title: Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells.
abstract: 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.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.|Department of Hygienic Analysis and Detection, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China.|Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Minjian
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Hygienic Analysis and Detection, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Safety Assessment and Research Center for Drug, Pesticide and Veterinary Drug of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Huan
authors.affiliation: Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Li
authors.affiliation: Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China.|Key Laboratory of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.affiliation: National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jin-Ao
authors.initials: JA
authors.lastname: Duan
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000090722:Dihydroorotate Dehydrogenase; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D055432:Metabolomics; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014529:Uridine / Q000172:deficiency / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D044925:Oxidoreductases Acting on CH-CH Group Donors; C050414:celastrol; D014529:Uridine
keywords: acute promyelocytic leukemia; apoptosis; celastrol; metabolomics; uridine