title: Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy.
abstract: Cisplatin is a widely used antineoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show not only that mitochondrial dysfunction is a feature of cisplatin nephrotoxicity, but also that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin's antineoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Because similar compounds seem to be safe in humans, mitochondrially targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.
authors: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Partha
authors: P
authors: Mukhopadhyay
authors: Béla
authors: B
authors: Horváth
authors: Zsuzsanna
authors: Z
authors: Zsengellér
authors: Jacek
authors: J
authors: Zielonka
authors: Galin
authors: G
authors: Tanchian
authors: Eileen
authors: E
authors: Holovac
authors: Malek
authors: M
authors: Kechrid
authors: Vivek
authors: V
authors: Patel
authors: Isaac E
authors: IE
authors: Stillman
authors: Samir M
authors: SM
authors: Parikh
authors: Joy
authors: J
authors: Joseph
authors: Balaraman
authors: B
authors: Kalyanaraman
authors: Pál
authors: P
authors: Pacher
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects*; D003497:Cyclic N-Oxides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019610:Cytoprotection; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009245:NADH Dehydrogenase / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D009943:Organophosphorus Compounds; C571715:mito-carboxy proxyl; D014451:Ubiquinone; C429014:mitoquinone; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D002945:Cisplatin