Selective inhibition of cyclooxygenase-2 enhances mitomycin-C-induced apoptosis Journal Article
| Authors: | Hsueh, C. T.; Chiu, C. F.; Kelsen, D. P.; Schwartz, G. K. |
| Article Title: | Selective inhibition of cyclooxygenase-2 enhances mitomycin-C-induced apoptosis |
| Abstract: | Purpose: Cyclooxygenase-2 (COX-2) is involved in antiapoptosis signaling, and its induction may require activation of protein kinase C (PKC). Safingol (SAF), a PKC inhibitor, has been shown to enhance apoptosis induced by mitomycin-C (MMC) in human gastric cancer MKN-74 cells. The aim of this study was to identify the role of COX-2 in MMC-induced apoptosis in MKN- 74 cells. Methods: Protein expression of COX-2 and Bcl-2 and activation of PKCα were examined by Western blot analysis. Apoptosis induction was examined by staining with bisbenzimide trihydrochloride (Hoechst-33258) of condensed chromatin, which characterizes the cells undergoing apoptosis. COX- 2 mRNA levels were examined by Northern blot analysis. Results: After exposure for 1-2 h to 1 μg/ml MMC, upregulation of COX-2 and Bcl-2 protein expression was noted. The activation of PKCα occurred within 1 h of MMC exposure, and temporally preceded the induction of COX-2. Similar results were observed in cells exposed to the PKC activator, 3-phorbol 12-myristate 13-acetate. Cotreatment with SAF and MMC abolished the induction of COX-2 by MMC. Furthermore, NS-398, a selective COX-2 inhibitor, significantly enhanced MMC-induced apoptosis by fivefold from 4 ± 2% (MMC alone) to 20 ± 2% (MMC plus NS-398). There was no discernible change in COX-2 mRNA levels after a 2- h exposure to MMC but a twofold increase after a 24-h exposure. Conclusions: MMC upregulates COX-2 expression, which appears to be an antiapoptotic signal downstream of PKC. Selective inhibition of COX-2 can therefore provide a novel way to enhance MMC-induced apoptosis independent of inhibiting PKC. |
| Keywords: | cancer chemotherapy; controlled study; protein expression; human cell; protein bcl 2; apoptosis; enzyme inhibition; gene expression; membrane proteins; tumor cells, cultured; drug synergism; messenger rna; rna, messenger; cyclooxygenase 2 inhibitors; cyclooxygenase 2; stomach cancer; mitomycin c; fluorescence microscopy; protein kinase c; safingol; antibiotics, antineoplastic; mitomycin; proto-oncogene proteins c-bcl-2; isoenzymes; phorbol esters; northern blotting; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; bcl-2; prostaglandin-endoperoxide synthases; 4 [5 (4 methyl 1 piperazinyl)[2,5' bi 1h benzimidazol] 2' yl]phenol; cyclooxygenase inhibitors; humans; human; priority journal; article |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 45 |
| Issue: | 5 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2000-05-01 |
| Start Page: | 389 |
| End Page: | 396 |
| Language: | English |
| PUBMED: | 10803922 |
| PROVIDER: | scopus |
| DOI: | 10.1007/s002800051007 |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work