The role of caspase-8 in resistance to cancer chemotherapy.

Toxicity of chemotherapeutic agents against cancer cells is mediated through the initiation of programmed cell death. Apoptosis is an evolutionarily conserved cascade of intracellular proteolytic events propagated by a family of cysteine proteases called caspases. Many receptor- and non-receptor-mediated death signals induce apoptosis via activation of caspase-8 (FLICE/MACH). Mechanisms of tumor resistance to cytotoxic drugs through decreased apoptosis may occur by altered expression of caspase-8, upregulation of caspase-8 inhibitors like FLIP (FLICE-like Inhibitory Protein), or sequestration of caspase-8 by Bcl-2. Modulation of caspase-8 and apoptosis may be a therapeutic strategy for sensitization of drug-resistant malignancies to radiation or combination chemotherapy.