Abstract
It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.
Highlights
Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne VIC 3010, Australia
Faye and colleagues identified the dependence of RhabdoMyoSarcoma (RMS) tumors on cIAP1 and observed that LCL161 treatment of mice with established Kym-1 RMS xenograft tumors led to tumor cell death and prolonged survival [90]
It has been proposed that because SMs are targeted drugs and affect Inhibitor of APoptosis (IAP) signaling pathways, they have less toxicity than chemotherapies which alter many pathways [164,165,166,167]. Another explanation might be that abnormal expression of IAPs and/or TNF by the tumor or stromal cells in its environment leads to addiction to NF-κB and/or TNFR1 signaling pathways
Summary
One of the hallmarks of cancer is failure to undergo genetically programmed cell death in response to signals that would normally promote a suicide response in untransformed cells. Failure to undergo cell death allows cancer cells to mutate, evolve and proliferate. Reactivating their ability to commit suicide is an appealing anti-cancer treatment strategy and has been explored in a variety of chemotherapeutic drug approaches. Necrosis, an unregulated form of cell death, leads to loss of cell homeostasis and membrane integrity, resulting in cell rupture [5,6] Another form of programmed cell death termed necroptosis, which shares features with necrosis such as cell rupture and release of cellular contents, has recently been explored as an anti-cancer therapeutic strategy [7,8]. The proteins that carry out the necroptotic program are the Receptor-Interacting serine/threonine-Protein Kinases (RIPK) 1 and 3 and the pseudokinase Mixed Lineage Kinase domain-Like protein (MLKL) [9]
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