title: Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.
abstract: Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France; Cardiology Department, University Hospital, Dijon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Guenancia
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France; Cardiology Department, University Hospital, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hachet
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France.
authors.forename: Eve
authors.initials: E
authors.lastname: Rigal
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France; Cardiology Department, University Hospital, Dijon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Cottin
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutartre
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Rochette
authors.affiliation: INSERM UMR866, University of Burgundy, LPPCM, Faculties of Medicine and Pharmacy, Dijon, France. Electronic address: cvergely@u-bourgogne.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vergely
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D066126:Cardiotoxicity / Q000209:etiology* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003911:Dextrans / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000378:metabolism / Q000633:toxicity*; D019190:Iron Overload / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D024723:Ventricular Myosins / Q000378:metabolism
chemical_list: D003911:Dextrans; D020097:Natriuretic Peptide, Brain; D004317:Doxorubicin; D007501:Iron; D024723:Ventricular Myosins
keywords: Cardiotoxicity; Cell proliferation; Doxorubicin; Iron overload; Oxidative stress