Therapeutic activation of caspases in cancer: a question of selectivity.

Caspase activation is the hallmark of programmed cell death (apoptosis) and because apoptosis is a regulated cellular process, it offers several opportunities for therapeutic intervention. In addition to conventional therapeutic agents, which trigger apoptosis by activating cellular stress sensors, new therapeutic agents are being discovered that modulate the key regulators of apoptosis. Examples include inhibitors of anti-apoptotic Bcl-2 proteins, small molecule mimetics of the inhibitor Smac, which blocks caspase inhibition by inhibitor-of-apoptosis proteins, and synthetic ligands of death receptors. These agents promise to be useful clinically, either alone, by selectively inducing apoptosis in cancer cells, or by sensitizing resistant cancer cells to conventional cytotoxic agents.