CROSS-RESISTANCE OF CD95-INDUCED AND DRUG-INDUCED APOPTOSIS AS A CONSEQUENCE OF DEFICIENT ACTIVATION OF CASPASES (ICE CED-3 PROTEASES)/

The cytotoxic effect of anticancer drugs has been shown to involve ind uction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-ind uced by anticancer drugs. Apoptosis induced in tumor cells by cytarabi ne, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system, After drug treatm ent, a strong increase of caspase activity was found that preceded cel l death, Drug-induced activation of caspases was also found in ex vivo -derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin, T he peptide inhibitor was effective even if added several hours after d rug treatment, indicating a direct involvement of caspases in the exec ution and not in the trigger phase of drug action. Drug-induced apopto sis was also strongly inhibited by antisense approaches targeting casp ase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspa ses upon CD95 triggering were cross-resistant to drug-mediated apoptos is, Our data strongly support the concept that sensitivity for drug-in duced cell death depends on intact apoptosis pathways leading to activ ation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor ce lls. (C) 1997 by The American Society of Hematology.