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Variability of pro-apoptotic properties of cyclooxygenase-2 inhibitors in rheumatoid synovial fibroblasts and cancer cell lines

Recent attention has been focused on selective cyclooxygenase (COX)-2 inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-2 without inhibition of COX-1, resulting in fewer incidences of adverse reactions. Various clinical studies have confirmed that the efficacy of selective COX-2 inhibitors for the patients with rheumatoid arthritis (RA) is similar to that of conventional NSAIDs; however, they cause fewer severe gastrointestinal complications. Recently, we found that some conventional NSAIDs such as indometacin and diclofenac induced apoptosis in association with activation of peroxisome proliferator-activated receptor gamma (PPARγ) in rheumatoid synovial fibroblasts (RSF). We also found that celecoxib, a selective COX-2 inhibitor, specifically induced apoptosis and inhibited proliferation of RSF in COX-2-independent and PPARγ-independent manners. Other selective COX-2 inhibitors such as etodolac, meloxicam, nimesulide, NS-398, and rofecoxib, even in very high concentrations, did not induce apoptosis in RSF at all. These results suggested that some NSAIDs including a selective COX-2 inhibitor might be used as disease-modifying antirheumatic drugs if they could be delivered with good efficiency to the affected synovia of patients with RA. It is well known that administration of celecoxib decreases the number of colon polyps in patients with familiar adenomatous polyposis. The pro-apoptotic effect of celecoxib was also observed in several kinds of cell lines derived from colon cancer and ovarian cancer, suggesting a common mechanism of action of celecoxib-induced apotosis among RSF and cancer cell lines. Inactivation of Akt might explain the pro-apoptotic effect of celecoxib on at least colon cancer cell lines.


This work is supported in part by the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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  • Rheumatoid Arthritis
  • Ovarian Cancer
  • Celecoxib
  • Rofecoxib
  • Nimesulide