Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies

Abstract

Cisplatin is one of the most widely used and most potent chemotherapy drugs. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of cisplatin and related platinum-based therapeutics. Recent research has shed significant new lights on the mechanism of cisplatin nephrotoxicity, especially on the signaling pathways leading to tubular cell death and inflammation. Renoprotective approaches are being discovered, but the protective effects are mostly partial, suggesting the need for combinatorial strategies. Importantly, it is unclear whether these approaches would limit the anticancer effects of cisplatin in tumors. Examination of tumor-bearing animals and identification of novel renoprotective strategies that do not diminish the anticancer efficacy of cisplatin are essential to the development of clinically applicable interventions.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Cisplatin treatment can induce several types of adverse effects including GI disorders, kidney injury, neurotoxicity, hepatotoxicity, and cardiotoxicity (Kitamura 2008; Pabla and Dong 2008; Florea and Büsselberg 2011). Many investigations have been performed to decipher the mechanisms of cisplatin‐induced acute kidney injury because this frequent adverse effect limits the use of cisplatin in cancer therapy (Kitamura 2008; Pabla and Dong 2008).…”

“…Many investigations have been performed to decipher the mechanisms of cisplatin‐induced acute kidney injury because this frequent adverse effect limits the use of cisplatin in cancer therapy (Kitamura 2008; Pabla and Dong 2008). The emerging picture to explain cisplatin‐induced tubular cell injury and death is a combination of different pathophysiological events including mitochondrial dysfunction, ROS overproduction, increased tumor necrosis factor‐ α (TNF α ) generation, and ER stress (Kruidering et al.…”

“…The emerging picture to explain cisplatin‐induced tubular cell injury and death is a combination of different pathophysiological events including mitochondrial dysfunction, ROS overproduction, increased tumor necrosis factor‐ α (TNF α ) generation, and ER stress (Kruidering et al. 1997; Kitamura 2008; Pabla and Dong 2008; Servais et al. 2008; Mukhopadhyay et al.…”

Cisplatin Binding and Inactivation of Mitochondrial Glutamate Oxaloacetate Transaminase in Cisplatin-Induced Rat 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.…”

Predicting Acute Renal Injury in Cancer Patients Receiving Cisplatin Using Urinary Neutrophil Gelatinase‐Associated Lipocalin and Cystatin C

“…Additionally, there was observed variability in intrapatient biomarker levels, as well as underlying variance in the number of cisplatin treatment cycles each patient received; however, these differences were accounted for in the formal statistical analyses. Finally, cisplatin is known to work by various mechanisms leading to acute and chronic kidney injury 34. We were unable to definitively decipher from our data the exact molecular mechanism(s) of kidney injury in our patients.…”