Stimulus dependence of non-steroidal antiinflammatory drug potency in a cellular assay of prostaglandin H synthase-2

The prostaglandin H synthase-2 selective non-steroidal antiinflammatory drugs nimesulide, NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide), flosulide and SC 58125 (5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H- pyrazole) as well as the non-selective non-steroidal antiinflammatory drugs indomethacin, meclofenamate and ibuprofen were compared in a WISH (human amnionic epithelial cell) cellular assay of prostaglandin H synthase-2 activity. Varying amounts of prostaglandin E-2 were induced in WISH cells using either interleukin-1 beta, tumor necrosis factor-alpha or phorbol 12-myristate 13-acetate, alone or in combination, or with okadaic acid as stimulants. The results from these studies demonstrated that under conditions which generate greater amounts of prostaglandin E-2, the potency of both prostaglandin H synthase-2 selective and non-selective non-steroidal antiinflammatory drugs may be reduced. Dexamethasone, a transcriptional inhibitor of prostaglandin H synthase-2, also became progressively less effective in cells activated by combinations of stimuli or with okadaic acid. We conclude that decreases in potency under conditions of high levels of prostaglandin H synthase-2 expression and prostaglandin E-2 production are observed equally with prostaglandin H synthase-2 selective and non-selective inhibitors. (C) 1997 Elsevier Science B.V.