Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells
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Xiaoling Zhang1,2,*, Jing Yang1,*, Minjian Chen3,4,*, Lei Li2, Fei Huan5, Aiping Li4, Yanqing Liu4, Yankai Xia3,4, Jin-ao Duan6, Shiping Ma1
1Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China
2Department of Hygienic Analysis and Detection, Nanjing Medical University, Nanjing 211166, China
3State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
4Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China
5Safety Assessment and Research Center for Drug, Pesticide and Veterinary Drug of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
6National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
*These authors have contributed equally to this work
Shiping Ma, email: firstname.lastname@example.org
Jin-ao Duan, email: email@example.com
Keywords: celastrol, acute promyelocytic leukemia, apoptosis, metabolomics, uridine
Received: February 22, 2016 Accepted: May 20, 2016 Published: June 25, 2016
Celastrol, extracted from “Thunder of God Vine”, is a promising anti-cancer natural product. However, its effect on acute promyelocytic leukemia (APL) and underlying molecular mechanism are poorly understood. The purpose of this study was to explore its effect on APL and underlying mechanism based on metabolomics. Firstly, multiple assays indicated that celastrol could induce apoptosis of APL cells via p53-activated mitochondrial pathway. Secondly, unbiased metabolomics revealed that uridine was the most notable changed metabolite. Further study verified that uridine could reverse the apoptosis induced by celastrol. The decreased uridine was caused by suppressing the expression of gene encoding Dihydroorotate dehydrogenase, whose inhibitor could also induce apoptosis of APL cells. At last, mouse model confirmed that celastrol inhibited tumor growth through enhanced apoptosis. Celastrol could also decrease uridine and DHODH protein level in tumor tissues. Our in vivo study also indicated that celastrol had no systemic toxicity at pharmacological dose (2 mg/kg, i.p., 21 days). Altogether, our metabolomics study firstly reveals that uridine deficiency contributes to mitochondrial apoptosis induced by celastrol in APL cells. Celastrol shows great potential for the treatment of APL.
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