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 (DeltaPsi(m)) in T-acute lymphoblastic leukemia cells and swelling of isolated rat mitochondria. The breakdown of DeltaPsi(m) was accompanied by the production of reactive oxygen species (ROS), and preceded phosphatidylserine exposure and DNA fragmentation. Breakdown of DeltaPsi(m) 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 DeltaPsi(m) 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 DeltaPsi(m) 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.