Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties

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.

Journal of the American Society of Nephrology : JASN. 2016 Mar 09 [Epub ahead of print]

Ramindhu Galgamuwa, Kristine Hardy, Jane E Dahlstrom, Anneke C Blackburn, Elize Wium, Melissa Rooke, Jean Y Cappello, Padmaja Tummala, Hardip R Patel, Aaron Chuah, Luyang Tian, Linda McMorrow, Philip G Board, Angelo Theodoratos

Departments of Cancer Biology and Therapeutics and., Faculty of Education, Science, Technology and Mathematics, University of Canberra, Australian Capital Territory, Australia;, ACT Pathology and ANU Medical School, The Canberra Hospital, Australian Capital Territory, Australia;, Departments of Cancer Biology and Therapeutics and., Departments of Cancer Biology and Therapeutics and., Departments of Cancer Biology and Therapeutics and., Departments of Cancer Biology and Therapeutics and., Departments of Cancer Biology and Therapeutics and., Genome Sciences, and., Genome Discovery Unit, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia;, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; and., Archaeogeochemistry and Marine Biogeochemistry Groups, Research School of Earth Sciences, Australian National University, Australian Capital Territory, Australia., Departments of Cancer Biology and Therapeutics and., Departments of Cancer Biology and Therapeutics and .

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