Caspase I related protease inhibition retards the execution of okadaic acid and camptothecin induced apoptosis and PAI-2 cleavage, but not commitmentto cell death in HL-60 cells

We have previously reported that the putative cytoprotective protease inhib itor, plasminogen activator inhibitor type 2 (PAI-2), is specifically cleav ed during okadaic acid-induced apoptosis in a myeloid leukaemic cell line ( Br J Cancer (1994) 70: 834-840). HL-60 cells exposed to okadaic acid and ca mptothecin underwent morphological and biochemical changes typical of apopt osis, including internucleosomal DNA fragmentation and PAI-2 cleavage. Sign ificant endogenous PAI-2 cleavage was observed 9 h after exposure to okadai c acid; thus correlating with other signs of macromolecular degradation, li ke internucleosomal DNA fragmentation. In camptothecin-treated cells, PAI-2 cleavage was an early event, detectable after 2 h of treatment, and preced ing internucleosomal DNA fragmentation. The caspase I selective protease in hibitor, YVAD-cmk, inhibited internucleosomal DNA fragmentation and PAI-2 c leavage of okadaic acid and camptothecin-induced apoptotic cells. YVAD-cmk rather sensitively and non-toxically inhibited camptothecin-induced morphol ogy, but not okadaic acid-induced morphology. In in vitro experiments recom binant PAI-2 was not found to be a substrate for caspase I. The results sug gest that caspase I selective protease inhibition could antagonize paramete rs coupled to the execution phase of okadaic acid- and camptothecin-induced apoptosis, but not the commitment to cell death.