c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.

中文翻译：

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Dynasore通过使c-Met不稳定来增强针对肝细胞癌的c-Met抑制剂。

c-Met受体通常在肝细胞癌中过表达，因此被认为是小分子酪氨酸激酶抑制剂进行药物干预的诱人靶标。尽管已开发出多种c-Met抑制剂，但至今尚无一种在肝癌治疗中得到临床应用。为了提高c-Met抑制剂对肝细胞癌的疗效，我们研究了dynamin抑制剂dynasore与几种c-Met抑制剂（包括tivantinib，PHA-665752和JNJ-38877605）的联合作用。我们提供了几条证据，表明dynasore增强了这些抑制剂对肝癌细胞增殖和迁移的抑制作用，并伴随着细胞周期停滞和凋亡的增加。机械上，AKT和MEK磷酸化的急剧下降表明，组合治疗降低了c-Met水平，因此显着破坏了下游信号传导。综上所述，我们的发现表明候选药物代纳洛尔增强了c-Met抑制剂对肝癌细胞的抑制作用，并将为靶向c-Met的新型治疗策略在肝细胞癌患者的临床管理中的发展提供启示。