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RESEARCH PRODUCT

Iron overload does not potentiate doxorubicin induced cardiotoxicity in vivo in mice and in vitro in cardiomyocytes cell cultures

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Background: Doxorubicin (DOX), an anticancer anthracycline, is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relations between iron metabolism and DOX-induced cardiotoxicity remain a matter of controversy. Methods: Firstly, we used an in vivo murine model of iron overloading (IO) where male C57BL/6 mice received during 3 weeks (D0-D20) a daily dextran-iron injection (15 mg/kg/day.) and then (D21) a single dose of 6 mg/kg DOX. We evaluated cardiac function with echocardiography, myocardial gene's expression, nitro-oxidative stress levels and iron status. Secondly, the anti-proliferative activity of DOX, in combination with dextran-iron, was evaluated in vitro in cultures of cancerous cells (EMT-6) or cardiomyocytes (H9c2). Results: At D30, there was a significant decrease in left-ventricular ejection fraction (LVEF) in all groups of DOX-treated mice. In IO mice treated by DOX, the LVEF fall was not majored and there was no increase in atrial natriuretic peptide mRNA cardiac gene-expression. IO alone resulted in cardiac hypertrophy and up-regulation of b-myosin heavy-chain expression. In myocardial tissue, electron spin resonance spectroscopy revealed an increase in nitro-oxidative stress in IO groups. While 1 μM of DOX induced a significant reduction of EMT-6 or H9c2 cells proliferation, dextran-iron (125-1000 μg/mL) alone did not modify cell viability and did not impair DOX cytotoxicity. Conclusions: IO did not result in a significant increase in DOX cardiotoxicity neither in mice, nor in cardiomyocytes, and did not impair DOX capacity to inhibit cancerous cells proliferation.