Inhibitor of apoptosis proteins as targets for anticancer therapy

Abstract

Cell death by apoptosis plays a critical role in regulating the subtle balance between cell death and proliferation to maintain tissue homeostasis. Accordingly, tipping the balance in either direction may cause human disease. Too little cell death may promote tumor formation and progression. In addition, killing of cancer cells by current therapies is largely due to induction of apoptosis in tumor cells. Since a hallmark of human cancers is their resistance to apoptosis, there is a demand to develop novel strategies that restore the apoptotic machinery in order to overcome cancer resistance. Inhibitor of apoptosis proteins (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases. Elevated levels of IAPs are found in many human cancers and have been associated with poor prognosis. Recent insights into the role of IAPs have provided the basis for various exciting developments that aim to modulate the expression or function of IAPs in human cancers. Targeting IAPs (e.g., by antisense approaches or small-molecule inhibitors) presents a promising novel approach to either directly trigger apoptosis or to potentiate the efficacy of cytotoxic therapies in cancer cells. Thus, inhibition of IAPs such as X chromosome-linked IAP may prove to be a successful strategy to overcome apoptosis resistance of human cancers that deserves further exploitation.

Keywords::

• apoptosis
• cancer
• caspase
• IAP
• Smac

Financial disclosure

Work in the author’s laboratory is supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Forschung und Technologie, Landesstiftung Baden-Württemberg, Wilhelm-Sander-Stiftung and Else-Kröner-Fresenius Stiftung, and the European Community.