The Glutaminase-1 Inhibitor 968 Enhances Dihydroartemisinin-Mediated Antitumor Efficacy in Hepatocellular Carcinoma Cells.
Reprogrammed metabolism and redox homeostasis are potential targets of cancer therapy. Our previous study demonstrated that the kidney form of glutaminase (GLS1) is highly expressed in hepatocellular carcinoma (HCC) cells and can be used as a target for effective anticancer therapy. Dihydroartemisinin (DHA) increases intracellular reactive oxygen species (ROS) levels leading to cytotoxicity in cancer cells. However, the heterogeneity of cancer cells often leads to differing responses to oxidative lesions. For instance, cancer cells with high ratio of GSH/GSSG, a critical ROS scavenger, are resistant to ROS-induced cytotoxicity. We postulate that a combinatorial strategy firstly disrupting redox homeostasis followed by DHA might yield a profound antitumor efficacy. In this study, when HCC cells were treated with a GLS1 inhibitor 968, the ROS elimination capacity was significantly reduced in HCC cells, which rendered HCC cells but not normal endothelial cells more sensitive to DHA-mediated cytotoxicity. We further confirmed that this synergistic antitumor efficacy was mediated by excessive ROS generation in HCC cells. NAC, a ROS inhibitor, partly rescued the combinatorial cytotoxic effect of 968 and DHA. Given that GLS1 is a potential antitumor target and DHA has been safely used in clinic, our findings provide new insight into liver cancer therapy targeting glutamine metabolism combined with the ROS generator DHA, which can be readily translated into cancer clinical trials.
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.
Diancheng
D
Wang
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.
Gang
G
Meng
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.
Meihong
M
Zheng
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.
Yonghui
Y
Zhang
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.
Aiping
A
Chen
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.
Junhua
J
Wu
Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, 210093, China.|Nanjing University Hightech Institute at Suzhou, Suzhou, 215123, China.
Jiwu
J
Wei
D000111:Acetylcysteine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004338:Drug Combinations; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009928:Organ Specificity; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D037621:Artemisinins; D053119:Benzophenanthridines; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C000598981:compound 968; C039060:artenimol; C579480:GLS protein, human; D005972:Glutaminase; D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine