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Creatine Supplementation Reduces Doxorubicin-Induced Cardiomyocellular Injury

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Abstract

Heart failure is a common complication of doxorubicin (DOX) therapy. Previous studies have shown that DOX adversely impacts cardiac energy metabolism, and the ensuing energy deficiencies antedate clinical manifestations of cardiac toxicity. Brief exposure of cultured cardiomyocytes to DOX significantly decreases creatine transport, which is the cell’s sole source of creatine. We present the results of a study performed to determine if physiological creatine supplementation (5 mmol/L) could protect cardiomyocytes in culture from cellular injury resulting from exposure to therapeutic levels of DOX. Creatine supplementation significantly decreased cytotoxicity, apoptosis, and reactive oxygen species production caused by DOX. The protective effect was specific to creatine and depended on its transport into the cell.

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References

  1. Lipshultz, S. E., Colan, S. D., Gelber, R. D., Perez-Atayde, A. R., Sallan, S. E., & Sanders, S. P. (1991). Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. New England Journal of Medicine, 324, 808–815.

    Article  CAS  PubMed  Google Scholar 

  2. Tokarska-Schlattner, M., Zaugg, M., Zuppinger, C., Wallimann, T., & Schlattner, U. (2006). New insights into doxorubicin-induced cardiotoxicity: The critical role of cellular energetics. Journal of Molecular and Cellular Cardiology, 41, 389–405.

    Article  CAS  PubMed  Google Scholar 

  3. Tokarska-Schlattner, M., Wallimann, T., & Schlattner, U. (2006). Alterations in myocardial energy metabolism induced by the anti-cancer drug doxorubicin. Comptes Rendus Biologies, 329, 657–668.

    Article  CAS  PubMed  Google Scholar 

  4. Maslov, M., Chacko, V., Hirsch, G., Akki, A., Leppo, M., Steenbergen, C., et al. (2010). Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction. American Journal of Physiology Heart and Circulatory Physiology, 299, H332–H337.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Wyss, M., & Kaddurah-Daouk, R. (2000). Creatine and creatinine metabolism. Physiological Reviews, 80, 1107–1213.

    CAS  PubMed  Google Scholar 

  6. Ohhara, H., Kanaide, H., & Nakamura, M. (1981). A protective effect of coenzyme Q10 on the adriamycin-induced cardiotoxicity in the isolated perfused rat heart. Journal of Molecular and Cellular Cardiology, 13, 741–752.

    Article  CAS  PubMed  Google Scholar 

  7. Seraydarian, M. W., Artaza, L., & Goodman, M. F. (1977). Adriamycin: Effect on mammalian cardiac cells in culture. I. Cell population and energy metabolism. Journal of Molecular and Cellular Cardiology, 9, 375–382.

    Article  CAS  PubMed  Google Scholar 

  8. Neubauer, S. (2007). The failing heart—an engine out of fuel. New England Journal of Medicine, 356, 1140–1151.

    Article  PubMed  Google Scholar 

  9. Ingwall, J. S. (2009). Energy metabolism in heart failure and remodelling. Cardiovascular Research, 81, 412–419.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Neubauer, S., Horn, M., Cramer, M., Harre, K., Newell, J. B., Peters, W., et al. (1997). Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation, 96, 2190–2196.

    Article  CAS  PubMed  Google Scholar 

  11. Nash, S., Giros, B., Kingsmore, S., Rochelle, J., Suter, S., Gregor, P., et al. (1994). Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Receptors and Channels, 2, 165–174.

    CAS  PubMed  Google Scholar 

  12. Darrabie, M. D., Arciniegas, A. J., Mishra, R., Bowles, D. E., Jacobs, D. O., & Santacruz, L. (2011). AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes. American Journal of Physiology-Endocrinology and Metabolism, 300, E870–E876.

    Article  CAS  PubMed  Google Scholar 

  13. Darrabie, M. D., Zhao, Z. F., Goers, L., Santacruz-Toloza, L., Toloza, E. M., & Jacobs, D. O. (2007). Creatine transport is modulated by PKC and PPI/PP2A. Biophysical Journal, 92, 63a.

