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

Abstract

Cisplatin is a widely used anti-neoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show that mitochondrial dysfunction is not only a feature of cisplatin nephrotoxicity, but 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 anti-neoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Since similar compounds appear to be safe in humans, mitochondrially-targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.

Cisplatin Binding and Inactivation of Mitochondrial Glutamate Oxaloacetate Transaminase in Cisplatin-Induced Rat Nephrotoxicity

“…It is well known that cisplatin preferentially accumulates in the kidney, especially in the proximal tubular epithelial cells. [17][18][19][20][21][22] Our results suggest that cisplatin does not bind to liver mitochondrial GOT because cisplatin does not accumulate readily in liver tissue.…”

“…2,4,14,15) It is well established that mitochondria are target of cisplatin toxicity, and that mitochondrial injury is a very early event in cisplatininduced nephrotoxicity, 17,20,21,37) but why and how cisplatin causes mitochondrial dysfunction is not understood. The present study partially clarified the mechanisms of cisplatin-induced nephrotoxicity.…”

“…14,15) Depending on the cisplatin concentration or cellular status, tubular cell death occurs by both apoptosis and necrosis. 16) Several lines of evidence suggest that cisplatin accumulates in the mitochondria of renal cells, impairs mitochondrial bioenergetics, increases reactive oxygen species (ROS) developments, and causes the release of pro-apoptotic factors, all of which ultimately lead to renal tubular cell death, [17][18][19][20][21][22] but the mechanisms of the mitochondrial dysfunction are not yet understood. Therefore, the identification of cisplatin targets in mitochondria would be helpful to counteract cisplatininduced renal damage.…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2008; Mukhopadhyay et al. 2012). Indeed, markers of ER stress such as increased BiP/GRP78 and CHOP expression and caspase 12 activation have been found in different investigations performed in renal cells and kidneys of rodents treated with cisplatin (Liu and Baliga 2005; Peyrou et al.…”

Cisplatin-Induced Ovarian Cytotoxicity and the Modulating Role of Aqueous Zest Extract of Citrus limonium (AZECL) in Rat Models

“…On the other hand, therapeutic effects of cisplatin based on the interaction with DNA in the cell, preventing proliferation and inducing apoptosis in tumor cells. According to Mukhopadhyay et al [61]; cisplatin induced mitochondrial ROS generation triggered inflammatory response, cell death and ovarian dysfunction.…”