Faculty Collaboration Database

Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic Biol Med 2012 Jan 15;52(2):497-506

Date

11/29/2011

Pubmed ID

22120494

Pubmed Central ID

PMC3253235

DOI

10.1016/j.freeradbiomed.2011.11.001

Scopus ID

2-s2.0-84855448154 (requires institutional sign-in at Scopus site)   177 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.

Author List

Mukhopadhyay P, Horváth B, Zsengellér Z, Zielonka J, Tanchian G, Holovac E, Kechrid M, Patel V, Stillman IE, Parikh SM, Joseph J, Kalyanaraman B, Pacher P

Authors

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Kidney Injury
Animals
Antineoplastic Agents
Antioxidants
Apoptosis
Cell Line, Tumor
Cell Survival
Cisplatin
Cyclic N-Oxides
Cytoprotection
Electron Transport Complex IV
Humans
Inflammation
Kidney Tubules
Male
Mice
Mice, Inbred C57BL
Mitochondria
NADH Dehydrogenase
Organophosphorus Compounds
Oxidative Stress
Ubiquinone