Inhibitors of Apoptosis as Targets for Cancer Therapy

This chapter deals with inhibitors of apoptosis (IAP) and discusses the pros and cons of targeting these molecules in the development of novel anticancer agents. IAPs form a growing family of proteins that inhibit apoptosis induced by a wide variety of insults. Structure function analyses have revealed that all IAPs harbor varying numbers of baculoviral inhibitor of apoptosis repeat (BIR) domains. IAPs have also been implicated in the activation of anti-apoptotic nuclear factor κB (NF-κB). NF-κB is a transcription factor that is formed by the NF-κB/Rel protein family. Apollon is the largest human IAP discovered to date. It encodes a single BIR domain-containing protein of 530 κDa. Apollon is expressed at high levels in human gliomas. Survivin, the smallest IAP, is expressed at high levels in a wide variety of cancers compared with normal tissues and Survivin is expressed at high levels in fetal but not in adult tissues. The constitutive overexpression of Survivin in various cancer tissues fits the onco-fetal pattern of expression. The small peptides corresponding to the amino terminal end of Smac have been reported to relieve the XIAP-mediated inhibition of caspase 9. The utility of small peptides corresponding to the NH2 terminal region of Smac either alone or in combination with other chemotherapeutic drugs is predicated to be a novel therapeutic strategy, particularly in IAP overexpressing tumors.