Kidney-Type Glutaminase Inhibitor Hexylselen Selectively Kills Cancer Cells via a Three-Pronged Mechanism.
Jennifer Jin Ruan, Yan Yu, Wei Hou, Zhao Chen, Jinzhang Fang, Jingjing Zhang, Muowei Ni, Di Li, Shiying Lu, Jingjing Rui, Rui Wu, Wei Zhang, Benfang Helen Ruan
Author Information
Jennifer Jin Ruan: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Yan Yu: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Wei Hou: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Zhao Chen: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Jinzhang Fang: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Jingjing Zhang: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Muowei Ni: Center for Cancer Research, Zhejiang Cancer Hospital, Hangzhou 310022, PR China.
Di Li: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Shiying Lu: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Jingjing Rui: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Rui Wu: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Wei Zhang: Department of Urology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
Benfang Helen Ruan: College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, IDD & CB, Zhejiang University of Technology, Hangzhou 310014, China.
Tumor metabolism has been deeply investigated for cancer therapeutics. Here, we demonstrate that glutamine deficiency alone could not completely inhibit cancer cell growth and that many potent kidney-type glutaminase (KGA) inhibitors did not show satisfying efficacy. The potent KGA allosteric inhibitor, CB-839, resulted in up to 80% growth inhibition of all tested cell lines, whereas Hexylselen (CPD-3B), a KGA/glutamate dehydrogenase (GDH) inhibitor, showed essentially no toxicity to normal cells up to a 10 μM concentration and could completely inhibit the growth of many aggressive cell lines. Further analyses showed that CPD-3B targets not only KGA and GDH but also thioredoxin reductase (TrxR) and amidotransferase (GatCAB), which results in corresponding regulation of Akt/Erk/caspase-9 signaling pathways. In an aggressive liver cancer xenograft model, CPD-3B significantly reduced tumor size, caused massive tumor tissue damage, and prolonged survival rate. These provide important information for furthering the drug design of an effective anticancer KGA allosteric inhibitor.
References
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[PMID: 22579620]
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[PMID: 24287781]
