Biomedicine & Pharmacotherapy (May 2020)
A novel multitarget kinase inhibitor BZG with potent anticancer activity in vitro and vivo enhances efficacy of sorafenib through PI3K pathways in hepatocellular carcinoma cells
Abstract
Objectives: BZG 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. Methods: We 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. Results: BZG 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. Conclusions: BZG 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.
