Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings?
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.
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Olga
O
Lenčová-Popelová
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Hana
H
Jansová
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Eduard
E
Jirkovský
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Jan
J
Bureš
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Anna
A
Jirkovská-Vávrová
Department of Histology and Embryology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Yvona
Y
Mazurová
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Petra
P
Reimerová
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Lucie
L
Vostatková
Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Michaela
M
Adamcová
Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Miloš
M
Hroch
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Zuzana
Z
Pokorná
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Petra
P
Kovaříková
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Tomáš
T
Šimůnek
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic. Electronic address: sterbam@lfhk.cuni.cz.
Martin
M
Štěrba
D000818:Animals; D018943:Anthracyclines / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D003630:Daunorubicin / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006333:Heart Failure / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects; D008981:Molsidomine / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D008981:Molsidomine; D003630:Daunorubicin
Anthracyclines; Cardioprotection; Daunorubicin; Doxorubicin; Molsidomine; Morpholinosydnoimine; Nitric oxide; SIN-1