Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met.

Abstract

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.

• Authors: Mohamed Y Zaky, Xiuxiu Liu, Taishu Wang, Shanshan Wang, Fang Liu, Duchuang Wang, Yueguang Wu, Yang Zhang, Dong Guo, Qianhui Sun, Qiong Li, Jinrui Zhang, Yingqiu Zhang, Weijie Dong, Zhenhua Liu, Shuyan Liu, Han Liu
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 680 Pg. 108239 (02 15 2020) ISSN: 1096-0384 [Electronic] United States
• PMID: 31881189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Hydrazones
• N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-met

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Line
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Hep G2 Cells
• Humans
• Hydrazones (pharmacology)
• Liver Neoplasms (drug therapy, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)