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Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity

Abstract : 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 similar to 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 beta-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.
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Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mercredi 11 janvier 2017 - 09:49:17
Dernière modification le : mercredi 14 août 2019 - 17:48:02



Charles Guenancia, Olivier Hachet, Mona Aboutabl, Na Li, Eve Rigal, et al.. Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity. Cancer Chemotherapy and Pharmacology, Springer Verlag, 2016, 77 (4), pp.777 - 785. ⟨10.1007/s00280-016-2995-9⟩. ⟨hal-01431557⟩



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