一种新型的多靶点激酶抑制剂 BZG，在体外和体内具有强大的抗癌活性，通过 PI3K 通路增强肝癌细胞中索拉非尼的疗效。

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.

机构信息

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.

出版信息

Biomed Pharmacother. 2020 May;125:110033. doi: 10.1016/j.biopha.2020.110033. Epub 2020 Feb 25.

DOI:10.1016/j.biopha.2020.110033

PMID:32187962

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.

摘要

目的

BZG 作为一种新型多靶点激酶抑制剂，先前已被证实可抑制肝癌（HCC）的增殖。在本研究中，我们旨在研究 BZG 联合或不联合索拉非尼的潜在作用机制，并评估其抗肿瘤作用，以及 BZG 是否可以抑制与索拉非尼获得性耐药相关的磷酸肌醇 3-激酶（PI3K）/AKT 信号的激活。

方法

我们通过 CCK-8 检测法和集落形成实验评估 HCC 细胞的增殖。通过 Hoechst 33342 染色检测和流式细胞术评估细胞凋亡。Western blot 用于检测 PI3K 通路中的关键酶以及 BZG 单独和联合索拉非尼处理后 p-ERK 的表达。使用 Huh-7 肝癌异种移植模型在体内评估 BZG 单独和联合的抗癌作用。HE 染色和 TUNEL 检测评估肿瘤组织坏死和肿瘤细胞凋亡。

结果

BZG 可呈剂量依赖性抑制 HCC 细胞的增殖。BZG 与索拉非尼联合使用产生协同作用。PI3K 和 p-ERK 通路参与了 BZG 单独和联合使用的抗肿瘤作用。此外，联合治疗更有效地抑制了 p-AKT、p-ERK 和 p-mTOR 的表达。此外，还观察到 Huh-7 肝癌异种移植模型中的肿瘤坏死和细胞凋亡。