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.
Castaño
E
E
Unitat de Bioquímica, Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet, Barcelona, Spain.
Bartrons
R
R
Gil
J
J
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis; D005347:Fibroblasts; D007527:Isoenzymes; D051379:Mice; D009578:Nitrobenzenes / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D000096926:Benzenesulfonamides
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004247:DNA; D015232:Dinoprostone; D007527:Isoenzymes; D009578:Nitrobenzenes; D010982:Platelet-Derived Growth Factor; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; D013936:Thymidine; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide