Skip to main content

The cytotoxicity of celecoxib towards cardiac myocytes is cyclooxygenase-2 independent

Cardiovascular Toxicology volume 7, pages 19–27 (2007)Cite this article

Abstract

The cyclooxygenase (COX)-2 inhibitors celecoxib and rofecoxib were studied for their effects on neonatal rat cardiac myocytes as a possible model for the adverse cardiovascular effects that this class of compounds have shown in their clinical use. Celecoxib, but not rofecoxib, as measured by lactate dehydrogenase release was toxic to myocytes in the low micromolar concentration range. This toxicity shown by celecoxib was also associated with a high degree of myofibrillar disruption similar to that caused by doxorubicin. As measured by induction of caspase-3/7 activity and by changes in nuclear morphology, neither celecoxib nor rofecoxib strongly induced apoptosis in myocytes. The stable prostacyclin analog iloprost was unable to reduce celecoxib-induced damage, which suggested that celecoxib exerted its cytotoxicity through prostacyclin-independent pathways. Celecoxib treatment did not increase intracellular oxidation of 2′,7′-dichlorofluorescin in myocytes, which suggested that its cytotoxicity was not due to reactive oxygen species generation. The evidence supports the conclusion that celecoxib exerts its cytotoxicity towards myocytes through COX-2-independent mediated pathways.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

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

    PubMed  Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. Billingham, M., & Bristow, M. (1984). Evaluation of anthracycline cardiotoxicity: Predictive ability and functional correlation of endomycardial biopsy. Cancer Treatment Symposia, 3, 71–76.

    Google Scholar 

  4. Brooks, G., Poolman, R. A., & Li, J. M. (1998). Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors. Cardiovascular Research, 39, 301–311.

    PubMed  Article  CAS  Google Scholar 

  5. Chan, C. C., Boyce, S., Brideau, C., Charleson, S., Cromlish, W., Ethier, D., Evans, J., Ford-Hutchinson, A. W., Forrest, M. J., Gauthier, J. Y., Gordon, R., Gresser, M., Guay, J., Kargman, S., Kennedy, B., Leblanc, Y., Leger, S., Mancini, J., O’Neill, G. P., Ouellet, M., Patrick, D., Percival, M. D., Perrier, H., Prasit, P., Rodger, I., et al. (1999). Rofecoxib [Vioxx, MK-0966; 4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. The Journal of Pharmacology and Experimental Therapeutics, 290, 551–560.

    PubMed  CAS  Google Scholar 

  6. Cocco, T., Di Paola, M., Papa, S., & Lorusso, M. (1999). Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Free Radical Biology and Medicine, 27, 51–59.

    PubMed  Article  CAS  Google Scholar 

  7. Davies, N. M., McLachlan, A. J., Day, R. O., & Williams, K. M. (2000). Clinical pharmacokinetics and pharmacodynamics of celecoxib: A selective cyclo-oxygenase-2 inhibitor. Clinical Pharmacokinetics, 38, 225–242.

    PubMed  Article  CAS  Google Scholar 

  8. Davies, N. M., Teng, X. W., & Skjodt, N. M. (2003). Pharmacokinetics of rofecoxib: A specific cyclo-oxygenase-2 inhibitor. Clinical Pharmacokinetics, 42, 545–556.

    PubMed  Article  CAS  Google Scholar 

  9. Dowd, N. P., Scully, M., Adderley, S. R., Cunningham, A. J., & Fitzgerald, D. J. (2001). Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. The Journal of Clinical Investigation, 108, 585–590.

    PubMed  Article  CAS  Google Scholar 

  10. Fosslien, E. (2005). Cardiovascular complications of non-steroidal anti-inflammatory drugs. Annals of Clinical and Laboratory Science, 35, 347–385.

    PubMed  CAS  Google Scholar 

  11. Gabizon, A. A., Lyass, O., Berry, G. J., & Wildgust, M. (2004). Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies. Cancer Investigation, 22, 663–669.

    PubMed  Article  CAS  Google Scholar 

  12. Grosser, T., Fries, S., & FitzGerald, G. A. (2006). Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. The Journal of Clinical Investigation, 116, 4–15.

    PubMed  Article  CAS  Google Scholar 

  13. Hasinoff, B. B., Abram, M. E., Barnabé, N., Khelifa, T., Allan, W. P., & Yalowich, J. C. (2001). The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. Molecular Pharmacology, 59, 453–461.

    PubMed  CAS  Google Scholar 

  14. Hasinoff, B. B., Abram, M. E., Chee, G.-L., Huebner, E., Byard, E. H., Barnabé, N., Ferrans, V. J., Yu, Z.-X., & Yalowich, J. C. (2000). The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces endopolyploidy in Chinese hamster ovary cells. The Journal of Pharmacology and Experimental Therapeutics, 295, 474–483.

    PubMed  CAS  Google Scholar 

  15. 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.

