Omega-3 Fatty Acid Protects Against Arsenic Trioxide-Induced Cardiotoxicity In Vitro and In Vivo
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Arsenic trioxide (As2O3) is a highly effective therapeutic against acute promyelocytic leukaemia, but its clinical efficacy is burdened by serious cardiac toxicity. The present study was performed to evaluate the effect of omega (ω)-3 fatty acid on As2O3-induced cardiac toxicity in in vivo and in vitro settings. In in vivo experiments, male Wistar rats were orally administered with As2O3 4 mg/kg body weight for a period of 45 days and cardiotoxicity was assessed. As2O3 significantly increased the tissue arsenic deposition, micronuclei frequency and creatine kinase (CK)-MB activity. There were a rise in lipid peroxidation and a decline in reduced glutathione, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase in heart tissue of arsenic-administered rats. The cardioprotective role of ω-3 fatty acid was assessed by combination treatment with As2O3. ω-3 fatty acid co-administration with As2O3 significantly alleviated these changes. In in vitro study using H9c2 cardiomyocytes, As2O3 treatment induced alterations in cell viability, lactate dehydrogenase (LDH) release, lipid peroxidation, cellular calcium levels and mitochondrial membrane potential (∆Ψm). ω-3 fatty acid co-treatment significantly increased cardiomyocyte viability, reduced LDH release, lipid peroxidation and intracellular calcium concentration and improved the ∆Ψm. These findings suggested that the ω-3 fatty acid has the potential to protect against As2O3-induced cardiotoxicity.
KeywordsArsenic trioxide Omega-3 fatty acid Cardioprotection Micronuclei Arsenic deposition
This work was supported by University Grants Commission, New Delhi (F. No.: 39-683/2010SR), and awarded the research fellowship in sciences for meritorious student to Mr. Mathews V. Varghese (F. No.: 4-1/2006 (BSR)/11-29/2008(BSR)). We are grateful to Prof. C.C Kartha, Professor of Eminence, Cardiovascular Disease Biology, Rajiv Gandhi Centre for Biotechnology, Trivandrum, for providing laboratory facilities during in vitro studies.
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Conflict of interest
The authors declare that they have no conflict of interest.
- 1.IARC. (1987). Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl., 7, 1–440.Google Scholar
- 11.Mathews, V. V., Paul, M. V., Abhilash, M., Manju, A., Abhilash, S., & Nair, R. H. (2013). Myocardial toxicity of acute promyelocytic leukaemia drug-arsenic trioxide. European Review for Medical and Pharmacological Sciences, 1, 34–38.Google Scholar
- 13.Buege, J. A., & Aust, S. D. (1978). The thiobarbituric acid assay. Methods in Enzymology, 52, 306–307.Google Scholar
- 23.Bhattacharya, A., Lawrence, R. A., Krishnan, A., Zaman, K., Sun, D., & Fernandes, G. (2003). Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice. Journal of the American College of Nutrition, 22(5), 388–399.CrossRefPubMedGoogle Scholar
- 27.Thompson, J. A., White, C. C., Cox, D. P., Chan, J. Y., Kavanagh, T. J., Fausto, N., & Franklin, C. C. (2009). Distinct Nrf1/2-independent mechanisms mediate As 3+-induced glutamatecysteine ligase subunit gene expression in murine hepatocytes. Free Radical Biology and Medicine, 46, 1614–1625.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Komatsu, W., Ishihara, K., Murata, M., Saito, H., & Shinohara, K. (2003). Docosahexaenoic acid suppresses nitric oxide production and inducible nitric oxide synthase expression in interferon-gamma plus lipopolysaccharide-stimulated murine macrophages by inhibiting the oxidative stress. Free Radical Biology and Medicine, 34(8), 1006–1016.CrossRefPubMedGoogle Scholar
- 32.World Health Organization (2015) Interim summary of conclusions and dietary recommendations on total fat. http://www.who.int/nutrition/topics/FFA_summary_rec_conclusion.pdf. Accessed December 18, 2015.
- 33.American Heart Association, “Fish 101,” (2014).http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/Fish-101_UCM_305986_Article.jsp. Accessed December 18, 2015.
- 39.O’Shea, K. M., Khairallah, R. J., Sparagna, G. C., Xu, W., Hecker, P. A., Robillard-Frayne, I., et al. (2009). Dietary omega-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+-induced permeability transition. Journal of Molecular and Cellular Cardiology, 47(6), 819–827.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Khairallah, R. J., Sparagna, G. C., Khanna, N., O’Shea, K. M., Hecker, P. A., Kristian, T., et al. (2010). Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochimica et Biophysica Acta, 1797(8), 1555–1562.CrossRefPubMedPubMedCentralGoogle Scholar