Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B.
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-kappaB) 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-kappaB 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-kappaB signaling and facilitating TNFalpha-triggered, caspase-8-mediated apoptosis in a certain cancer cell types. In other cancer cells that are resistant to TNFalpha 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 TNFalpha-resistant, NF-kappaB constitutively active cancers that account for the majority of patients who are refractory to current therapeutic approaches.
Dai
Yao
Y
Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan Medical School Ann Arbor, MI 48109, USA.
Lawrence
Theodore S
TS
Xu
Liang
L