Review Article Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B
Yao Dai, Theodore S. Lawrence, Liang Xu
Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109
Received October 10, accepted October 20 and available online October 25, 2008
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).
Key Words: Chemoresistance, inhibitors of apoptosis proteins, NF-kB, small molecule inhibitors
Address all correspondence to: Liang Xu, M.D., Ph.D. Department of Radiation Oncology Division of Cancer Biology University of Michigan 4424E Med Sci I 1301 Catherine St. Ann Arbor, MI 48109-5637 Tel: 734-615-7017 Fax: 734-615-3422 E-mail: email@example.com