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01-04-2016 | Original Article

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

Authors: Charles Guenancia, Olivier Hachet, Mona Aboutabl, Na Li, Eve Rigal, Yves Cottin, Luc Rochette, Catherine Vergely

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2016

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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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Title: Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity
Authors: Charles Guenancia
Olivier Hachet
Mona Aboutabl
Na Li
Eve Rigal
Yves Cottin
Luc Rochette
Catherine Vergely
Publication date: 01-04-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-2995-9

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