Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow.

The main mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of cycloxygenases COX-1 and COX-2. During recent years, combined 5-LOX/COX-inhibition, interfering with the biosynthesis of both prostaglandins and leukotrienes (LTs), has emerged as a possibility to avoid side effects related to COX-inhibition. The aim of the present study was to investigate if there is a contribution of mechanisms other than the reduction of inflammatory prostaglandins and leukotrienes to the anti-inflammatory effect of the LOX/COX inhibitor licofelone. In a flow chamber assay, licofelone (10-30 microM) dose-dependently decreased both the rolling and adhesion of leukocytes on endothelial cells (EC). In contrast, no effects were found after treatment of EC with the unselective COX-1/COX-2 inhibitor indomethacin (30 microM), the potent and selective 5-LOX inhibitor, ZD-2138 (30 microM), the mainly COX-2 inhibitor aceclofenac (30 microM), the selective COX-2 inhibitor celecoxib (30 microM) and the combination of ZD-2138 with the selective COX-2 inhibitor celecoxib (30 microM). In the presence of licofelone (30 microM) the expression of E-selectin mRNA in cytokine-stimulated EC was attenuated, whereas no NSAID (30 microM) tested showed any effect on E-selectin expression. Moreover, licofelone treatment (30 microM) attenuated expression of VCAM-1 and ICAM-1 on inflammatory EC. The effect of licofelone on leukocyte recruitment was also evaluated in vivo. Using a mouse peritonitis model it was found that leukocyte accumulation was markedly reduced in licofelone treated animals (100mg/kg) compared to untreated mice. Thus, the novel 5-LOX/COX inhibitor licofelone possesses anti-inflammatory activity that, in addition to COX/LOX inhibition, involves effects on leukocyte-endothelial interactions.

[1]  Volker Herzog,et al.  Establishment of a human cell line (mono mac 6) with characteristics of mature monocytes , 1988, International journal of cancer.

[2]  J M Alvaro-Gracia,et al.  Licofelone--clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. , 2004, Rheumatology.

[3]  N. V. Chandrasekharan,et al.  COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Koboldt,et al.  Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationships. , 1996, Journal of medicinal chemistry.

[5]  N. Patel,et al.  Reduction of renal ischemia-reperfusion injury in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton. , 2004, Molecular pharmacology.

[6]  C. Koboldt,et al.  Novel terphenyls as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents. , 1996, Journal of medicinal chemistry.

[7]  R. Black,et al.  Structure-Function Relationship and Role of Tumor Necrosis Factor-α-converting Enzyme in the Down-regulation of L-selectin by Non-steroidal Anti-inflammatory Drugs* , 2002, The Journal of Biological Chemistry.

[8]  J. Haeggström,et al.  Human endothelial cells stimulate leukotriene synthesis and convert granulocyte released leukotriene A4 into leukotrienes B4, C4, D4 and E4. , 1988, European journal of biochemistry.

[9]  S. Laufer,et al.  The pharmacological profile of ML3000: A new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase , 2001, InflammoPharmacology.

[10]  W. Campbell,et al.  Cultured bovine coronary arterial endothelial cells synthesize HETEs and prostacyclin. , 1988, The American journal of physiology.

[11]  Stefan Laufer,et al.  The Gastrointestinal Tolerability of the LOX/COX Inhibitor, Licofelone, is Similar to Placebo and Superior to Naproxen Therapy in Healthy Volunteers: Results From a Randomized, Controlled Trial , 2004, American Journal of Gastroenterology.

[12]  C. Cerletti,et al.  Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors. , 2003, Trends in pharmacological sciences.

[13]  E. Jaffe,et al.  Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. , 1973, The Journal of clinical investigation.

[14]  C. Cerletti,et al.  Licofelone, a dual lipoxygenase-cyclooxygenase inhibitor, downregulates polymorphonuclear leukocyte and platelet function. , 2002, European journal of pharmacology.

[15]  D. Breuer,et al.  Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. , 1994, The Journal of pharmacology and experimental therapeutics.

[16]  J. Loscalzo,et al.  Expression of 5-lipoxygenase in pulmonary artery endothelial cells. , 2002, The Biochemical journal.

[17]  S. Laufer,et al.  (6,7-Diaryldihydropyrrolizin-5-yl)acetic acids, a novel class of potent dual inhibitors of both cyclooxygenase and 5-lipoxygenase. , 1994, Journal of medicinal chemistry.

[18]  J. Wallace,et al.  Evidence that 5‐lipoxygenase and acetylated cyclooxygenase 2‐derived eicosanoids regulate leukocyte–endothelial adherence in response to aspirin , 2003, British journal of pharmacology.

[19]  F. Sánchez‐Madrid,et al.  Down-regulation of L-selectin Expression in Neutrophils by Nonsteroidal Anti-Inflammatory Drugs: Role of Intracellular ATP Concentration , 2000 .

[20]  G. Dannhardt,et al.  In-vitro test system for the evaluation of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors based on a single HPLC run with UV detection using bovine aortic coronary endothelial cells (BAECs) , 2001, Inflammation Research.