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Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B
Dai, Yao Lawrence, Theodore S. Xu, Liang
Dai, Yao
Lawrence, Theodore S.
Xu, Liang
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Abstract
Chemo- or radioresistance markedly impairs the efficacy of cancer therapy and involves anti-apoptotic
signal transduction pathways that prevent cell death. In resistant cancer cells, both inhibitors of apoptosis
proteins (IAPs) and nuclear factor-kappa B (NF-κB) play a pivotal role in preventing apoptosis triggered by a
variety of stresses, facilitating them as potential targets in cancer treatment. Furthermore, mounting evidences
have established the crosstalks between IAPs (eg. XIAP, cIAP-1, cIAP-2) and proteins involved in NF-κB signaling
(eg. TRAF2, RIP1, TAB1). Second mitochondria-derived activator of caspases (Smac) is a mitochondrial protein
that released into cytoplasm upon apoptotic stimuli. As Smac functions as an endogenous IAP inhibitor, small
molecule Smac-mimetics are believed to neutralize IAPs function that results in liberating caspase activity and
promoting apoptosis. Moreover, recent studies show that Smac-mimetics may kill cancer cells in a different
manner, which involves inducing ubiquitination of cIAPs, regulating NF-κB signaling and facilitating TNFα-
triggered, caspase-8-mediated apoptosis in a certain cancer cell types. In other cancer cells that are resistant to
TNFα or chemo/radiotherapy, Smac-mimetic IAP-inhibitors can enhance ionizing radiation or tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, indicating the potential role of Smac-
mimetics in overcoming acquired therapy-resistance. Such findings provide important impetus for utilizing IAP-
inhibitors as novel adjuvant therapy for the TNFα–resistant, NF-κB constitutively active cancers that account for the
majority of patients who are refractory to current therapeutic approaches. (AJTR810001).
Description
This is the published version, also available here: http://www.ajtr.org/810001A.html.
Date
2008-10-25
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e-Century Publishing
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Keywords
Chemoresistance, inhibitors of apoptosis proteins, NF-kB, small molecule inhibitors
Citation
Dai, Yao., Lawrence, Theodore S., Xu, Liang. "Overcoming cancer therapy resistance by targeting inhibitors of
apoptosis proteins and nuclear factor-kappa B." (2008) Am J Transl Res 2009;1(1):1-15.