Apoptosis in Cancer. Mechanisms, Deregulation, and Therapeutic Targeting.

Effective clinical management of cancer requires that tumor cells die following therapeutic intervention. Of the several possible modes of cell death in cancer therapy, apoptosis is by far the most important, with wild-type p53 playing a central role in regulating this cell death program. Apoptosis can also occur in mutant p53 cancers, albeit less efficiently, but irrespective of p53 status, this mode of cell death is often deregulated in many cancers and results in a general failure of the therapeutic modality. Apoptosis can occur through the intrinsic and/or extrinsic mitochondrial pathways, depending on the cell death signal, and both pathways can be impacted by various mechanisms to induce therapeutic resistance. Therefore, much effort has been devoted to targeting the apoptotic program in refractory cancers and restoring tumor cell sensitivity. Several options are available or are under development to activate apoptosis by modulating intrinsic and/or extrinsic pathways in a p53-dependent or p53-independent manner, and these include gene therapy, small-molecule inhibitors and activators, peptide mimetics, therapeutic antibodies, and cytotoxic drugs, with some demonstrating a potential for wide-spectrum activity. The broader success, however, will depend on the rational selection of the agent or approach that best complements the specific defect in the apoptotic pathway.