title: Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation.
abstract: The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Choi
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Han-Kyul
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Shim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Muhammad Ayaz
authors.initials: MA
authors.lastname: Anwar
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Ji-Woong
authors.initials: JW
authors.lastname: Kwon
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Hyuk-Kwon
authors.initials: HK
authors.lastname: Kwon
authors.affiliation: Division of Energy Systems Research, Ajou University, Suwon, 443-749, Korea.
authors.forename: Hyung Joong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, 790-784, Korea.
authors.forename: Hyobin
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Division of Energy Systems Research, Ajou University, Suwon, 443-749, Korea.
authors.forename: Hwan Myung
authors.initials: HM
authors.lastname: Kim
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, 790-784, Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D002952:Citric Acid Cycle / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase; D002945:Cisplatin; D000111:Acetylcysteine