Chemotherapy primes malignant glioma cells for CD95 ligand-induced apoptosis up-stream of caspase 3 activation.

The cytotoxic cytokine, CD95 ligand, is an experimental anti-cancer agent. Here, we describe a novel pathway of drug-mediated augmentation of CD95 ligand-induced apoptosis. We report that prolonged pre-exposure of human malignant glioma cells to different cytotoxic agents, VM26, cytarabine and cisplatin, induces strong sensitization to CD95 ligand-induced apoptosis. CD95 gene transfer does not prevent sensitization, suggesting that sensitization is not mediated by drug-induced CD95 expression. Priming with cytotoxic drugs greatly increases CD95 ligand-induced caspase 3 activity, indicating that the cytotoxic drugs positively modulate the CD95-dependent signalling cascade up-stream of caspase 3 activation.