title: An integrative view of cisplatin-induced renal and cardiac toxicities: Molecular mechanisms, current treatment challenges and potential protective measures.
abstract: Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell's antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies including combination therapy with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide.
authors.affiliation: Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. Electronic address: profduu@yahoo.com.
authors.forename: George J
authors.initials: GJ
authors.lastname: Dugbartey
authors.affiliation: Department of Surgery, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY, United States.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Peppone
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Groningen, Netherlands.
authors.forename: Inge A M
authors.initials: IA
authors.lastname: de Graaf
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D066126:Cardiotoxicity / Q000473:pathology* / Q000517:prevention & control*; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; Cisplatin-induced renal and cardiac toxicities; Inflammation; Reactive oxygen species