Skip to main content
SpringerLink
Log in

Mechanisms of Myocyte Cytotoxicity Induced by the Multikinase Inhibitor Sorafenib

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

The use of the anticancer multikinase inhibitor sorafenib is associated with cardiac ischemia or infarction and an increase in hypertension. We investigated various mechanisms that might be responsible for its cardiotoxicity in a neonatal rat myocyte model. As measured by lactate dehydrogenase release, sorafenib treatment of myocytes caused dose-dependent damage at therapeutically relevant concentrations. It had been hypothesized that inhibition of RAF1 and BRAF kinases may be responsible for sorafenib-induced cardiotoxicity. However, because sorafenib treatment did not inhibit phosphorylation of ERK (extracellular signal-regulated kinase), it was concluded that sorafenib did not exert its damaging effects through RAF inhibition of the RAF/MEK/ERK kinase cascade. The clinically approved doxorubicin cardioprotective agent dexrazoxane did not protect myocytes from damage. At lower sorafenib concentrations, at least, these results are consistent with sorafenib not being able to induce significant oxidative damage. In conclusion, given the extreme lack of kinase selectivity that sorafenib exhibits, it is likely that inhibition of kinases other than RAF, or combinations of kinases, contributes to the cardiotoxic effects of sorafenib.

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

Similar content being viewed by others

References

  1. Strumberg, D., Clark, J. W., Awada, A., Moore, M. J., Richly, H., Hendlisz, A., et al. (2007). Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors. The Oncologist, 12, 426–437.

    Article  CAS  PubMed  Google Scholar 

  2. Chen, M. H., Kerkela, R., & Force, T. (2008). Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation, 118, 84–95.

    Article  PubMed  Google Scholar 

  3. Wilhelm, S. M., Carter, C., Tang, L., Wilkie, D., McNabola, A., Rong, H., et al. (2004). BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Research, 64, 7099–7109.

    Article  CAS  PubMed  Google Scholar 

  4. Karaman, M. W., Herrgard, S., Treiber, D. K., Gallant, P., Atteridge, C. E., Campbell, B. T., et al. (2008). A quantitative analysis of kinase inhibitor selectivity. Nature Biotechnology, 26, 127–132.

    Article  CAS  PubMed  Google Scholar 

  5. Kane, R. C., Farrell, A. T., Madabushi, R., Booth, B., Chattopadhyay, S., Sridhara, R., et al. (2009). Sorafenib for the treatment of unresectable hepatocellular carcinoma. The Oncologist, 14, 95–100.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, X., Crespo, A., & Fernandez, A. (2008). Turning promiscuous kinase inhibitors into safer drugs. Trends in Biotechnology, 26, 295–301.

    Article  PubMed  Google Scholar 

  7. Orphanos, G. S., Ioannidis, G. N., & Ardavanis, A. G. (2009). Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncologica, 48, 964–970.

    Article  CAS  PubMed  Google Scholar 

  8. FDA. (2009). FDA sorafenib product label information 2009. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm129234.htm. Accessed September 21, 2009.

  9. Schmidinger, M., Zielinski, C. C., Vogl, U. M., Bojic, A., Bojic, M., Schukro, C., et al. (2008). Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology, 26, 5204–5212.

    Article  PubMed  Google Scholar 

  10. Hasinoff, B. B., Patel, D., & O’Hara, K. A. (2008). Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib. Molecular Pharmacology, 74, 1722–1728.

    Article  CAS  PubMed  Google Scholar 

  11. Force, T., Krause, D. S., & Van Etten, R. A. (2007). Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature Reviews Cancer, 7, 332–344.

    Article  CAS  PubMed  Google Scholar 

  12. Hasinoff, B. B., & Herman, E. H. (2007). Dexrazoxane: How it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovascular Toxicology, 7, 140–144.

    Article  CAS  PubMed  Google Scholar 

  13. Hasinoff, B. B., Patel, D., & Wu, X. (2003). The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Free Radical Biology and Medicine, 35, 1469–1479.

    Article  CAS  PubMed  Google Scholar 

  14. Barnabé, N., Butler, M., & Hasinoff, B. B. (2001). The effect of the catalytic topoisomerase II inhibitor dexrazoxane (ICRF-187) on CC9C10 hybridoma viability and productivity. Cytotechnology, 37, 107–117.

    Article  PubMed  Google Scholar 

  15. Hasinoff, B. B., Patel, D., & Wu, X. (2007). The cytotoxicity of celecoxib towards cardiac myocytes is cyclooxygenase-2 independent. Cardiovascular Toxicology, 7, 19–27.

