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

Abstract

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.

• Authors: 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
• Journal: International journal of cancer (Int J Cancer) Vol. 122 Issue 8 Pg. 1765-73 (Apr 15 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18076062 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Cyclooxygenase Inhibitors
• Cytokines
• GDF15 protein, human
• Gdf15 protein, mouse
• Growth Differentiation Factor 15
• RNA, Small Interfering
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclooxygenase Inhibitors (pharmacology)
• Cytokines (drug effects, genetics, 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, metabolism, pathology)
• RNA, Small Interfering
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Transfection
• Up-Regulation