Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 479, Issue 2, Pages 179-185Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2016.09.019
Keywords
IAP antagonist; T-3256336; TNF alpha; cIAP
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Inhibitors of apoptosis proteins (IAPs) are a family of antiapoptotic regulators that have attracted attention as potential targets for cancer therapeutics. Although recent studies have revealed that small molecule IAP antagonists induce tumor selective cell death in an autocrine tumor necrosis factor (TNF)alpha-dependent manner, the single-agent efficacy of IAP antagonists is restricted to a small subset of cancer cells. In this study, we showed that the single-agent activity of T-3256336 was limited to a few cancer cell lines in vitro, and these cell lines were defined by relatively high levels of TNF alpha mRNA expression. However, some other cancer cells, including PANC-1 cells, become drastically sensitive to T-3256336 when costimulated with exogenous TNF alpha. In PANC-1 mouse xenograft models, the administration of T-3256336 increased levels of several cytokines including TNF alpha and lead to tumor regression as a single agent, which was attenuated by the neutralization of circulating mouse TNF alpha with an antibody. These results suggest dual roles of IAP antagonists, increase systemic cytokines including TNF alpha, and sensitization of tumors to IAP antagonist-induced death. (C) 2016 Elsevier Inc. All rights reserved.
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