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Open Access Highly Accessed Research article

N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes

Rong Shi1, Chuan-Chin Huang2, Robert S Aronstam2, Nuran Ercal1, Adam Martin2 and Yue-Wern Huang2*

Author Affiliations

1 Department of Chemistry, Missouri University of Science and Technology, 400 W. 11st Street, 142 Schrenk Hall, Rolla, MO 65409, USA

2 Department of Biological Sciences and M S&T cDNA Resource Center, Missouri University of Science and Technology, 400 W. 11st Street, 105 Schrenk Hall, Rolla, MO 65409, USA

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BMC Pharmacology 2009, 9:7  doi:10.1186/1471-2210-9-7

Published: 15 April 2009



While doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use. This is the first report of the chemoprotective efficacy of a relatively new thiol antioxidant, N-acetylcysteine amide (NACA), on DOX-induced cell death in cardiomyocytes. We hypothesized that NACA would protect H9c2 cardiomyocytes from DOX-induced toxicity by reducing oxidative stress. Accordingly, we determined the ability of NACA to mitigate the cytotoxicity of DOX in H9c2 cells and correlated these effects with the production of indicators of oxidative stress.


DOX at 5 μM induced cardiotoxicity while 1) increasing the generation of reactive oxygen species (ROS), 2) decreasing levels and activities of antioxidants and antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase) and 3) increasing lipid peroxidation. NACA at 750 μM substantially reduced the levels of ROS and lipid peroxidation, as well as increased both GSH level and GSH/GSSG ratio. However, treating H9c2 cells with NACA did little to protect H9c2 cells from DOX-induced cell death.


Although NACA effectively reduced oxidative stress in DOX-treated H9c2 cells, it had minimal effects on DOX-induced cell death. NACA prevented oxidative stress by elevation of GSH and CYS, reduction of ROS and lipid peroxidation, and restoration of antioxidant enzyme activities. Further studies to identify oxidative stress-independent pathways that lead to DOX-induced cell death in H9c2 are warranted.