An integrative view of cisplatin-induced renal and cardiac toxicities: Molecular mechanisms, current treatment challenges and potential protective measures

George J Dugbartey, Luke J Peppone, Inge A M de Graaf

    Research output: Contribution to journalReview articleAcademicpeer-review

    88 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)58-66
    Number of pages9
    JournalToxicology
    Volume371
    DOIs
    Publication statusPublished - 14-Sep-2016

    Keywords

    • Cisplatin
    • Cisplatin-induced renal and cardiac toxicities
    • Reactive oxygen species
    • Inflammation
    • Apoptosis
    • GAMMA-GLUTAMYL-TRANSPEPTIDASE
    • ENDOPLASMIC-RETICULUM STRESS
    • KIDNEY EPITHELIAL-CELLS
    • HIGH-DOSE CISPLATIN
    • INDUCED NEPHROTOXICITY
    • OXIDATIVE STRESS
    • INDUCED CARDIOTOXICITY
    • LIPID-PEROXIDATION
    • PHYSIOLOGICAL DISPOSITION
    • REPERFUSION INJURY

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