| 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. | |
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MedLine Citation:
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PMID: 19360361 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Byeong Mo Kim; Juyoon Won; Kyung Ah Maeng; Young Soo Han; Yeon-Sook Yun; Sung Hee Hong |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of oncology Volume: 34 ISSN: 1019-6439 ISO Abbreviation: Int. J. Oncol. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-04-10 Completed Date: 2009-08-03 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9306042 Medline TA: Int J Oncol Country: Greece |
Other Details:
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Languages: eng Pagination: 1467-73 Citation Subset: IM |
Affiliation:
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Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Nowon-Gu, Seoul 139-706, Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carcinoma, Non-Small-Cell Lung / pathology, radiotherapy* Caspase 3 / metabolism* Caspase 8 / metabolism* Cell Line, Tumor Cyclooxygenase 2 Inhibitors / pharmacology Drug Synergism Enzyme Activation / drug effects Female Humans Lung Neoplasms / pathology, radiotherapy* Mice Mice, Inbred BALB C Mice, Nude Radiation, Ionizing* Radiation-Sensitizing Agents / pharmacology, therapeutic use Substrate Specificity / drug effects Sulfonamides / pharmacology*, therapeutic use* Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Cyclooxygenase 2 Inhibitors; 0/Radiation-Sensitizing Agents; 0/Sulfonamides; 51803-78-2/nimesulide; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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