxygen species (ROS), and preceded phosphatidylserine exposure and DNA fragmentation. Breakdown of ∆Ψm was not caused by the activation of caspase-8 or Bid, as no significant cleavage of these proteins could be detected in the induction phase of resveratrol-induced apoptosis. Though loss of ∆Ψm was not followed by cytochrome c translocation to the cytosol, the mitochondrial changes triggered significant activation of caspase-9, -2, -3, and -6. Inhibition of ∆Ψm breakdown and of ROS generation by N-acetylcysteine, or by overexpression of Bcl-2 protein, prevented apoptosis induction by resveratrol. The Bcl-2 expression status of tumor cells should therefore be considered relevant for potential clinical application of resveratrol as anticancer agent.