Journal Article

Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity

Djonov, Valentin, Volarevic, Vladislav, Fellabaum, Crissy, Arsenijevic, Nebojsa, Harrell, C. Randall, Djokovic, Bojana, Jankovic, Marina Gazdic

2019

Overview

Background Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury (AKI) which develop due to renal accumulation and biotransformation of CDDP. The alleviation or prevention of CDDP-caused nephrotoxicity is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis which is considered for high-dose CDDP-treated patients. However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical use of safe and efficacious renoprotective drug as an additive therapy for high dose CDDP-treated patients. Main body In this review article we describe in detail signaling pathways involved in CDDP-induced apoptosis of renal tubular cells, oxidative stress and inflammatory response in injured kidneys in order to pave the way for the design of new therapeutic approaches that can minimize CDDP-induced nephrotoxicity. Most of these molecular pathways are, at the same time, crucially involved in cytotoxic activity of CDDP against tumor cells and potential alterations in their function might mitigate CDDP-induced anti-tumor effects. Conclusion Despite the fact that many molecules were designated as potential therapeutic targets for renoprotection against CDDP, modulation of CDDP-induced nephrotoxicity still represents a balance on the knife edge between renoprotection and tumor toxicity.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute kidney injury / Analysis / Animals / Anticancer properties / Antineoplastic Agents - toxicity / Apoptosis / Apoptosis - drug effects / Biomedical and Life Sciences / Biomedicine / Biotransformation / Cell division / Chemotherapy / Cisplatin / Cisplatin - toxicity / Cytokines / Cytotoxicity / Dehydration / Dendritic cells / Diuresis / Dosage and administration / Drug dosages / Epithelial Cells - drug effects / Epithelial Cells - immunology / Epithelial Cells - physiology / Genetic aspects / Humans / Hydration / Inflammation / Inflammation - chemically induced / Inflammatory response / Kidney - drug effects / Kidney diseases / Kidneys / Knife-edge / Magnesium / Mannitol / Mice / Molecular mechanics / Molecular modelling / Nephrotoxicity / Neutrophils / Oxidative stress / Oxidative Stress - drug effects / Patients / Phosphate esters / Rats / Review / Side effects / Signal Transduction - drug effects / Supplements / Therapeutic applications / TNF inhibitors / Toxicity / Tumor cells / Tumor necrosis factor-TNF / Tumors / Urine