title: Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties.
abstract: Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin.
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Ramindhu
authors.initials: R
authors.lastname: Galgamuwa
authors.affiliation: Faculty of Education, Science, Technology and Mathematics, University of Canberra, Australian Capital Territory, Australia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Hardy
authors.affiliation: ACT Pathology and ANU Medical School, The Canberra Hospital, Australian Capital Territory, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Dahlstrom
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Anneke C
authors.initials: AC
authors.lastname: Blackburn
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Elize
authors.initials: E
authors.lastname: Wium
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Rooke
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Cappello
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Tummala
authors.affiliation: Genome Sciences, and.
authors.forename: Hardip R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Genome Discovery Unit, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chuah
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; and.
authors.forename: Luyang
authors.initials: L
authors.lastname: Tian
authors.affiliation: Archaeogeochemistry and Marine Biogeochemistry Groups, Research School of Earth Sciences, Australian National University, Australian Capital Territory, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: McMorrow
authors.affiliation: Departments of Cancer Biology and Therapeutics and.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Board
authors.affiliation: Departments of Cancer Biology and Therapeutics and angelo.theodoratos@anu.edu.au.
authors.forename: Angelo
authors.initials: A
authors.lastname: Theodoratos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D005260:Female; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000970:Antineoplastic Agents; D003999:Dichloroacetic Acid; D002945:Cisplatin
keywords: acute renal failure; cisplatin nephrotoxicity; renal protection