Unveiling the cytotoxicity of a new gold(I)complex towards hepatocellular carcinoma by inhibiting TrxR activity  

作　　者：Yuan Wang Haokun Yuan Ruiqin Fang Ran Zhang Wei-jia Wang 

机构地区：[1]Fujian Provincial Key Laboratory of Translational Cancer Medicine,Clinical Oncology School of Fujian Medical University,Fujian Cancer Hospital,Fuzhou 350014,China [2]The School of Medicine,University of Electronic Science and Technology of China,Chengdu 610054,China [3]The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine,Sichuan Provincial People′s Hospital,School of Medicine,University of Electronic Science and Technology of China,Chengdu 610072,China [4]The School of Life Science,University of Electronic Science and Technology of China,Chengdu 610054,China [5]Faculty of Science and Engineering,University of Groningen,Groningen,9713 AV,the Netherlands [6]State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen 361104,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第10期1537-1548,共12页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(No.82072727);the Department of Science and Technology of Sichuan Province(Nos.2021ZYD0092 and 2022NSFSC0721).

摘　　要：Hepatocellular carcinoma(HCC),the predominant type of liver cancer,is an aggressive malignancy with limited therapeutic options.In this study,we assess a collection of newly designed gold(I)phosphine complexes.Remarkably,the compound GC002 exhibits the greatest toxicity to HCC cells and outperforms established medications,such as sorafenib and auranofin,in terms of antitumor efficacy.GC002 triggers irreversible necroptosis in HCC cells by increasing the intracellular accumulation of reactive oxygen species(ROS).Mechanistically,GC002 significantly suppresses the activity of thioredoxin reductase(TrxR),which plays a crucial role in regulating redox homeostasis and is often overexpressed in HCC by binding directly to the enzyme.Our in vivo xenograft study confirms that GC002 possesses remarkable antitumor activity against HCC without severe side effects.These findings not only highlight the novel mechanism of controlling necroptosis via TrxR and ROS but also identify GC002 as a promising candidate for the further development of antitumor agents targeting HCC.

关 键 词：gold complex hepatocellular carcinoma NECROPTOSIS thioredoxin reductase reactive oxygen species 

分 类 号：R735.7[医药卫生—肿瘤]