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Targeting IAP proteins for therapeutic intervention in cancer
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Journal Article
Targeting IAP proteins for therapeutic intervention in cancer
2012
Overview
Key Points
Inhibitor of apoptosis (IAP) proteins are a family of anti-apoptotic proteins that promote cancer cell survival and inhibit cell death.
IAP proteins represent promising targets for therapeutic intervention in human cancers, as they are expressed at high levels in various malignancies and have been linked to tumour progression, treatment failure and poor prognosis.
Several therapeutic strategies have been designed in recent years to target IAP proteins, including second mitochondria-derived activator of caspase (SMAC)-mimicking IAP antagonists.
Preclinical studies indicate that the therapeutic potential of IAP antagonists might best be exploited in combination protocols, including conventional chemotherapeutics, death receptor agonists, signal transduction modulators or radiation therapy.
IAP antagonists have already entered the clinical stage and are currently being evaluated in early-stage clinical trials.
Inhibitor of apoptosis (IAP) antagonists have recently entered the stage of clinical evaluation for many different types of cancer. Here, Fulda and Vucic review the different approaches that have been used to target IAP proteins, and discuss their translation into therapeutic anticancer strategies.
Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases — pro-apoptotic executioner proteases — whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of
IAP
genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 67
/ Animals
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Biomedical and Life Sciences
/ Humans
/ Inhibitor of Apoptosis Proteins - antagonists & inhibitors
/ Inhibitor of Apoptosis Proteins - drug effects
/ Inhibitor of Apoptosis Proteins - physiology
/ Oligodeoxyribonucleotides, Antisense - pharmacology
/ Oligodeoxyribonucleotides, Antisense - therapeutic use
/ Signal Transduction - drug effects
/ Signal Transduction - physiology
