Abstract
The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for the inhibition of apoptosis in some, but not all, family members. We describe each of the family members with respect to their structural and functional similarities and differences and their respective roles in cancer. Finally, we also review the current state of IAPs as targets for anti-cancer therapeutics and discuss the current clinical state of IAP antagonists.
Highlights
The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation and from a lack of accompanying homeostatic cell death
The various inhibitor of apoptosis protein (IAP) have somewhat differing functions, they are linked by one unique domain: membership of the IAP family is ascribed if the gene/protein in question possesses a baculovirus IAP repeat (BIR) domain
Conclusions and future work As detailed above, the IAPs are at the nexus of cancer cell survival and, apoptosis
Summary
The IAPs are at the nexus of cancer cell survival and, apoptosis. Targeting TRAIL receptors with simultaneous IAP inhibition is toxic to cancer cells and leaves non-transformed cells untouched, a “holy grail” of anti-cancer therapy. Expanding on these observations are studies by Beug et al, who show that concomitant induction of an immune response when IAPs are inhibited can produce a profound tumor regression in animal models[289]. The notion of targeted activation of certain TNFRs in combination with IAP inhibition is a potential potent intervention point in many cancers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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