Received for publication March 28, 2008.
Revised May 15, 2008.
Accepted for publication June 6, 2008.

Licofelone suppresses prostaglandin E₂ formation by interference with the inducible microsomal prostaglandin E₂ synthase-1

Abstract

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, 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-1-treated A549 cells, being about equipotent to MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a well-recognized mPGES-1 inhibitor. In intact interleukin-1-treated A549 cells, licofelone potently (IC₅₀ < 1 µM) blocked formation of PGE₂ in response to ionophore A23187 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.

Key words: cyclooxygenase, inflammation, leukotriene, lipoxygenase, prostaglandin, prostaglandin E2 synthase