Sumi Hiroyuki, Inazuka Masakazu, Hashimoto Kentaro, Ishikawa Tomoyasu, Yoshida Sei, Yabuki Masato
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Biochem Biophys Res Commun. 2016 Oct 14;479(2):179-185. doi: 10.1016/j.bbrc.2016.09.019. Epub 2016 Sep 5.
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.
凋亡抑制蛋白（IAPs）是一类抗凋亡调节因子，作为癌症治疗的潜在靶点受到关注。尽管最近的研究表明，小分子IAP拮抗剂以自分泌肿瘤坏死因子（TNF）α依赖的方式诱导肿瘤选择性细胞死亡，但IAP拮抗剂的单药疗效仅限于一小部分癌细胞。在本研究中，我们表明T-3256336的单药活性在体外仅限于少数癌细胞系，这些细胞系由相对高水平的TNFα mRNA表达所定义。然而，包括胰腺癌细胞（PANC-1）在内的其他一些癌细胞在与外源性TNFα共刺激时，对T-3256336变得极度敏感。在PANC-1小鼠异种移植模型中，单独给予T-3256336可增加包括TNFα在内的多种细胞因子水平，并导致肿瘤消退，而用抗体中和循环中的小鼠TNFα可减弱这种作用。这些结果提示IAP拮抗剂具有双重作用，即增加包括TNFα在内的全身细胞因子水平，以及使肿瘤对IAP拮抗剂诱导的死亡敏感。
