The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5‐lipoxygenase products

摘要: Background and purpose: Licofelone is a dual inhibitor of the cyclooxygenase 5-lipoxygenase (5-LO) pathway, has been developed for treatment inflammatory diseases. Here, we investigated molecular mechanisms underlying inhibition by licofelone formation 5-LO products. Experimental approach: The efficacy to inhibit products was analysed in human isolated polymorphonuclear leukocytes (PMNL) or transfected HeLa cells, as well cell-free assays using respective cell homogenates purified recombinant 5-LO. Moreover, effects on subcellular redistribution were studied. Key results: Licofelone potently blocked synthesis Ca2+-ionophore-activated PMNL (IC50=1.7 μM) but weak activity (IC50≫10 μM). The structures MK-886, an 5-LO-activating protein (FLAP), superimposable. potencies both MK-886 ionophore-activated impaired upon increasing concentration arachidonic acid, under conditions where product evoked genotoxic, oxidative hyperosmotic stress. Furthermore, prevented nuclear PMNL, had observed FLAP inhibitors. Finally, caused only moderate unless co-transfected. Conclusions implications: Our data suggest that potent biosynthesis requires intact cellular environment appears be due interference with FLAP. British Journal Pharmacology (2007) 152, 471–480; doi:10.1038/sj.bjp.0707416; published online 20 August 2007