Abstract
Background
In the breast cancer setting, anticancer therapies including doxorubicin (DOX) and
trastuzumab (TRZ) are associated with a significantly increased risk of cardiotoxicity.
Despite the increasing support for the role of oxidative stress (OS) in its pathophysiology,
we still do not have an optimal antioxidant for the prevention of DOX + TRZ–mediated
cardiac dysfunction. The objective of this study was to investigate whether the novel
antioxidant N-acetylcysteine amide (NACA) can attenuate DOX + TRZ–induced heart failure
in a murine model.
Methods
A total of 100 C57Bl/6 female mice received 1 of the following drug regimens: (1)
saline, (2) NACA, (3) DOX, (4) TRZ, (5) DOX + TRZ, (6) NACA + DOX, (7) NACA + TRZ,
and (8) NACA + DOX + TRZ. Serial echocardiography was performed over a 10-day study
period, after which the mice were killed for histologic and biochemical analyses.
Results
In mice receiving DOX, the left ventricular ejection fraction (LVEF) decreased from
73% ± 4% to 43% ± 2% on day 10. In mice receiving DOX + TRZ, the LVEF decreased from
72% ± 3% to 32% ± 2% on day 10. Prophylactic administration of NACA to mice receiving
DOX or DOX + TRZ was cardioprotective, with an LVEF of 62% ± 3% and 55% ± 3% on day
10, respectively. Histologic and biochemical analyses demonstrated a loss of cellular
integrity, increased OS, and increased cardiac apoptosis in mice treated with DOX +
TRZ, which was attenuated by the prophylactic administration of NACA.
Conclusions
NACA attenuated the cardiotoxic side effects of DOX + TRZ in a murine model of chemotherapy-induced
cardiac dysfunction by decreasing OS and apoptosis.
Résumé
Introduction
Dans le domaine du cancer du sein, les traitements anticancer, dont la doxorubicine
(DOX) et le trastuzumab (TRZ), sont associés à une augmentation significative du risque
de cardiotoxicité. En dépit de l’appui accru concernant le rôle du stress oxydatif
(SO) dans sa physiopathologie, nous n’avons pas encore d’antioxydant qui agit de façon
optimale dans la prévention de la dysfonction cardiaque médiée par le traitement DOX +
TRZ. L’objectif de cette étude était d’examiner si le nouvel antioxydant N-acétylcystéine
(NAC) peut atténuer l’insuffisance cardiaque induite par le DOX + TRZ chez un modèle
murin.
Méthodes
Un total de 100 souris femelles C57B1/6 recevaient 1 des régimes médicamenteux suivants
: 1) solution saline, 2) NACA, 3) DOX, 4) TRZ, 5) DOX + TRZ, 6) NACA + DOX, 7) NACA +
TRZ, 8) NACA + DOX + TRZ. L’échocardiographie sérielle était réalisée sur une période
de 10 jours après lesquels les souris étaient tuées pour procéder aux analyses histologiques
et biochimiques.
Résultats
Chez les souris recevant la DOX, la fraction d’éjection ventriculaire gauche (FEVG)
diminuait de 73 % ± 4 % à 43 % ± 2 % au 10e jour. Chez les souris recevant le DOX + TRZ, la FEVG diminuait de 72 % ± 3 % à 32
% ± 2 % au 10e jour. L’administration prophylactique de NAC aux souris recevant la DOX ou le DOX +
TRZ était cardioprotectrice, et entraînait une FEVG respective de 62 % ± 3 % et de
55 % ± 3 % au 10e jour. Les analyses histologiques et biochimiques démontraient une perte d’intégrité
cellulaire, une augmentation du SO et une augmentation de l’apoptose cardiaque chez
les souris traitées par le DOX + TRZ, qui étaient atténuées par l’administration prophylactique
de NACA.
Conclusions
La NACA atténuait les effets secondaires cardiotoxiques du DOX + TRZ chez un modèle
murin de dysfonction cardiaque induite par chimiothérapie en diminuant le SO et l’apoptose.
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Article info
Publication history
Published online: June 22, 2016
Accepted:
June 3,
2016
Received:
January 21,
2016
Footnotes
See page 1518 for disclosure information.
Identification
Copyright
© 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
