Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy

Partha Mukhopadhyay, Béla Horváth, Zsuzsanna Zsengellér, Jacek Zielonka, Galin Tanchian, Eileen Holovac, Malek Kechrid, Vivek Patel, Isaac E. Stillman, Samir M. Parikh, Joy Joseph, Balaraman Kalyanaraman, Pál Pacher

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)497-506
Number of pages10
JournalFree Radical Biology and Medicine
Volume52
Issue number2
DOIs
StatePublished - Jan 15 2012
Externally publishedYes

Keywords

  • Cisplatin
  • Free radicals
  • Mitochondria
  • Mitochondrial antioxidants
  • Nephropathy
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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