Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity
Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ.
Immediately after birth, litters of C57BL/6 mice were either maintained at 9 pups (normal litter, NL) or reduced to 3 (small litter, SL) in order to induce programming of ~15 % overweight through postnatal overfeeding. At 4 months, NL and SL mice received a single intra-peritoneal injection of either saline, DOX (6 mg/kg), TRZ (10 mg/kg) or both (DOX–TRZ). Transthoracic echocardiography was performed 24 h before as well as 10 and 20 days after treatments.
Twenty days after DOX administration, systolic dysfunction was observed only in the overweight SL group, while NL mice group had a normal left ventricular ejection fraction. However, in the NL group, functional impairment appeared when TRZ was co-administered. Forty-eight hours after drug administration, gene expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX–TRZ mice of both the NL and SL group, whereas the expression of β-MHC increased significantly in overweight SL mice only.
In an acute model of DOX cardiotoxicity, moderately overweight adult mice were more sensitive to cardiac systolic impairment. Moreover, our results confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in lean mice.
KeywordsDoxorubicin Trastuzumab Cardiotoxicity Overweight Postnatal programming
The authors thank Françoise Bechet for technical assistance and Mr. Philip Bastable for English revision of the manuscript.
This work was supported by grants from the French Ministry of Research, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Société Française de Cardiologie (SFC), the Regional Council of Burgundy, the Association de Cardiologie de Bourgogne (ACB) and the French Government through a fellowship granted by the French Embassy in Egypt (Institut Français d’Egypte).
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest including financial and personal relationships with other people or organizations that could inappropriately influence this work.
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