Inhibiting the inhibitors: Targeting anti-apoptotic proteins in cancer and therapy resistance.

The cytotoxic effect of anti-cancer drugs relies on their ability to induce programmed cell death known as apoptosis. Evading apoptosis is a common characteristic of cancer cells and it is linked to both carcinogenesis and anticancer drug resistance. To escape apoptosis, cancer cells often express high levels of anti-apoptotic proteins and become "addicted "to them for their survival. Consequently, anti-apoptotic proteins have emerged as attractive druggable targets for the development of cancer therapeutics. In this review we focus on two major anti-apoptotic protein families: IAPs (Inhibitor of Apoptosis) proteins and Bcl-2 (B-cell lymphoma-2) family members. We also discuss insights into the regulation of these proteins by natural antagonists, which has provided the conceptual basis for developing novel anti-cancer drugs. Significantly, the pro-apoptotic protein ARTS (apoptosis-related protein in the TGF-β signaling pathway; Sept4_i2) acts as a dual antagonist of both X-linked inhibitor of apoptosis protein (XIAP) and Bcl-2. Because upregulation of anti-apoptotic proteins in response to cancer therapy contributes to drug resistance, targeted inhibition of these proteins is expected to enhance the efficacy of chemotherapy. Finally, we discuss the role of proteasome-mediated degradation in the regulation of apoptosis, and how this mechanism can be harnessed to develop small molecules that stimulate degradation of anti-apoptotic proteins for cancer therapy. This strategy has the potential to overcome drug resistance more effectively than mere inhibition. Therefore, this approach may allow use of lower drug concentrations and thereby reduce cytotoxicity and untoward side effects.