Inhibition of cyclooxygenase-2 decreases DNA synthesis induced by platelet-derived growth factor in Swiss 3T3 fibroblasts.
NS-398 [N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide], a selective inhibitor of cyclooxygenase-2 (COX-2), inhibited proliferation induced by platelet-derived growth factor (PDGF) in Swiss 3T3 fibroblasts. The effect of NS-398 was found to be concentration-dependent. The half-maximal effect occurred at approximately 0.1 microM. NS-398 decreased mitogenesis at subsaturating PDGF concentrations and the inhibitory effect of NS-398 was overcome by increasing PDGF concentration. SC-236, another COX-2 selective inhibitor, also inhibited PDGF-induced proliferation. In contrast, two selective COX-1 inhibitors, valeryl salicylate and ketorolac, had no significant inhibitory effect on PDGF-stimulated DNA synthesis. The inhibition was obtained when NS-398 was added during the first hour after PDGF addition. At 1 h, PDGF induced COX-2 protein and prostaglandin (PG)E(2) synthesis, and NS-398 blocked the synthesis of PGE(2). The inhibitory effect of NS-398 on PDGF-stimulated DNA synthesis was counteracted by 280 nM PGE(2). The antimitogenic action of NS-398 and SC-236 suggests that selective inhibition of COX-2 may produce antiproliferative effects with substantial safety advantages over nonselective COX inhibitors.