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Can J Cardiol. 2016 Dec;32(12):1513-1519. doi: 10.1016/j.cjca.2016.06.002. Epub 2016 Jun 20.

The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab-Mediated Cardiac Dysfunction.

Author information

1
Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
2
Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
3
Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.
4
Sections of Oncology and Hematology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
5
Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Sections of Oncology and Hematology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: djassal@sbgh.mb.ca.

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.

PMID:
27650929
DOI:
10.1016/j.cjca.2016.06.002
[Indexed for MEDLINE]

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