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Drug-induced Apoptosis Is Associated with Enhanced Fas (Apo-1/CD95) Ligand Expression but Occurs Independently of Fas (Apo-1/CD95) Signaling in Human T-Acute Lymphatic Leukemia Cells

Laboratory of Molecular Cytology, Department of Internal Medicine [A. V., A. E., M. K., R. G.], and Division of Molecular Pathophysiology, Institute of Experimental and General Pathology [B. L. H., S. G., R. K.], University of Innsbruck, A-6020 Innsbruck, Austria

Induction of apoptosis is considered to be the underlying mechanism that accounts for the efficiency of chemotherapeutic drugs. It has recently been proposed that induction of Fas ligand (FasL) expression with subsequent autocrine and/or paracrine induction of cell death through binding to the Fas (Apo-1/CD95) membrane accounts for chemotherapy-associated apoptosis. In the present study, we analyzed the significance of FasL expression in the mediation of drug-induced apoptosis in the T-acute lymphatic leukemia model CEM. In particular, we examined the potential of the tumor drugs fludarabine, doxorubicin, and cisplatin to induce FasL expression. We also raised the question of whether apoptosis induced by these drugs occurs through the Fas pathway and hence can be blocked by the cowpox virus protein CrmA, a specific inhibitor of this pathway. All tumor drugs examined led to an increase in FasL protein. However, overexpression of CrmA had no effect on drug-induced apoptosis. Moreover, neither incubation with inhibitory monoclonal antibodies against Fas that completely prevented Fas-induced apoptosis in these cells nor pretreatment with a monoclonal antibody to FasL affected drug-induced cell death. Our observations suggest a Fas/FasL-independent mechanism for drug-induced apoptosis and exclude the involvement of caspase 1 and caspase 8 in this process in T-acute lymphatic leukemia cells.

¹ Present address: Institute of Medical Chemistry and Biochemistry, Fritz-Pregl-Str. 3, University of Innsbruck, A-6020 Innsbruck, Austria.

² R. G. and R. K. were supported by Grant 6287 from the Austrian National Bank and by Grants F-204 and P8947Med from the Austrian Science Foundation and the Province of Tyrol, respectively.

³ To whom requests for reprints should be addressed, at Laboratory of Molecular Cytology, Department of Internal Medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Phone: 43-0512-504-3343; Fax: 43-0512-504-3343.

Received 5/ 8/97. Accepted 7/ 2/97.

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