The inhibitors of apoptosis (IAPs) as cancer targets.
Apoptosis has been accepted as a fundamental component in the pathogenesis of cancer, in addition to other human diseases including neurodegeneration, coronary disease and diabetes. The origin of cancer involves deregulated cellular proliferation and the suppression of apoptotic processes, ultimately leading to tumor establishment and growth. Several lines of evidence point toward the IAP family of proteins playing a role in oncogenesis, via their effective suppression of apoptosis. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of, and by, the transcription factor NF-kappaB. Thus, when the IAPs are over-expressed or over-active, as is the case in many cancers, cells are no longer able to die in a physiologically programmed fashion and become increasingly resistant to standard chemo- and radiation therapies. To date several approaches have been taken to target and eliminate IAP function in an attempt to re-establish sensitivity, reduce toxicity, and improve efficacy of cancer treatment. In this review, we address IAP proteins as therapeutic targets for the treatment of cancer and emphasize the importance of novel therapeutic approaches for cancer therapy. Novel targets of IAP function are being identified and include gene therapy strategies and small molecule inhibitors that are based on endogenous IAP antagonists. As well, molecular mechanistic approaches, such as RNAi to deplete IAP expression, are in development.
Hunter
Allison M
AM
Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
LaCasse
Eric C
EC
Korneluk
Robert G
RG
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D000071877:Checkpoint Kinase 1; D004789:Enzyme Activation; D005822:Genetic Vectors; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology / Q000627:therapeutic use; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors; D024101:Mitochondrial Proteins / Q000502:physiology / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D010454:Peptide Termination Factors / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D012697:Serine Endopeptidases / Q000502:physiology; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D010454:Peptide Termination Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C417551:XAF1 protein, human; C087971:peptide-chain-release factor 3; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases