Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Department(s)

Biological Sciences

Second Department

Chemistry

Keywords and Phrases

Amide; Catalase; Doxorubicin; Glutathione Peroxidase; Glutathione Reductase; N Acetylcysteine Amide; Reactive Oxygen Metabolite; Unclassified Drug; Acetylcysteine; Antineoplastic Antibiotic; Cysteine; Drug Derivative; Glutathione; Glutathione Disulfide; N-Acetylcysteinamide; Animal Cell; Antioxidant Activity; Cell Death; Concentration Response; Controlled Study; Cytotoxicity; Heart Muscle Cell; Heart Protection; Lipid Peroxidation; Nonhuman; Oxidative Stress; Rat; Cell Line; Cell Survival; Cytology; Dose Response; Drug Effect; Metabolism; Time; Animals; Antibiotics, Antineoplastic; Cysteine; Dose-Response Relationship, Drug; Myocytes, Cardiac; Reactive Oxygen Species; Time Factors

International Standard Serial Number (ISSN)

1471-2210

Document Type

Article - Journal

Document Version

Final Version

File Type

text

Language(s)

English

Rights

© 2009 BioMed Central, All rights reserved.

PubMed ID

19368719

Included in

Biology Commons

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