Skip to main content

Advertisement

SpringerLink
Log in

Omega-3 Fatty Acid Protects Against Arsenic Trioxide-Induced Cardiotoxicity In Vitro and In Vivo

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  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 

  2. Iland, H. J., & Seymour, J. F. (2013). Role of arsenic trioxide in acute promyelocytic leukemia. Current Treatment Options in Oncology, 14(2), 170–184.

    Article  PubMed  Google Scholar 

  3. Huan, S. Y., Yang, C. H., & Chen, Y. C. (2000). Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy. Leukaemia & Lymphoma, 38(3–4), 283–293.

    Article  CAS  Google Scholar 

  4. Barbey, J. T., & Soignet, S. (2001). Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Annals of Internal Medicine, 135, 842–843.

    Article  CAS  PubMed  Google Scholar 

  5. Teng, L. L., Shao, L., Zhao, Y. T., Yu, X., Zhang, D. F., & Zhang, H. (2010). The beneficial effect of n-3 polyunsaturated fatty acids on doxorubicin-induced chronic heart failure in rats. Journal of International Medical Research, 38(3), 940–948.

    Article  CAS  PubMed  Google Scholar 

  6. Stanley, W. C., Khairallah, R. J., & Dabkowski, E. R. (2012). Update on lipids and mitochondrial function: impact of dietary n-3 polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care., 15, 122–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Leaf, A., Xiao, Y. F., Kang, J. X., & Billman, G. E. (2003). Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids. Pharmacology & Therapeutics, 98, 355–377.

    Article  CAS  Google Scholar 

  8. Hardman, W. E. (2002). Omega-3 fatty acids to augment cancer therapy. Journal of Nutrition, 132, 3508s–3512s.

    CAS  PubMed  Google Scholar 

  9. Merendino, N., Costantini, L., Manzi, L., Molinari, R., D’Eliseo, D., & Velotti, F. (2013). Dietary omega-3 polyunsaturated fatty acid DHA: A potential adjuvant in the treatment of cancer. Biomedicine Research International, 2013, 310186.

    Article  Google Scholar 

  10. Hardman, W. E., Avula, C. P., Fernandes, G., & Cameron, I. L. (2001). Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast cancer xenografts. Clinical Cancer Research, 7(7), 2041–2049.

    CAS  PubMed  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 

  12. Fenech, M. (1993). The cytokinesis-block micronucleus technique: a detailed description of the method and its application to genotoxicity studies in human populations. Mutation Research, 285, 35–44.

    Article  CAS  PubMed  Google Scholar 

  13. Buege, J. A., & Aust, S. D. (1978). The thiobarbituric acid assay. Methods in Enzymology, 52, 306–307.

    Google Scholar 

  14. Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1), 70–77.

    Article  CAS  PubMed  Google Scholar 

  15. Rotruck, J. T., Pope, A. L., Ganther, H. E., Swanson, A. B., Hafeman, D. G., & Hoekstra, W. G. (1973). Selenium: Biochemical role as a component of glutathione peroxidase. Science, 179, 588–590.

    Article  CAS  PubMed  Google Scholar 

  16. Habig, W. H., Pabst, M. J., & Jakoby, W. B. (1974). Glutathione S-transferase, the first enzymatic step in mercapturic acid formation. Journal of Biological Chemistry, 249(22), 7130–7139.

    CAS  PubMed  Google Scholar 

  17. Kakkar, P., Das, B., & Viswanathan, P. N. (1984). A modified spectrophotometric assay of superoxide dismutase. Indian Journal of Biochemistry Biophysics, 21(2), 130–132.

    CAS  PubMed  Google Scholar 

  18. Aebi, H. (1974). Catalase. In H. U. Bergmeyer (Ed.), Methods of enzymatic analysis (Vol. 2, pp. 673–678). New York: Academic Press.

    Chapter  Google Scholar 

  19. Zhao, X. Y., Li, G. Y., Liu, Y., Chai, L. M., Chen, J. X., Zhang, Y., et al. (2008). Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo. British Journal of Pharmacology, 154(1), 105–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ratnaike, R. N. (2003). Acute and chronic arsenic toxicity. Postgraduate Medical Journal, 79(933), 391–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li, Y. M., & Broome, J. D. (1999). Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells. Cancer Research, 59, 776–780.

