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

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