DOXORUBICIN-INDUCED APOPTOSIS IN HUMAN T-CELL LEUKEMIA IS MEDIATED BYCASPASE-3 ACTIVATION IN A FAS-INDEPENDENT WAY

It has recently been proposed that doxorubicin (DOX) can induce apopto sis in human T-leukemia cells via the Fas/FasL system in an autocrine/ paracrine way. We show here that treatment of Jurkat cells with either anti-Fas antibodies, anthracyclin drugs or actinomycin D induces the activation of CPP32 (caspase-3) and apoptosis, However, DOX treatment did not induce the expression of membrane FasL or the release of solub le FasL and co-incubation with blocking anti-Fas antibodies prevented Fas-induced but not DOX-induced apoptosis. All the morphological and b iochemical signs of apoptosis induced by anti-Fas or DOX can be preven ted by Z-VAD-fmk, a general caspase inhibitor, DEVD-cho, a specific in hibitor of CPP32-like caspases which completely blocks Fas-mediated ap optosis, prevented drug-induced nuclear apoptosis but not cell death, We conclude that: (i) DOX-induced apoptosis in human T-leukemia/lympho ma is Fas-independent and (ii) caspase-3 is responsible of DOX-induced nuclear apoptosis but other Z-VAD-sensitive caspases are implicated i n cell death. (C) 1997 Federation of European Biochemical Societies.