    PubMed  Article  CAS  Google Scholar 

  16. Kearney, P. M., Baigent, C., Godwin, J., Halls, H., Emberson, J.R., & Patrono, C. (2006). Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. British Medical Journal, 332, 1302–1308.

    PubMed  Article  CAS  Google Scholar 

  17. Knudsen, J. F., Carlsson, U., Hammarstrom, P., Sokol, G. H., & Cantilena, L. R. (2004). The cyclooxygenase-2 inhibitor celecoxib is a potent inhibitor of human carbonic anhydrase II. Inflammation, 28, 285–290.

    PubMed  Article  CAS  Google Scholar 

  18. 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 Cell Cardiology, 28, 1737–1746.

    Article  CAS  Google Scholar 

  19. Lim, C. C., Zuppinger, C., Guo, X., Kuster, G. M., Helmes, M., Eppenberger, H. M., Suter, T. M., Liao, R., & Sawyer, D. B. (2004). Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. The Journal of Biological Chemistry, 279, 8290–8299.

    PubMed  Article  CAS  Google Scholar 

  20. Lin, H. P., Kulp, S. K., Tseng, P. H., Yang, Y. T., Yang, C. C., & Chen, C. S. (2004). Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms. Molecular Cancer Therapeutics, 3, 1671–1680.

    PubMed  CAS  Google Scholar 

  21. Maier, T. J., Schilling, K., Schmidt, R., Geisslinger, G., & Grosch, S. (2004). Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochemical Pharmacology, 67, 1469–1478.

    PubMed  Article  CAS  Google Scholar 

  22. Mitchell, J. A., & Warner, T. D. (2006). COX isoforms in the cardiovascular system: Understanding the activities of non-steroidal anti-inflammatory drugs. Nature Reviews Drug Discovery, 5, 75–86.

    PubMed  Article  CAS  Google Scholar 

  23. O’Connell, T. D., Berry, J. E., Jarvis, A. K., Somerman, M. J., & Simpson, R. U. (1997). 1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy. The American Journal of Physiology, 272, H1751–H1758.

    PubMed  CAS  Google Scholar 

  24. O’Malley, Y. Q., Reszka, K. J., & Britigan, B. E. (2004). Direct oxidation of 2′,7′-dichlorodihydrofluorescein by pyocyanin and other redox-active compounds independent of reactive oxygen species production. Free Radical Biology and Medicine, 36, 90–100.

    PubMed  Article  CAS  Google Scholar 

  25. Solomon, S. D., McMurray, J. J., Pfeffer, M. A., Wittes, J., Fowler, R., Finn, P., Anderson, W.F., Zauber, A., Hawk, E., & Bertagnolli, M. (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. The New England Journal of Medicine, 352, 1071–1080.

    PubMed  Article  CAS  Google Scholar 

  26. Subhashini, J., Mahipal, S. V., & Reddanna, P. (2005). Anti-proliferative and apoptotic effects of celecoxib on human chronic myeloid leukemia in vitro. Cancer Letters, 224, 31–43.

    PubMed  CAS  Google Scholar 

  27. Tong, Z., Wu, X., Chen, C. S., & Kehrer, J. P. (2006). Cytotoxicity of a non-cyclooxygenase-2 inhibitory derivative of celecoxib in non-small-cell lung cancer A549 cells. Lung Cancer, 52, 117–124.

    PubMed  Article  Google Scholar 

  28. Wang, D., Wang, M., Cheng, Y., & Fitzgerald, G. A. (2005). Cardiovascular hazard and non-steroidal anti-inflammatory drugs. Current Opinion in Pharmacology, 5, 204–210.

    PubMed  Article  CAS  Google Scholar 

  29. Zhang, G. S., Liu, D. S., Dai, C. W., & Li, R. J. (2006). Antitumor effects of celecoxib on K562 leukemia cells are mediated by cell-cycle arrest, caspase-3 activation, and downregulation of Cox-2 expression and are synergistic with hydroxyurea or imatinib. American Journal of Hematology, 81, 242–255.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Canadian Institutes of Health Research, the Canada Research Chairs program, the Province of Manitoba, through the Manitoba Research and Innovation Fund and a Canada Research Chair in Drug Development for Brian Hasinoff.

Author information

Affiliations

  1. Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, R3T 2N2, Winnipeg, MB, Canada

    Brian B. Hasinoff, Daywin Patel & Xing Wu

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

  3. Xing Wu
    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. & Wu, X. The cytotoxicity of celecoxib towards cardiac myocytes is cyclooxygenase-2 independent. Cardiovasc Toxicol 7, 19–27 (2007). https://doi.org/10.1007/s12012-007-0002-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-007-0002-8

Keywords

  • Celecoxib
  • Rofecoxib
  • Cyclooxygenase
  • Myocyte
  • COX-2
  • Apoptosis
  • Iloprost
  • Cytotoxicity