The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2

Tries, S.; Neupert, Werner; Laufer, Stefan

doi:10.1007/pl00000285

Cited by 96 publications

(78 citation statements)

References 47 publications

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“…It was previously found that licofelone suppresses cellular COX-1 in bovine platelets (IC 50 ϭ 0.21 M) (Laufer et al, 1994b) and thromboxane B 2 synthesis in ionophore-stimulated whole blood (IC 50 ϭ 3.9 M) (Tries et al, 2002b) or COX-2-mediated PGE 2 synthesis in ionomycin-stimulated human subchondral osteoblasts (IC 50 Ͻ 0.8 M) (Paredes et al, 2002). To investigate the direct interference of licofelone with isolated COX enzymes, purified ovine COX-1 and purified human recombinant COX-2 were preincubated with licofelone (or vehicle, DMSO) for 5 min; arachidonic acid (5 M for COX-1; 2 M for COX-2) was added and after 5 min, the formation of 12-HHT as the major COX-1/2-derived product under these experimental conditions (Capdevila et al, 1995) was determined.…”

Section: Resultsmentioning

confidence: 99%

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

Koeberle

Siemoneit²,

Bühring³

et al. 2008

J Pharmacol Exp Ther

153

237

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The anti-inflammatory drug licofelone [ϭML3000; 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 PGE 2 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 PGE 2 biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE 2 synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC 50 ϭ 0.8 M), whereas isolated COX-2 was less affected (IC 50 Ͼ 30 M). However, licofelone efficiently blocked the conversion of PGH 2 to PGE 2 mediated by mPGES-1 (IC 50 ϭ 6 M) derived from microsomes of interleukin-1␤-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-1␤-treated A549 cells, licofelone potently (IC 50 Ͻ 1 M) blocked formation of PGE 2 in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF 1␣ , used as a biomarker for COX-2 activity, was not inhibited. We conclude that licofelone suppresses inflammatory PGE 2 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.Prostaglandins (PGs) and leukotrienes are powerful bioactive lipid mediators that are involved not only in numerous homeostatic biological functions but also in inflammation (Funk, 2001). The biosynthesis of PGs is initialized by COX isoenzymes, namely, COX-1, a constitutively expressed enzyme in numerous cell types thought to provide PGs mainly for physiological functions; and COX-2, an inducible isoform in inflammatory cells, primarily producing PGs relevant for inflammation, fever, and pain (Hawkey, 1999). After conversion of arachidonic acid to PGH 2 by COX enzymes, PGH 2 is subsequently isomerized by three different PGE 2 synthases to PGE 2 . Whereas the cytosolic PGE 2 synthase (cPGES) and the membrane-bound PGE 2 synthase (mPGES)-2 are constitutive enzymes, the mPGES-1 is an inducible isoform (Samuelsson et al., 2007). Cotransfection experiments of COX-1/2 with PGES isoenzymes imply that select molecular interactions between COX and PGES isoenzymes cause preferential functional coupling (Murakami et al., 2000;Samuelsson et al., 2007). Thus, cPGES uses PGH 2 produced by COX-1, whereas mPGES-1 receives PGH 2 from COX-2. PGE 2 plays a major role in the pathophysiology of inflammation, pain, and pyresis, but it also regulates physiological functions in the gastrointestinal tract, the kidney, and in the immune and nervous system (Smith, 1989). The nonsteroidal anti-inflamm...

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Section: Resultsmentioning

confidence: 99%

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

Koeberle

Siemoneit²,

Bühring³

et al. 2008

J Pharmacol Exp Ther

153

237

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“…To activate 5-LOX, A-23187 (3 mM) was added and the cells were incubated for 15 min with a slight modification of the previously described procedure. 16) Media was collected and the concentration of the 5-LOX products, cysteinyl leukotrienes (LTC 4 /D 4 /E 4 ), was measured using an ELISA kit (Cayman Chem.) as recommended by the manufacturer.…”

Section: -Lox Assaymentioning

confidence: 99%

Anti-inflammatory Activity of Pectolinarigenin and Pectolinarin Isolated from Cirsium chanroenicum

Lim

Son

Chang

et al. 2008

Biological & Pharmaceutical Bulletin

109

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“…The concentrations of CP-105,696 and MK-571 were selected from previous publications demonstrating selective blockade of LTB 4 and LTD 4 receptors, respectively (Titos et al, 2000;Huang et al, 2004). The licofelone concentration was selected from Tries et al (2002), Marcouiller et al (2005), and Vidal et al (2007).…”

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confidence: 99%

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

Horrillo

Planagumà²,

González-Périz³

et al. 2007

J Pharmacol Exp Ther

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In this study, we examined the relative contribution of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), two major proinflammatory pathways up-regulated in liver disease, to the progression of hepatic inflammation and fibrosis. Separate administration of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-236), a selective COX-2 inhibitor, and CJ-13,610, a 5-LO inhibitor, to carbon tetrachloride-treated mice significantly reduced fibrosis as revealed by the analysis of Sirius Red-stained liver sections without affecting necroinflammation. Conversely, combined administration of SC-236 and 4-[3-[4-(2-methylimidazol-1-yl)-phenylthio]]phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (CJ-13,610) reduced both necroinflammation and fibrosis. These findings were confirmed in5-LO-deficient mice receiving SC-236, which also showed reduced hepatic monocyte chemoattractant protein 1 expression. Interestingly, SC-236 and CJ-13,610 significantly increased the number of nonparenchymal liver cells with apoptotic nuclei (terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive). Additional pharmacological profiling of SC-236 and CJ-13,610 was performed in macrophages, the primary hepatic inflammatory cell type. In these cells, SC-236 inhibited prostaglandin (PG) E 2 formation in a concentration-dependent manner, whereas CJ-13,610 blocked leukotriene B 4 biosynthesis. Of note, the simultaneous addition of SC-236 and CJ-13,610 resulted in a higher inhibitory profile on PGE 2 biosynthesis than the dual COX/5-LO inhibitor licofelone. These drugs differentially regulated interleukin-6 mRNA expression in macrophages. Taken together, these findings indicate that both COX-2 and 5-LO pathways are contributing factors to hepatic inflammation and fibrosis and that these two pathways of the arachidonic acid cascade represent potential targets for therapy.

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The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2

Abstract: These results provide further evidence, that ML3000 inhibits 5-LOX as well as COX-1 and COX-2 in vitro and in animal experiments. The favourable gastrointestinal (GI) tolerability of the compound is believed to be linked to the mechanism of combined 5-LOX and COX-1/2 inhibition of ML3000.

Cited by 96 publications

References 47 publications

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

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

Anti-inflammatory Activity of Pectolinarigenin and Pectolinarin Isolated from Cirsium chanroenicum

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

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The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2

Abstract: These results provide further evidence, that ML3000 inhibits 5-LOX as well as COX-1 and COX-2 in vitro and in animal experiments. The favourable gastrointestinal (GI) tolerability of the compound is believed to be linked to the mechanism of combined 5-LOX and COX-1/2 inhibition of ML3000.

Cited by 96 publications

References 47 publications

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

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

Anti-inflammatory Activity of Pectolinarigenin and Pectolinarin Isolated from Cirsium chanroenicum

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

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

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