In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: Suppression of collagenase 1 and interleukin-1? synthesis

Jovanović, Dragan; Fernandes, Julio C.; Martel‐Pelletier, Johanne; Jolicoeur, F C; Reboul, Pascal; Laufer, Stefan; Tries, S.; Pelletier, Jean‐Pierre

doi:10.1002/1529-0131(200110)44:10<2320::aid-art394>3.0.co;2-p

Cited by 97 publications

(116 citation statements)

References 32 publications

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“…Several subsequent investigations confirmed inhibition of the 5-lipoxygenase pathway and of PGE 2 or thromboxane B 2 formation by licofelone in cell-based models (Jovanovic et al, 2001;Paredes et al, 2002;Tries et al, 2002b;Fischer et al, 2007;Vidal et al, 2007). Moreover, reduction of prostanoids (i.e., PGE 2 and thromboxane B 2 ) and leukotriene B 4 by licofelone in vivo was shown in animal models such as experimental dog osteoarthritis (Jovanovic et al, 2001;Lajeunesse et al, 2004) (Rotondo et al, 2006). However, the experimental settings in all these studies did not allow the 3 H]PGE 2 was analyzed by RP-HPLC and liquid scintillation counting as described under Materials and Methods.…”

Section: Licofelone Inhibits Mpges-1 Discussionmentioning

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

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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: Licofelone Inhibits Mpges-1 Discussionmentioning

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

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153

237

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“…Although much is known about the overall process of wound healing, the biochemical signals involved during the different stages of wound resolution remain unclear. Leukotriene B 4 (LTB 4 ), which is produced by the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), is known to be an active chemoattractant for fibroblasts and monocytes and may regulate fibroblast activities in wound healing (14,25). Furthermore, inhibitor studies indicate that LOX metabolites regulate reepithelialization in wounded corneas (11).…”

mentioning

confidence: 84%

5-Lipoxygenase and cyclooxygenase regulate wound closure in NIH/3T3 fibroblast monolayers

Green

Stockton²,

Johnson³

et al. 2004

American Journal of Physiology-Cell Physiology

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involves multiple cell signaling pathways, including those regulating cell-extracellular matrix adhesion. Previous work demonstrated that arachidonate oxidation to leukotriene B4 (LTB4) by 5-lipoxygenase (5-LOX) signals fibroblast spreading on fibronectin, whereas cyclooxygenase-2 (COX-2)-catalyzed prostaglandin E2 (PGE2) formation facilitates subsequent cell migration. We investigated arachidonate metabolite signaling in wound closure of perturbed NIH/3T3 fibroblast monolayers. We found that during initial stages of wound closure (0 -120 min), all wound margin cells spread into the wound gap perpendicularly to the wound long axis. At regular intervals, between 120 and 300 min, some cells elongated to project across the wound and meet cells from the opposite margin, forming distinct cell bridges spanning the wound that act as foci for later wound-directed cell migration and resulting closure. 5-LOX inhibition by AA861 demonstrated a required LTB4 signal for initial marginal cell spreading and bridge formation, both of which must precede wound-directed cell migration. 5-LOX inhibition effects were reversible by exogenous LTB4. Conversely, COX inhibition by indomethacin reduced directed migration into the wound but enhanced early cell spreading and bridge formation. Exogenous PGE2 reversed this effect and increased cell migration into the wound. The differential effects of arachidonic acid metabolites produced by LOX and COX were further confirmed with NIH/3T3 fibroblast cell lines constitutively over-and underexpressing the 5-LOX and COX-2 enzymes. These data suggest that two competing oxidative enzymes in arachidonate metabolism, LOX and COX, differentially regulate sequential aspects of fibroblast wound closure in vitro.

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“…The anti-inflammatory action of this drug has been shown in animal models of osteoarthritis (Jovanovic et al, 2001;Pelletier et al, 2005), and it is currently being evaluated in phase III clinical trials in this disorder. Moreover, antithrombotic effects of licofelone due to inhibition of COX-1-mediated platelet function have been reported in mice and rat models (Tries et al, 2002) and in human platelets (Rotondo et al, 2004).…”

mentioning

confidence: 99%

Licofelone, a Balanced Inhibitor of Cyclooxygenase and 5-Lipoxygenase, Reduces Inflammation in a Rabbit Model of Atherosclerosis

Vidal¹,

Gómez-Hernández²,

Sánchez-Galán³

et al. 2006

J Pharmacol Exp Ther

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Licofelone, a dual anti-inflammatory drug that inhibits 5-lipoxygenase (LOX) and cyclooxygenase (COX) enzymes, may have a better cardiovascular profile that cycloxygenase-2 inhibitors due to cycloxygenase-1 blockade-mediated antithrombotic effect and a better gastrointestinal tolerability. We examined the anti-inflammatory effect of licofelone on atherosclerotic lesions as well as in isolated neutrophils from whole blood of rabbits compared with a selective inhibitor of COX-2, rofecoxib. We also assessed the antithrombotic effect of licofelone in rabbit platelet-rich plasma. For this purpose, 30 rabbits underwent injury of femoral arteries, and they were randomized to receive 10 mg/kg/day licofelone or 5 mg/kg/day rofecoxib or no treatment during 4 weeks with atherogenic diet in all cases. Ten healthy rabbits were used as controls. Neutrophils and platelets were isolated from peripheral blood of rabbits for ex vivo studies. Licofelone reduced intima/media ratio in injured arteries, the macrophages infiltration in the neointimal area, monocyte chemoattractant protein-1 (MCP-1) gene expression, and the activation of nuclear factor-B in rabbit atheroma. Moreover, licofelone inhibited COX-2 and 5-LOX protein expression in vascular lesions. Rofecoxib only diminished COX-2 protein expression and MCP-1 gene expression in vascular atheroma. Prostaglandin E 2 in rabbit plasma was attenuated by both drugs. Licofelone almost abolished 5-LOX activity by inhibiting leukotriene B4 generation in rabbit neutrophils and prevented platelet thromboxane B 2 production from whole blood. Licofelone reduces neointimal formation and inflammation in an atherosclerotic rabbit model more markedly than rofecoxib. This effect, together with the antiplatelet activity of licofelone, suggests that this drug may have a favorable cardiovascular profile.

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In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: Suppression of collagenase 1 and interleukin-1? synthesis

Cited by 97 publications

References 32 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

5-Lipoxygenase and cyclooxygenase regulate wound closure in NIH/3T3 fibroblast monolayers

Licofelone, a Balanced Inhibitor of Cyclooxygenase and 5-Lipoxygenase, Reduces Inflammation in a Rabbit Model of Atherosclerosis

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In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: Suppression of collagenase 1 and interleukin-1? synthesis

Cited by 97 publications

References 32 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

5-Lipoxygenase and cyclooxygenase regulate wound closure in NIH/3T3 fibroblast monolayers

Licofelone, a Balanced Inhibitor of Cyclooxygenase and 5-Lipoxygenase, Reduces Inflammation in a Rabbit Model of Atherosclerosis

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Product

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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