Targeting Inhibitors of Apoptosis Proteins (IAPs) For New Breast Cancer Therapeutics (original) (raw)

2012, Journal of Mammary Gland Biology and Neoplasia

Apoptosis resistance is a hallmark of human cancer. Research in the last two decades has identified key regulators of apoptosis, including inhibitor of apoptosis proteins (IAPs). These critical apoptosis regulators have been targeted for the development of new cancer therapeutics. In this article, we will discuss three members of IAP proteins, namely XIAP, cIAP1 and cIAP2, as cancer therapeutic targets and the progress made in developing new cancer therapeutic agents to target these IAP proteins. Apoptosis and human cancer Apoptosis, or programmed cell-death, is a fundamental cellular process to remove damaged or unwanted cells in multiple cellular organisms. Improper regulation of apoptosis is therefore linked in many human diseases, including cancer, autoimmune diseases, inflammation and neurological diseases. 1-3 In fact, defective regulation of apoptosis is a hallmark of human cancer. 4 Basic apoptosis pathways Apoptosis is a tightly regulated process. Several major apoptosis pathways have been identified and characterized in the last two decades, although these pathways often have extensive cross-talks. The intrinsic and extrinsic apoptosis pathways are two of the best studied (Figure 1). 5 The intrinsic, or mitochondria, apoptotic pathway integrates a variety of cell stress signals and is initiated by permeabilization of the outer membrane of mitochondria and loss of mitochondrial potential. On the molecular level, the intrinsic pathway involves the translocation and oligomerization of Bax or Bak, members of the Bcl-2 family proteins, which forms a pore in the outer member of mitochondria and leads to the release of proapoptotic molecules such as cytochrome C. Upon its release from mitochondria into cytosol, cytochrome C, together with dATP, Apaf-1 and procaspase-9, forms the apoptosome, which processes the procaspase-9 zymogen into the active form of caspase-9. Caspase-9 then cleaves and activates caspase-3,-6 and-7, which leads to further processing of downstream cell-death substrates, and ultimately apoptosis. The extrinsic, or death-receptor, apoptotic pathway, is initiated by the binding of death ligands such as Fas/Apo-1, TNF-alpha, Apo2L/TRAIL, and Apo3L ligands to their cognate cell-surface receptors, FasR, TNFR1, DR4/DR5 and DR3, respectively. The binding of these Phone: