An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells

被引：11

作者：

Xie, Yanqiu ^{[1
,2
]}

Fan, Shijie ^{[2
,3
]}

Ni, Dongxuan ^{[4
,5
,6
]}

Wan, Wei ^{[2
]}

Xu, Pan ^{[2
]}

Ding, Yiluan ^{[2
]}

Zhang, Ruihan ^{[4
,5
]}

Lu, Jing ^{[1
]}

Zhang, Naixia ^{[2
]}

Zhang, Yuanyuan ^{[2
]}

Xiao, Weilie ^{[4
,5
,6
]}

Zhao, Kehao ^{[1
]}

Luo, Cheng ^{[2
,3
,7
,8
]}

机构：

[1] Yantai Univ, Collaborat Innovat Ctr Adv Drug Delivery Syst & Bi, Minist Educ, Sch Pharm,Key Lab Mol Pharmacol & Drug Evaluat, Yantai 264005, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

[3] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

[4] Yunnan Univ, Key Lab Med Chem Nat Resource, Minist Educ, Yunnan Characterist Plant Extract Lab,Yunnan Res &, Kunming 650500, Peoples R China

[5] Yunnan Univ, Sch Med, Kunming 650500, Peoples R China

[6] Yunnan Univ, State Key Lab Conservat & Utilizat Bioresources Yu, Kunming 650091, Peoples R China

[7] Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan 528437, Peoples R China

[8] Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2023年 / 84卷

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

ATG4B inhibitor; DC-ATG4in; Sorafenib; Hepatocellular Carcinoma; Combination therapy; CANCER; MECHANISM; DISEASE; TARGET; ENZYME;

D O I：

10.1016/j.bmc.2023.117262

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Autophagy related 4B (ATG4B) which regulates autophagy by promoting the formation of autophagosome through reversible modification of LC3, is closely related to cancer cell growth and drug resistance, and therefore is an attractive therapeutic target. Recently, ATG4B inhibitors have been reported, yet with drawbacks including weak potency. To discover more promising ATG4B inhibitors, we developed a high-throughput screening (HTS) assay and identified a new ATG4B inhibitor named DC-ATG4in. DC-ATG4in directly binds to ATG4B and inhibits its enzyme activity with an IC50 of 3.08 +/- 0.47 mu M. We further confirmed that DC-ATG4in is an autophagy inhibitor and blocks autophagy induced by Sorafenib in Hepatocellular Carcinoma (HCC) cells. More impor-tantly, combination of DC-ATG4in with Sorafenib synergized the cancer cell killing effect and proliferation in-hibition activities on HCC cells. Our data suggested that inactivation of autophagy via ATG4B inhibition may be a viable strategy to sensitize existing targeted therapy such as Sorafenib in the future.

引用

页数：11

共 55 条

[1] Sorafenib-based combination as a first line treatment for advanced hepatocellular carcinoma: A systematic review of the literature [J].