Abstract
Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity.
Highlights
Cisplatin is an inorganic, platinum-based agent used as a single agent or in combination with other agents for the treatment of a plethora of malignancies, including ovarian, cervical, head and neck, testicular, lymphoma, myeloma, small cell lung, and non-small cell lung cancers [1,2,3,4,5,6,7,8]
Several definitions of acute kidney injury (AKI) have been validated, including the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) classification based on serum creatinine or urinary outputs (UO) (Table 1) [69], with the acute kidney in-jury network (AKIN) classification being based on a ≥50% increase in absolute sCr
Murine studies have demonstrated disruptions in mitochondrial metabolism that lead to increased levels of mitochondrial superoxide following treatment with cisplatin, which may play an important role in AKI and chronic kidney disease (CKD) [25]
Summary
Platinum-based agent used as a single agent or in combination with other agents for the treatment of a plethora of malignancies, including ovarian, cervical, head and neck, testicular, lymphoma, myeloma, small cell lung, and non-small cell lung cancers [1,2,3,4,5,6,7,8]. Cisplatin-induced acute kidney injury (AKI) is characterized by decreased renal function in conjunction with the accumulation of metabolic waste products such as Antioxidants 2021, 10, 1329. Increased levels of ROS can contribute to tubular cell apoptosis, as well as increased oxidative and nitrative stress, thereby causing kidney injury during AKI and CKD [27]. Generation of ROS in tubular cell mitochondria may potentially contribute to cisplatin-induced kidney injury. Several cancer cell lines have demonstrated the potential role of mitochondrial dynamics in cisplatin resistance or sensitivity [35,36]. Studies in ovarian cancer cell lines treated with cisplatin resulted in mitochondrial morphology changes including punctate and fragmented mitochondria [30,37]. Increased mitochondrial fission mediated by Drp enhanced cisplatin sensitivity in ovarian cancer, leading to apoptosis [35]. The dynamic nature of mitochondria may potentially be utilized as a biomarker to predict cisplatin response
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