Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells

被引：94
|
作者：
Zhang, Yingshi [1 ,2 ]
Li, Dandan [1 ,2 ]
Jiang, Qiyu [3 ]
Cao, Shuang [4 ]
Sun, Huiwei [3 ]
Chai, Yantao [3 ]
Li, Xiaojuan [3 ]
Ren, Tianshu
Yang, Ruichuang [3 ]
Feng, Fan [5 ]
Li, Bo-an [5 ]
Zhao, Qingchun [1 ,2 ]
机构：
[1] Gen Hosp Shenyang Mil Area Command, Dept Pharm, Shenyang 110840, Liaoning, Peoples R China
[2] Shenyang Pharmaceut Univ, Dept Clin Pharm, Shenyang 110016, Liaoning, Peoples R China
[3] 302nd Hosp Chinese PLA, Res Ctr Clin & Transit Med, Beijing 100039, Peoples R China
[4] Wuhan Inst Technol, Hubei Key Lab Novel Chem Reactor & Green Chem Tec, Wuhan 430073, Hubei, Peoples R China
[5] 302nd Hosp Chinese PLA, Ctr Clin Lab, Beijing 100039, Peoples R China
来源：
CELL DEATH & DISEASE | 2018年 / 9卷
关键词：
MOLECULAR KINASE INHIBITOR; PHASE-II TRIAL; RADIOFREQUENCY ABLATION; RADIATION-THERAPY; LUNG-CANCER; HEPATITIS-B; NOTCH; HCC; LIVER; PROLIFERATION;
D O I：
10.1038/s41419-018-0804-6
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of multi-drug resistance (MDR). In the present study, we demonstrated the discovery of a novel inhibitor for Notch activating/cleaving enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of NOTCH protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of HCC cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. ZLDI-8 treatment enhanced the effect of Sorafenib on inhibiting tumor growth in nude HCC-bearing mice model. These results suggest that ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib's anti-tumor effect and to overcome the MDR of HCC patients.
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页数：13
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