Apoptosis has been accepted as a fundamental component in the pathogenesis of cancer, in addition to other human diseases including neurodegeneration, coronary disease and diabetes. The origin of cancer involves deregulated cellular proliferation and the suppression of apoptotic processes, ultimately leading to tumor establishment and growth. Several lines of evidence point toward the IAP family of proteins playing a role in oncogenesis, via their effective suppression of apoptosis. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of, and by, the transcription factor NF-kappaB. Thus, when the IAPs are over-expressed or over-active, as is the case in many cancers, cells are no longer able to die in a physiologically programmed fashion and become increasingly resistant to standard chemo- and radiation therapies. To date several approaches have been taken to target and eliminate IAP function in an attempt to re-establish sensitivity, reduce toxicity, and improve efficacy of cancer treatment. In this review, we address IAP proteins as therapeutic targets for the treatment of cancer and emphasize the importance of novel therapeutic approaches for cancer therapy. Novel targets of IAP function are being identified and include gene therapy strategies and small molecule inhibitors that are based on endogenous IAP antagonists. As well, molecular mechanistic approaches, such as RNAi to deplete IAP expression, are in development.

Cytotoxic lymphocytes employ Granzyme B as a potent initiator of apoptosis to cleave and activate effector caspases. Unexpectedly, cells transfected with Bcl-2 were resistant to granzyme B-induced killing, suggesting that a mitochondrial pathway was critical. Utilizing cells expressing a dominant-negative caspase 9, the current study demonstrated that caspase activation via the apoptosome was not required. Indeed, cleavage of caspase 3 to p20 still occurred in Bcl-2-transfectants but processing to p17 was blocked. This blockade was recapitulated by the Inhibitor-of-Apoptosis-Protein XIAP and relieved by Smac/DIABLO. Thus granzyme B mediates direct cleavage of caspase 3 and also activates mitochondrial disruption, resulting in the release of proapoptotic proteins that suppress caspase inhibition. Engagement of both pathways is critical for granzyme-induced killing.

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