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 increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling 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 change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.
Department of Physiology and Oncology Research Institute, NUMI, National University of Singapore, Singapore.
M V
MV
Clément
J L
JL
Hirpara
S H
SH
Chawdhury
S
S
Pervaiz
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008563:Membrane Lipids / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D000077185:Resveratrol; D019685:Rosales / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D015853:Cysteine Proteinase Inhibitors; D004273:DNA, Neoplasm; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D009363:Neoplasm Proteins; D010718:Phosphatidylserines; D013267:Stilbenes; D019014:fas Receptor; D003546:Cysteine Endopeptidases; D000077185:Resveratrol