  14. Neubauer, S., Remkes, H., Spindler, M., Horn, M., Wiesmann, F., Prestle, J., et al. (1999). Downregulation of the Na(+)-creatine cotransporter in failing human myocardium and in experimental heart failure. Circulation, 100, 1847–1850.

    Article  CAS  PubMed  Google Scholar 

  15. Ten Hove, M., Chan, S., Lygate, C., Monfared, M., Boehm, E., Hulbert, K., et al. (2005). Mechanisms of creatine depletion in chronically failing rat heart. Journal of Molecular and Cellular Cardiology, 38, 309–313.

    Article  PubMed  Google Scholar 

  16. Darrabie, M. D., Arciniegas, A. J., Mantilla, J. G., Mishra, R., Pinilla Vera, M., Santacruz, L. & Jacobs, D. O. (2012). Exposing cardiomyocytes to subclinical concentrations of doxorubicin rapidly reduces their creatine transport. American Journal of Physiology-Heart and Circulatory Physiology.

  17. Greene, R. F., Collins, J. M., Jenkins, J. F., Speyer, J. L., & Myers, C. E. (1983). Plasma pharmacokinetics of adriamycin and adriamycinol: Implications for the design of in vitro experiments and treatment protocols. Cancer Research, 43, 3417–3421.

    CAS  PubMed  Google Scholar 

  18. White, S. M., Constantin, P. E., & Claycomb, W. C. (2004). Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. American Journal of Physiology Heart and Circulatory Physiology, 286, H823–H829.

    Article  CAS  PubMed  Google Scholar 

  19. Persky, A. M., Muller, M., Derendorf, H., Grant, M., Brazeau, G. A., & Hochhaus, G. (2003). Single- and multiple-dose pharmacokinetics of oral creatine. Journal of Clinical Pharmacology, 43, 29–37.

    Article  CAS  PubMed  Google Scholar 

  20. Sartini, S., Sestili, P., Colombo, E., Martinelli, C., Bartolini, F., Ciuffoli, S., et al. (2012). Creatine affects in vitro electrophysiological maturation of neuroblasts and protects them from oxidative stress. Journal of Neuroscience Research, 90, 435–446.

    Article  CAS  PubMed  Google Scholar 

  21. Gewirtz, D. A. (1999). A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochemical Pharmacology, 57, 727–741.

    Article  CAS  PubMed  Google Scholar 

  22. Minotti, G., Menna, P., Salvatorelli, E., Cairo, G., & Gianni, L. (2004). Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews, 56, 185–229.

    Article  CAS  PubMed  Google Scholar 

  23. Berthiaume, J. M., & Wallace, K. B. (2007). Persistent alterations to the gene expression profile of the heart subsequent to chronic Doxorubicin treatment. Cardiovascular Toxicology, 7, 178–191.

    Article  CAS  PubMed  Google Scholar 

  24. Berthiaume, J. M., & Wallace, K. B. (2007). Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biology and Toxicology, 23, 15–25.

    Article  CAS  PubMed  Google Scholar 

  25. Tokarska-Schlattner, M., Zaugg, M., da Silva, R., Lucchinetti, E., Schaub, M. C., Wallimann, T., et al. (2005). Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. American Journal of Physiology Heart and Circulatory Physiology, 289, H37–H47.

    Article  CAS  PubMed  Google Scholar 

  26. Gupta, A., Rohlfsen, C., Leppo, M. K., Chacko, V. P., Wang, Y., Steenbergen, C., et al. (2013). Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity. PLoS One, 8, e74675.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Tokarska-Schlattner, M., Dolder, M., Gerber, I., Speer, O., Wallimann, T., & Schlattner, U. (2007). Reduced creatine-stimulated respiration in doxorubicin challenged mitochondria: Particular sensitivity of the heart. Biochimica et Biophysica Acta, 1767, 1276–1284.

    Article  CAS  PubMed  Google Scholar 

  28. Darrabie, M. D., Arciniegas, A. J. L., Mishra, R., Bowles, D. E., Jacobs, D. O., & Santacruz, L. (2011). AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes. American Journal of Physiology-Endocrinology and Metabolism, 300, E870–E876.

