C0818, a novel curcumin derivative, induces ROS-dependent cytotoxicity in human hepatocellular carcinoma cells in vitro via disruption of Hsp90 function  

作　　者：Ahmed Attia Ahmed Abdelmoaty Ping Zhang Wen Lin Ying-juan Fan Sheng-nan Ye Jian-hua Xu 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Fujian Provincial Key Laboratory of Natural Medicine Pharmacology,Fujian Medical University,Fuzhou 350122,China [2]The First Affiliated Hospital of Fujian Medical University,Fuzhou 350004,China

出　　处：《Acta Pharmacologica Sinica》2022年第2期446-456,共11页中国药理学报（英文版）

基　　金：This work was funded by the National Natural Science Foundation of China(81973364);the Joint Funds for the Innovation of Science and Technology,Fujian province,China(2019Y9131);the external cooperation project of Fujian Provincial Department of Science and Technology(2020I0016);the National Science and Technology Foundation of China for Key Projects of“Major New Drugs Innovation and Development”(2012ZX09103-101-028).

摘　　要：Heat shock protein 90(Hsp90)is the most common molecular chaperone that controls the maturation of many oncoproteins critical in tumor development.Hsp90 has been considered as a promising target for cancer treatment,but the clinical significance of Hsp90 and the mechanisms of Hsp90 regulating the tumor-promoting effects in hepatocellular carcinoma(HCC)remain obscure.Previous studies have shown that curcumin,a polyphenol derived from the plant turmeric(Curcuma longa),inhibits tumor growth,which may provide an effective alternative therapy for HCC.Compared to curcumin,a novel derivative of curcumin,3,5-(E)-Bis(3-methoxy-4-hydroxybenzal)-4-piperidinone hydrochloride(C0818)that is more potent in Hsp90 inhibition and antitumor activity.In this study,we investigated the effect of C0818 on HCC cells in vitro and its relation to Hsp90 inhibition.We showed that C0818 concentration-dependently inhibited the proliferation,the colony formation and induced apoptosis in HepG2 and Sk-Hep-1 cells.C0818 concentration-dependently inhibited DNA synthesis and induced G2/M phase arrest in HepG2 and Sk-Hep-1 cells.We further demonstrated that C0818 induced ROS-and caspase-dependent apoptosis in HCC cells through the mitochondrial-mediated pathway.C0818 induced the degradation of Hsp90 client proteins as RAS,C-Raf,P-C-Raf,Erk,P-ERK,MEK,P-MEK,Akt and P-Akt,which led to subsequent inhibition of the RAS/RAF/MEK/ERK and PI3K/AKT pathways.We revealed that C0818 could inhibit the binding of Hsp90 with its clients without affecting their transcription,which subsequently induced the degradation of Hsp90 clients by the proteasome rather than the lysosome.These results are of potential importance for elucidating a novel Hsp90 inhibitor targeting HCC.

关 键 词：hepatocellular carcinoma curcumin C0818 Hsp90 inhibitor ROS apoptosis 

分 类 号：R73[医药卫生—肿瘤]