Apoptosis mechanisms: implications for cancer drug discovery

Defects in the regulation of apoptosis (programmed cell death) make important contributions to the pathogenesis and progression of most cancers and leukemias. Apoptosis defects also figure prominently in resistance to chemotherapy, radiotherapy, hormonal therapy, and immune-based treatments. Apoptosis is caused by activation of intracellular proteases, known as caspases, that are responsible directly or indirectly for the morphologic and biochemical events that characterize the apoptotic cell. Numerous proteins that regulate these cell death proteases have been discovered, including proteins belonging to the Bcl-2, inhibitor of apoptosis, caspase-associated recruitment domain, death domain, and death effector domain families. These caspase-regulating proteins provide mechanisms for linking environmental stimuli to cell death responses or to maintenance of cell survival. Alterations in the expression and function of several apoptosis-regulating genes have been demonstrated in cancer, suggesting targets for drug discovery. Knowledge of the molecular details of apoptosis regulation and the three-dimensional structures of apoptosis proteins has revealed new strategies for identifying small-molecule drugs that may yield more effective treatments for malignancies. Apoptosis-regulating genes are also beginning to find utility as targets for antisense oligonucleotides.