    Article  CAS  PubMed  Google Scholar 

  29. Prass, K., Royl, G., Lindauer, U., Freyer, D., Megow, D., Dirnagl, U., et al. (2007). Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. Journal of Cerebral Blood Flow and Metabolism, 27, 452–459.

    Article  CAS  PubMed  Google Scholar 

  30. Sestili, P., Martinelli, C., Bravi, G., Piccoli, G., Curci, R., Battistelli, M., et al. (2006). Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radical Biology & Medicine, 40, 837–849.

    Article  CAS  Google Scholar 

  31. Sestili, P., Martinelli, C., Colombo, E., Barbieri, E., Potenza, L., Sartini, S., et al. (2011). Creatine as an antioxidant. Amino Acids, 40, 1385–1396.

    Article  CAS  PubMed  Google Scholar 

  32. Sestili, P., Barbieri, E., Martinelli, C., Battistelli, M., Guescini, M., Vallorani, L., et al. (2009). Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts. Molecular Nutrition & Food Research, 53, 1187–1204.

    Article  CAS  Google Scholar 

  33. Zhu, S., Li, M., Figueroa, B. E., Liu, A., Stavrovskaya, I. G., Pasinelli, P., et al. (2004). Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. Journal of Neuroscience, 24, 5909–5912.

    Article  CAS  PubMed  Google Scholar 

  34. Perasso, L., Spallarossa, P., Gandolfo, C., Ruggeri, P., & Balestrino, M. (2013). Therapeutic use of creatine in brain or heart ischemia: available data and future perspectives. Medicinal Research Reviews, 33, 336–363.

    Article  CAS  PubMed  Google Scholar 

  35. Dedeoglu, A., Kubilus, J. K., Yang, L., Ferrante, K. L., Hersch, S. M., Beal, M. F., et al. (2003). Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. Journal of Neurochemistry, 85, 1359–1367.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Lygate, C. A., Bohl, S., ten Hove, M., Faller, K. M., Ostrowski, P. J., Zervou, S., et al. (2012). Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction. Cardiovascular Research, 96, 466–475.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Saks, V., Kuznetsov, A. V., Gonzalez-Granillo, M., Tepp, K., Timohhina, N., Karu-Varikmaa, M., et al. (2012). Intracellular energetic units regulate metabolism in cardiac cells. Journal of Molecular and Cellular Cardiology, 52, 419–436.

    Article  CAS  PubMed  Google Scholar 

  38. Couture, L., Nash, J. A., & Turgeon, J. (2006). The ATP-binding cassette transporters and their implication in drug disposition: A special look at the heart. Pharmacological Reviews, 58, 244–258.

    Article  CAS  PubMed  Google Scholar 

  39. Olson, R. D., Mushlin, P. S., Brenner, D. E., Fleischer, S., Cusack, B. J., Chang, B. K., et al. (1988). Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proceedings of the National Academy of Sciences of the United States of America, 85, 3585–3589.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by the Department of Surgery at Duke University Medical Center and performed in grateful remembrance of the life and times of Helen Marie Jacobs. The authors gratefully acknowledge Drs Ivan Spasojevic and Karel Base from the Pharmacokinetics/Pharmacodynamics Bioanalytical Core Laboratory (Duke Cancer Institute) for assistance with LC–ESI–MS/MS.

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Authors and Affiliations

  1. Surgery Department, Duke University Medical Center, Durham, NC, 20710, USA

    Marcus D. Darrabie, Jose Gabriel Mantilla, Rajashree Mishra, Bryan J. Feger & Danny O. Jacobs

  2. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA

    Lucia Santacruz

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  1. Lucia Santacruz
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  2. Marcus D. Darrabie
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  6. Danny O. Jacobs
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Corresponding author

Correspondence to Lucia Santacruz.

Additional information

Lucia Santacruz and Marcus D. Darrabie have contributed equally to this work.

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Santacruz, L., Darrabie, M.D., Mantilla, J.G. et al. Creatine Supplementation Reduces Doxorubicin-Induced Cardiomyocellular Injury. Cardiovasc Toxicol 15, 180–188 (2015). https://doi.org/10.1007/s12012-014-9283-x

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