Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings?
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
27816693
DOI
10.1016/j.tox.2016.11.002
PII: S0300-483X(16)30261-X
Knihovny.cz E-resources
- Keywords
- Anthracyclines, Cardioprotection, Daunorubicin, Doxorubicin, Molsidomine, Morpholinosydnoimine, Nitric oxide, SIN-1,
- MeSH
- Anthracyclines toxicity MeSH
- Chronic Disease MeSH
- Daunorubicin toxicity MeSH
- Nitric Oxide Donors pharmacology MeSH
- Doxorubicin toxicity MeSH
- Cardiotonic Agents pharmacology MeSH
- Cardiotoxicity MeSH
- Rabbits MeSH
- Molsidomine pharmacology MeSH
- Cell Line, Tumor MeSH
- Heart Diseases chemically induced prevention & control MeSH
- Oxidative Stress drug effects MeSH
- Lipid Peroxidation drug effects MeSH
- Cell Proliferation drug effects MeSH
- Antibiotics, Antineoplastic toxicity MeSH
- Reactive Oxygen Species metabolism MeSH
- Ventricular Remodeling drug effects MeSH
- Heart Failure prevention & control MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anthracyclines MeSH
- Daunorubicin MeSH
- Nitric Oxide Donors MeSH
- Doxorubicin MeSH
- Cardiotonic Agents MeSH
- Molsidomine MeSH
- Antibiotics, Antineoplastic MeSH
- Reactive Oxygen Species MeSH
Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study.
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