IAPs as a target for anticancer therapy

The avoidance of apoptosis is one of the hallmarks of cancer cells. In addition, failure to induce apoptosis by anticancer agents, either due to limitations of the drug or the tumour cell evading apoptosis, is a reason for chemotherapeutic failure. Two general pathways for apoptotic cell death have been characterised, the extrinsic and intrinsic pathways which merge in the final common pathway. X-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein in the final common pathway that inhibits caspases and suppresses apoptosis. XIAP is over-expressed in many cancer cell lines and cancer tissues. High XIAP expression has been correlated with resistance to chemotherapy and radiotherapy and to poor clinical outcome by some investigators. Manipulation of apoptosis is an attractive therapeutic concept. Much effort has been spent on inhibiting the anti-apoptotic protein, B cell lymphoma gene 2 (Bcl-2) which is part of the intrinsic pathway. Now attention is turning to inhibition of XIAP as a cancer drug target. It has been argued that it is more effective to block the final common pathway rather than just the intrinsic arm. Inhibition of XIAP can be with either antisense oligonucleotides (ASO) or small molecule inhibitors. In vitro, XIAP antagonists produce XIAP knockdown and apoptosis which is associated with sensitisation of tumour cells to radiotherapy and cytotoxic drugs. In vivo, XIAP antagonists have antitumour effects and sensitise tumours to the effects of chemotherapy. This review will summarise the preclinical data for both ASO and small molecule inhibition of XIAP and discuss emerging Phase I data. Future strategies for manipulation of XIAP and the clinical development of XIAP inhibitors will be discussed.