CHEMOPREVENTIVE AGENT RESVERATROL, A NATURAL PRODUCT DERIVED FROM GRAPES, TRIGGERS CD95 SIGNALING-DEPENDENT APOPTOSIS IN HUMAN TUMOR-CELLS

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increas e in externalization of inner membrane phosphatidylserine and in cellu lar content of subdiploid DNA, indicating loss of membrane phospholipi d asymmetry and DNA fragmentation. Resveratrol-induced cell death is m ediated by intracellular caspases as observed by the dose-dependent in crease in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resve ratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression an HL60 cells, as well as T47D breast carcinoma cells , and that resveratrol-mediated cell death is specifically CD95-signal ing dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant cha nge in either CD95 or CD95L expression on treated PBLs. These data sho w specific involvement of: the CD95-CD95L system in the anti-cancer ac tivity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreven tive activity. (C) 1998 by The American Society Hematology.