    Article  CAS  PubMed  Google Scholar 

  16. Schroeder, P. E., Patel, D., & Hasinoff, B. B. (2008). The dihydroorotase inhibitor 5-aminoorotic acid inhibits the metabolism in the rat of the cardioprotective drug dexrazoxane and its one-ring open metabolites. Drug Metabolism and Disposition, 36, 1780–1785.

    Article  CAS  PubMed  Google Scholar 

  17. Adderley, S. R., & Fitzgerald, D. J. (1999). Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. Journal of Biological Chemistry, 274, 5038–5046.

    Article  CAS  PubMed  Google Scholar 

  18. Hershko, C., Link, G., Tzahor, M., Kaltwasser, J. P., Athias, P., Grynberg, A., et al. (1993). Anthracycline cytotoxicity is potentiated by iron and inhibited by deferoxamine: Studies in rat heart cells in culture. Journal of Laboratory and Clinical Medicine, 122, 245–251.

    CAS  PubMed  Google Scholar 

  19. Barnabé, N., Zastre, J., Venkataram, S., & Hasinoff, B. B. (2002). Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Free Radical Biology and Medicine, 33, 266–275.

    Article  PubMed  Google Scholar 

  20. Li, F., Wang, X., Capasso, J. M., & Gerdes, A. M. (1996). Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. Journal of Molecular and Cellular Cardiology, 28, 1737–1746.

    Article  CAS  PubMed  Google Scholar 

  21. Will, Y., Dykens, J. A., Nadanaciva, S., Hirakawa, B., Jamieson, J., Marroquin, L. D., et al. (2008). Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicological Sciences, 106, 153–161.

    Article  CAS  PubMed  Google Scholar 

  22. Liu, L., Cao, Y., Chen, C., Zhang, X., McNabola, A., Wilkie, D., et al. (2006). Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Research, 66, 11851–11858.

    Article  CAS  PubMed  Google Scholar 

  23. Wang, G. Q., Gong, Y., Burczynski, F. J., & Hasinoff, B. B. (2008). Cell lysis with dimethyl sulfoxide produces stable homogeneous solutions in the dichlorofluorescin oxidative stress assay. Free Radical Research, 42, 435–441.

    Article  CAS  PubMed  Google Scholar 

  24. Yamaguchi, O., Watanabe, T., Nishida, K., Kashiwase, K., Higuchi, Y., Takeda, T., et al. (2004). Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. Journal of Clinical Investigation, 114, 937–943.

    CAS  PubMed  Google Scholar 

  25. Harris, I. S., Zhang, S., Treskov, I., Kovacs, A., Weinheimer, C., & Muslin, A. J. (2004). Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation, 110, 718–723.

    Article  CAS  PubMed  Google Scholar 

  26. McCubrey, J. A., Lahair, M. M., & Franklin, R. A. (2006). Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxidants & Redox Signaling, 8, 1775–1789.

    Article  CAS  Google Scholar 

  27. Klein, M., Schermuly, R. T., Ellinghaus, P., Milting, H., Riedl, B., Nikolova, S., et al. (2008). Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation, 118, 2081–2090.

    Article  CAS  PubMed  Google Scholar 

  28. Deeks, E. D., & Keating, G. M. (2006). Sunitinib. Drugs, 66, 2255–2266.

    Article  CAS  PubMed  Google Scholar 

  29. Force, T., & Kerkela, R. (2008). Cardiotoxicity of the new cancer therapeutics-mechanisms of, and approaches to, the problem. Drug Discovery Today, 13, 778–784.

    Article  CAS  PubMed  Google Scholar 

  30. Hsieh, P. C., MacGillivray, C., Gannon, J., Cruz, F. U., & Lee, R. T. (2006). Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation, 114, 637–644.

    Article  CAS  PubMed  Google Scholar 

  31. Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A., & Betsholtz, C. (1999). Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development, 126, 3047–3055.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Canadian Institutes of Health Research, the Canada Research Chairs program and a Canada Research Chair in Drug Development.

Author information

Authors and Affiliations

  1. Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada

    Brian B. Hasinoff & Daywin Patel

Authors
  1. Brian B. Hasinoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daywin Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian B. Hasinoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hasinoff, B.B., Patel, D. Mechanisms of Myocyte Cytotoxicity Induced by the Multikinase Inhibitor Sorafenib. Cardiovasc Toxicol 10, 1–8 (2010). https://doi.org/10.1007/s12012-009-9056-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-009-9056-0

Keywords

Search

Navigation