• Li Wang, Yaqiong Zhan, Zhe Wu, Mengjia Lin, Xuehang Jin, Lushun Jiang, and Yunqing Qiu.
• State Key Laboratory for Diagnosis and Treatment of Infectious Disease, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang, 310000, PR China.
• Biomed. Pharmacother. 2020 May 1; 125: 110033.

ObjectivesBZG as a novel multitarget kinase inhibitor, has been proved to inhibit the proliferation of hepatocellular carcinoma (HCC) previously. In this study, we aimed at investigating the underlying mechanisms of BZG with and without sorafenib and evaluating their anti-tumor effects as well as whether BZG could inhibit the activation of phosphoinositide 3-kinase (PI3K)/AKT signaling which is associated with acquired resistance to sorafenib.MethodsWe evaluated the proliferation of HCC cells by CCK-8 assay and colony formation assay. Cell apoptosis was assessed by Hoechst 33342 staining assay and flow cytometry. Western blot was used to detect the critical enzymes in the PI3K pathways and the expression of p-ERK after BZG alone and combined with sorafenib treatments. Huh-7 hepatocellular carcinoma xenograft model was used to evaluate the anti-carcinoma effects of BZG alone and in combination in vivo. HE staining and TUNEL assay tested the necrosis of tumor tissue and apoptosis of tumor cells.ResultsBZG could inhibit the proliferation of HCC cells in a dose-dependent manner. The combination of BZG and sorafenib produced synergistic effects. PI3K and p-ERK pathway were involved in the anti-tumor functions of BZG alone and when combined with sorafenib. In addition, the combination treatment was seen to be more effective in inhibiting the expression of p-AKT, p-ERK and p-mTOR. Furthermore, Tumor necrosis and cell apoptosis were also observed in Huh-7 hepatocellular carcinoma xenograft models.ConclusionsBZG is an attractive agent for treating HCC. The effects of BZG and sorafenib's co-treatment on HCC are more effective than BZG or sorafenib alone.Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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