Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3

  • Authors:
    • Byeong Mo Kim
    • Juyoon Won
    • Kyung Ah Maeng
    • Young Soo Han
    • Yeon-Sook Yun
    • Sung Hee Hong
  • View Affiliations

  • Published online on: May 1, 2009     https://doi.org/10.3892/ijo_00000276
  • Pages: 1467-1473
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Abstract

Several lines of evidence suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have a radiosensitizing effect on cancer cells in vitro and in vivo, but little is known about the underlying cellular mechanism. In this study, we found that the treatment with the NSAID nimesulide significantly increased the sensitivity of A549 human non-small cell lung cancer cells to radiotherapy. The combined nimesulide-radiation treatment increased apoptosis, induced the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP), activated caspase-8, and induced cleavage of Bid. A pan-caspase inhibitor, z-VAD-fmk, suppressed this increase in apoptosis and also suppressed the cleavage of caspase-8, caspase-3, and PARP, suggesting a caspase-dependent mechanism. In addition, z-IETD-fmk, a selective caspase-8 inhibitor, suppressed the nimesulide- and radiation-induced cleavage activation of caspase-9, caspase-3, caspase-8, and Bid, and suppressed the concomitant apoptosis, indicating that the nimesulide-induced increase in radiosensitivity was initiated by caspase-8. However, the caspase-3 inhibitor z-DEVD-fmk failed to suppress activation of the caspase-8/Bid pathway, indicating that caspase-3 activation occurred downstream of caspase-8 activation in our experiments. Marked antitumor effects, which were evaluated by measuring protracted tumor regression, were observed when nude mice were treated with a combination of nimesulide at a clinically achievable dose (0.5 mg/kg) and radiation therapy. Our results, demonstrating the radiosensitivity-increasing and tumor growth-inhibiting effects of nimesulide, suggest that nimesulide may be suitable as an adjuvant to enhance the efficacy and selectivity of radiotherapy.

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May 2009
Volume 34 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Kim BM, Won J, Maeng KA, Han YS, Yun Y and Hong SH: Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3. Int J Oncol 34: 1467-1473, 2009
APA
Kim, B.M., Won, J., Maeng, K.A., Han, Y.S., Yun, Y., & Hong, S.H. (2009). Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3. International Journal of Oncology, 34, 1467-1473. https://doi.org/10.3892/ijo_00000276
MLA
Kim, B. M., Won, J., Maeng, K. A., Han, Y. S., Yun, Y., Hong, S. H."Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3". International Journal of Oncology 34.5 (2009): 1467-1473.
Chicago
Kim, B. M., Won, J., Maeng, K. A., Han, Y. S., Yun, Y., Hong, S. H."Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3". International Journal of Oncology 34, no. 5 (2009): 1467-1473. https://doi.org/10.3892/ijo_00000276