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CELLULAR AND MOLECULAR

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Pharmaceutical Institute, University of Tuebingen, Tuebingen, Germany (A.K., U.S., U.B., S.L., W.A., O.W.); and Institute for Clinical and Experimental Transfusion Medicine, University Medical Center Tuebingen, Tuebingen, Germany (H.N.)

The anti-inflammatory drug licofelone [=ML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE₂ in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of licofelone with enzymes participating in PGE₂ biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE₂ synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC₅₀ = 0.8 µM), whereas isolated COX-2 was less affected (IC₅₀ > 30 µM). However, licofelone efficiently blocked the conversion of PGH₂ to PGE₂ mediated by mPGES-1 (IC₅₀ = 6 µM) derived from microsomes of interleukin-1β-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1β-treated A549 cells, licofelone potently (IC₅₀ < 1 µM) blocked formation of PGE₂ in response to calcimycin (A23187 [GenBank] ) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF₁, used as a biomarker for COX-2 activity, was not inhibited. We conclude that licofelone suppresses inflammatory PGE₂ formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.

Address correspondence to: Dr. Oliver Werz, Department of Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany. E-mail: oliver.werz{at}uni-tuebingen.de