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Cyclooxygenase inhibitors induce apoptosis in sinonasal cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene

 Jeong Hong Kim  ;  Jung Hyun Chang  ;  Kwang-Hyeon Rhee  ;  Joo-Heon Yoon  ;  Soon Ho Kwon  ;  Keejae Song  ;  Kun Wayn Lee  ;  Chang Il Cho  ;  Ju Hyun Jeon  ;  Kyung-Su Kim 
 INTERNATIONAL JOURNAL OF CANCER, Vol.122(8) : 1765-1773, 2008 
Journal Title
Issue Date
Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology* ; Antineoplastic Agents/pharmacology* ; Apoptosis/drug effects ; Blotting, Western ; Carcinoma/drug therapy* ; Carcinoma/metabolism ; Carcinoma/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclooxygenase Inhibitors/pharmacology* ; Cytokines/drug effects ; Cytokines/genetics ; Cytokines/metabolism* ; Dose-Response Relationship, Drug ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/drug effects ; Growth Differentiation Factor 15 ; Humans ; Indomethacin/pharmacology* ; Mice ; Mice, Nude ; Paranasal Sinus Neoplasms/drug therapy* ; Paranasal Sinus Neoplasms/metabolism ; Paranasal Sinus Neoplasms/pathology ; RNA, Small Interfering ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Transfection ; Up-Regulation
NSAIDs ; NAG‐1 ; sinonasal cancer ; chemoprevention
Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) has recently been shown to be induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and to have proapoptotic and antitumorigenic activities. Although sulindac sulfide induced apoptosis in sinonasal cancer cells, the relationship between NAG-1 and NSAIDs has not been determined. In this study, we investigated the induction of apoptosis in sinonasal cancer cells treated by various NSAIDs and the role of NAG-1 expression in this induction. The effect of NSAIDs on normal human nasal epithelial (NHNE) cells was also examined to evaluate their safety on normal cells. Finally, the in vivo anti-tumorigenic activity of NSAIDs in mice was investigated. In AMC-HN5 human sinonasal carcinoma cells, indomethacin was the most potent NAG-1 inducer and caused NAG-1 expression in a time- and dose-dependent manner. The induction of NAG-1 expression preceded the induction of apoptosis. Conditioned medium from NAG-1-overexpressing Drosophila cells inhibited proliferation of sinonasal cancer cells and induced apoptosis. In addition, in NAG-1 small interfering RNA-transfected cells, apoptosis induced by indomethacin was suppressed. In contrast, NAG-1 expression and apoptosis were not induced by NSAIDs or conditioned medium in NHNE cells. Furthermore, indomethacin induced a dose-dependent in vivo increase in the expression of NAG-1 mRNA in the mice tumors and the volume of xenograft tumors of AMC-HN5 cells in indomethacin-treated nude mice was reduced compared to that in control mice. In conclusion, indomethacin exerts proapoptotic and antitumorigenic effects in sinonasal cancer cells through the induction of NAG-1 and can be considered a safe and effective chemopreventive agent against sinonasal cancer
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Soon Ho(권순호)
Kim, Kyung Su(김경수) ORCID logo https://orcid.org/0000-0003-1460-0640
Yoon, Joo Heon(윤주헌)
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