Dong Gaopan, Ye Xiaohan, Wang Shumei, Li Wenhua, Cai Rong, Du Lupei, Shi Xiaodong, Li Minyong
Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China.
Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Chemistry, University of South Florida, Tampa, FL 33647, USA.
Pharmacol Res. 2022 Mar;177:106113. doi: 10.1016/j.phrs.2022.106113. Epub 2022 Feb 3.
A novel TrxR inhibitor Au-24 and its inhibitory ability to hepatocellular carcinoma in vitro and in vivo is reported herein. Au-24 can suppress HepG2 cells from proliferating by lowering mitochondrial membrane potential (MMP) and increasing reactive oxygen species (ROS) levels, resulting in oxidative stress, which causes DNA damage, autophagy, cell cycle arrest, and apoptosis. This compound can also affect the normal function of apoptosis, MAPK, PI3K/AKT/mTOR, NF-κB, STAT3 signaling pathways. In vivo experiments revealed that Au-24 inhibited HepG2 tumor growth more effectively than AA1 (chloro(triethylphosphine)gold(I)) by decreasing Ki67 and CD31 protein expression and promoting tumor cell apoptosis and necrosis lesions. As a result, Au-24 was found to be a promising candidate as a TrxR inhibitor for the treatment of hepatocellular carcinoma (HCC) in both in vivo and in vitro experiments.
本文报道了一种新型硫氧还蛋白还原酶（TrxR）抑制剂Au-24及其在体外和体内对肝细胞癌的抑制能力。Au-24可通过降低线粒体膜电位（MMP）和提高活性氧（ROS）水平来抑制HepG2细胞增殖，从而导致氧化应激，进而引起DNA损伤、自噬、细胞周期停滞和细胞凋亡。该化合物还可影响凋亡、丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）、核因子κB（NF-κB）、信号转导和转录激活因子3（STAT3）信号通路的正常功能。体内实验表明，Au-24通过降低Ki67和CD31蛋白表达并促进肿瘤细胞凋亡和坏死性病变，比AA1（氯（三乙膦）金（I））更有效地抑制HepG2肿瘤生长。因此，在体内和体外实验中，Au-24被发现是一种有前景的作为TrxR抑制剂用于治疗肝细胞癌（HCC）的候选药物。
