A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
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Canrong Wu1, Mengzhu Zheng1, Suyu Gao2, Shanshan Luan1, Li Cheng1, Liqing Wang2, Jiachen Li1, Lixia Chen2 and Hua Li1,2
1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
2Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
Hua Li , email: [email protected]
Lixia Chen, email: [email protected]
Keywords: KGA inhibitor; withanolide; physapubescin K; synergistic effects; structure-based virtual ligand screening
Received: July 12, 2017 Accepted: November 14, 2017 Published: December 08, 2017
Kidney-type glutaminase (KGA), a mitochondrial enzyme converting glutamine to glutamate for energy supply, was over-expressed in many cancers and had been regarded as a promising therapeutic target in recent years. Structure-based virtual ligand screening predicted physapubescin K, a new withanolide from Physalis pubescens, to be potential KGA inhibitor. Enzyme activity inhibition assays and microscale thermophoresis experiments had demonstrated the efficiency and specificity of physapubescin K targeting KGA. Additionally, physapubescin K exhibited potent proliferation inhibitory effects on a panel of human cancer cell lines, such as SW1990 and HCC827-ER. It blocked glutamine metabolism in SW1990 with increasing intracellular level of glutamine and decreasing glutamate and its downstream metabolites. Physapubescin K also significantly inhibited the tumor growth in a SW1990 xenograft mouse model. Interestingly, physapubescin K could reverse the resistance of HCC827-ER cells to erlotinib and synergize with the hexokinase 2 inhibitor to markedly enhance the inhibition of SW1990 cell proliferation.
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