T-3256336, a novel and orally available small molecule IAP antagonist, induced tumor cell death via induction of systemic TNF alpha production

• Published in: Biochemical and biophysical research communications Vol. 479; no. 2; pp. 179 - 185
• Main Authors: Sumi, Hiroyuki, Inazuka, Masakazu, Hashimoto, Kentaro, Ishikawa, Tomoyasu, Yoshida, Sei, Yabuki, Masato
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.10.2016
• Subjects: Administration, Oral; Animals; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; cIAP; Cytokines - blood; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic - drug effects; HL-60 Cells; Humans; IAP antagonist; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - metabolism; MCF-7 Cells; Mice; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Pyrazines - administration & dosage; Pyrazines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; T-3256336; TNFα; Tumor Burden - drug effects; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - pharmacology; Xenograft Model Antitumor Assays; T-3256336; NF-κB; TNFα; TRAIL; IAP antagonist; IAP; XIAP; SMAC; cIAP
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.09.019

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)α-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 TNFα mRNA expression. However, some other cancer cells, including PANC-1 cells, become drastically sensitive to T-3256336 when costimulated with exogenous TNFα. In PANC-1 mouse xenograft models, the administration of T-3256336 increased levels of several cytokines including TNFα and lead to tumor regression as a single agent, which was attenuated by the neutralization of circulating mouse TNFα with an antibody. These results suggest dual roles of IAP antagonists, increase systemic cytokines including TNFα, and sensitization of tumors to IAP antagonist-induced death. •The baseline TNFα expression correlates with the sensitivity to T-3256336.•T-3256336 drastically increases plasma TNFα and other cytokines in mice.•TNFα neutralizing antibody attenuates the antitumor efficacy of T-3256336.•An efficacy of IAP antagonist in vivo depends on the systemic TNFα production.