自分泌信号
肿瘤坏死因子α
细胞凋亡
癌症研究
程序性细胞死亡
药理学
癌细胞
癌症
免疫学
夏普
生物
医学
受体
内科学
半胱氨酸蛋白酶
生物化学
作者
Hiroyuki Sumi,Masakazu Inazuka,Kentaro Hashimoto,Tomoyasu Ishikawa,Sei Yoshida,Masato Yabuki
标识
DOI:10.1016/j.bbrc.2016.09.019
摘要
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.
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