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Published on: March 16, 2018
Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy
Partha Mukhopadhyay1, Béla Horváth, Zsuzsanna Zsengellér
1Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Insights
Mitochondrial dysfunction drives cisplatin nephrotoxicity. Targeted antioxidants delivered to mitochondria protected against kidney damage without reducing cisplatin
Area of Science:
- Nephrology
- Oncology
- Mitochondrial Medicine
Background:
- Cisplatin is a vital chemotherapy drug.
- Nephrotoxicity is a significant dose-limiting side effect of cisplatin.
- The exact mechanisms of cisplatin-induced kidney damage are not fully understood.
Purpose of the Study:
- To investigate the role of mitochondria in cisplatin nephrotoxicity.
- To evaluate the renoprotective potential of mitochondrially targeted antioxidants against cisplatin injury.
Main Methods:
- Administration of cisplatin to induce nephrotoxicity.
- Treatment with mitochondrially targeted antioxidants (MitoQ, Mito-CP).
- Assessment of renal function, oxidative stress, mitochondrial function, inflammation, and histopathology.
Main Results:
- Cisplatin induced significant renal oxidative stress, mitochondrial dysfunction, inflammation, and injury.
- Mitochondrially targeted antioxidants dose-dependently prevented cisplatin-induced renal dysfunction.
- Mito-CP mitigated mitochondrial damage, inflammation, and tubular injury, while preserving cisplatin's anti-cancer efficacy in vitro.
Conclusions:
- Mitochondrial-derived oxidants play a key role in cisplatin nephrotoxicity.
- Mitochondrially targeted antioxidants show promise as a novel therapeutic strategy to prevent cisplatin-induced kidney damage.
- This approach may allow for continued use of cisplatin chemotherapy with reduced renal side effects.
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