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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. 2009 May; 34(5):1467-73.IJ

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.

Authors+Show Affiliations

Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Nowon-Gu, Seoul 139-706, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19360361

Citation

Kim, Byeong Mo, et al. "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, vol. 34, no. 5, 2009, pp. 1467-73.
Kim BM, Won J, Maeng KA, et al. 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. 2009;34(5):1467-73.
Kim, B. M., Won, J., Maeng, K. A., Han, Y. S., Yun, Y. S., & 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(5), 1467-73.
Kim BM, et al. 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. 2009;34(5):1467-73. PubMed PMID: 19360361.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kim,Byeong Mo, AU - Won,Juyoon, AU - Maeng,Kyung Ah, AU - Han,Young Soo, AU - Yun,Yeon-Sook, AU - Hong,Sung Hee, PY - 2009/4/11/entrez PY - 2009/4/11/pubmed PY - 2009/8/4/medline SP - 1467 EP - 73 JF - International journal of oncology JO - Int J Oncol VL - 34 IS - 5 N2 - 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. SN - 1019-6439 UR - https://www.unboundmedicine.com/medline/citation/19360361/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_ L2 - http://www.spandidos-publications.com/ijo/34/5/1467 DB - PRIME DP - Unbound Medicine ER -