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The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5‐lipoxygenase products
Author(s) -
Fischer L,
Hornig M,
Pergola C,
Meindl N,
Franke L,
Tanrikulu Y,
Dodt G,
Schneider G,
Steinhilber D,
Werz O
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707416
Subject(s) - hela , transfection , chemistry , arachidonate 5 lipoxygenase , cell culture , biochemistry , pharmacology , microbiology and biotechnology , arachidonic acid , biology , cell , enzyme , genetics , gene
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 Ca 2+ ‐ionophore‐activated PMNL (IC 50 =1.7 μ M) but was a weak inhibitor of 5‐LO activity in cell‐free assays (IC 50 ≫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