    CAS  PubMed  Google Scholar 

  22. Mathews, V. V., Paul, M. S., Abhilash, M., Manju, A., Abhilash, S., & Nair, R. H. (2014). Mitigation of hepatotoxic effects of arsenic trioxide through omega-3 fatty acid in rats. Toxicology and Industrial Health, 30(9), 806–813.

    Article  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

  24. Yeh, J. Y., Cheng, L. C., Ou, B. R., Whanger, D. P., & Chang, L. W. (2002). Differential influences of various arsenic compounds on glutathione redox status and antioxidative enzymes in porcine endothelial cells. Cellular and Molecular Life Sciences, 59(11), 1972–1982.

    Article  CAS  PubMed  Google Scholar 

  25. Flora, S. J. (2011). Arsenic-induced oxidative stress and its reversibility. Free Radical Biology and Medicine, 51(2), 257–281.

    Article  CAS  PubMed  Google Scholar 

  26. Li, M., Zhu, Q., Hu, C., Giesy, J. P., Kong, Z., & Cui, Y. (2011). Protective effects of eicosapentaenoic acid on genotoxicity and oxidative stress of cyclophosphamide in mice. Environmental Toxicology, 26(3), 217–223.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google Scholar 

  29. Kumar, S. H. S., & Anandan, R. (2007). Biochemical studies on the cardioprotective effect of glutamine on tissue antioxidant defense system in isoprenaline-induced myocardial infarction in rats. Journal of Clinical Biochemistry and Nutrition, 40(1), 49–55.

    Article  CAS  Google Scholar 

  30. Hays, A. M., Lantz, R. C., Rodgers, L. S., Sollome, J. J., Vaillancourt, R. R., Andrew, A. S., et al. (2008). Arsenic-induced decreases in the vascular matrix. Toxicologic Pathology, 36, 805–817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iraz, M., Erdogan, H., Ozyurt, B., Ozugurlu, F., Ozgocmen, S., & Fadillioglu, E. (2005). Brief communication: omega-3 essential fatty acid supplementation and erythrocyte oxidant/antioxidant status in rats. Annals of Clinical and Laboratory Science, 35(2), 169–173.

    CAS  PubMed  Google 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.

  34. Fappi, A., Godoy, T. S., Maximino, J. R., Rizzato, V. R., de Neves, J. C., Chadi, G., & Zanoteli, E. (2014). The effects of omega-3 fatty acid supplementation on dexamethasone-induced muscle atrophy. Biomedicine Research International, 2014, 961438.

    Article  Google Scholar 

  35. Zhao, X., Feng, T., Chen, H., Shan, H., Zhang, Y., Lu, Y., & Yang, B. (2008). Arsenic trioxide-induced apoptosis in H9c2 cardiomyocytes: implications in cardiotoxicity. Basic & Clinical Pharmacology & Toxicology, 102(5), 419–425.

    Article  CAS  Google Scholar 

  36. Raghu, K. G., & Cherian, O. L. (2009). Characterization of cytotoxicity induced by arsenic trioxide (a potent anti-APL drug) in rat cardiac myocytes. Journal of Trace Elements in Medicine and Biology, 23, 61–68.

    Article  CAS  PubMed  Google Scholar 

  37. Crow, M. T., Mani, K., Nam, Y. J., & Kitsis, R. N. (2004). The mitochondrial death pathway and cardiac myocyte apoptosis. Circulation Research, 95, 957–970.

    Article  CAS  PubMed  Google Scholar 

  38. Halestrap, A. P. (2009). What is the mitochondrial permeability transition pore? Journal of Molecular and Cellular Cardiology, 46, 821–831.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. School of Biosciences, Mahatma Gandhi University, P.D Hills P.O, Kottayam, Kerala, 686560, India

    Mathews V. Varghese, M. Abhilash, M. V. Sauganth Paul, Manju Alex & R. Harikumaran Nair

Authors
  1. Mathews V. Varghese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Abhilash
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. V. Sauganth Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manju Alex
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Harikumaran Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Harikumaran Nair.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Varghese, M.V., Abhilash, M., Paul, M.V.S. et al. Omega-3 Fatty Acid Protects Against Arsenic Trioxide-Induced Cardiotoxicity In Vitro and In Vivo. Cardiovasc Toxicol 17, 109–119 (2017). https://doi.org/10.1007/s12012-016-9361-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-016-9361-3

Keywords

Search

Navigation