TY - JOUR
T1 - Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy
AU - Mukhopadhyay, Partha
AU - Horváth, Béla
AU - Zsengellér, Zsuzsanna
AU - Zielonka, Jacek
AU - Tanchian, Galin
AU - Holovac, Eileen
AU - Kechrid, Malek
AU - Patel, Vivek
AU - Stillman, Isaac E.
AU - Parikh, Samir M.
AU - Joseph, Joy
AU - Kalyanaraman, Balaraman
AU - Pacher, Pál
N1 - Funding Information:
This study was supported by the Intramural Research Program of NIH/NIAAA (to P.P.) and by National Institutes of Health Grant RO1CA152810 (B.K.). Dr. Horvath is the recipient of a Hungarian Scientific Research Fund fellowship (OTKA-NKTH-EU MB08 80238). The authors are indebted to Dan Brown and Lena Ellezian for help with electron microscopy sample preparation, Dr. George Kunos (the Scientific Director of the NIAAA) for providing key resources, and the American Society of Nephrology (Carl Gottschalk award to S.M.P.). Dr. Pacher dedicates this study to his beloved mother Iren Bolfert, who died from complications of chemotherapy.
PY - 2012/1/15
Y1 - 2012/1/15
N2 - 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.
AB - 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.
KW - Cisplatin
KW - Free radicals
KW - Mitochondria
KW - Mitochondrial antioxidants
KW - Nephropathy
KW - Oxidative stress
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U2 - 10.1016/j.freeradbiomed.2011.11.001
DO - 10.1016/j.freeradbiomed.2011.11.001
M3 - Article
C2 - 22120494
AN - SCOPUS:84855448154
SN - 0891-5849
VL - 52
SP - 497
EP - 506
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 2
ER -