Cardiovascular Toxicology

, Volume 7, Issue 1, pp 19–27

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

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.

Keywords

Celecoxib Rofecoxib Cyclooxygenase Myocyte COX-2 Apoptosis Iloprost Cytotoxicity 

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Fosslien, E. (2005). Cardiovascular complications of non-steroidal anti-inflammatory drugs. Annals of Clinical and Laboratory Science, 35, 347–385.PubMedGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Faculty of PharmacyUniversity of ManitobaWinnipegCanada

Personalised recommendations