The lipoxygenase–cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit

Rotondo, Serenella; Dell’Elba, Giuseppe; Manarini, Stefano; Cerletti, Chiara; Evangelista, Virgilio

doi:10.1016/j.ejphar.2006.06.052

Cited by 9 publications

(8 citation statements)

References 27 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: 83%

“…Moreover, licofelone in contrast to COX-2-selective inhibitors may have a favorable cardiovascular profile because of the presumed lack of impaired PGI 2 levels, and because of the ability to suppress the formation of leukotrienes, which are mediators of atherogenesis and cardiovascular disease (Peters-Golden and Henderson, 2007). In fact, licofelone reduced neointimal formation and inflammation in an atherosclerotic rabbit model (Vidal et al, 2007), protected rabbits from the cardiovascular derangement triggered by N-formyl-L-methionyl-L-leucyl-Lphenylalanine (Rotondo et al, 2006), and had a significant antithrombotic activity and a marked platelet aggregationinhibiting effect in rats (Tries et al, 2002a). Although licofelone, based on its unique and favorable molecular pharmacological profile regarding intervention with eicosanoid biosynthesis, may represent a suitable drug for the therapy of chronic inflammatory diseases with low risks of adverse effects, long-term studies evaluating the cardiovascular toxicity of licofelone have to be conducted to judge its cardiovascular safety in chronic use.…”

Section: Licofelone Inhibits Mpges-1 Discussionmentioning

confidence: 99%

“…The effectiveness of licofelone has been demonstrated in animal models as well as in studies on humans, and it is attributed mainly to the efficient suppression of PGE 2 formation (Kulkarni and Singh, 2007). It is interesting to note that in contrast to NSAIDs and selective COX-2 inhibitors, licofelone shows an improved gastrointestinal and potentially cardiovascular safety (Bias et al, 2004;Rotondo et al, 2006;Vidal et al, 2007). This effect of licofelone might be attributable to the accompanied suppression of leukotrienes (Celotti and Laufer, 2001), which significantly contribute to gastric epithelial injury as well as to atherogenesis (Peters-Golden and Henderson, 2007).…”

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confidence: 99%

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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: Licofelone Inhibits Mpges-1 Discussionmentioning

confidence: 83%

Section: Licofelone Inhibits Mpges-1 Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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 study results indicate that the inhibition of not only the COX activity alone but also the COX/LOX enzyme combination can be more effective and cause fewer serious side effects or limit adverse effects; therefore, such compounds can be used for design of new drugs or functional food (Rotondo, Dell, Manarini, Cerletti, & Evangelista, 2006).…”

Section: Discussionmentioning

confidence: 99%

Potential anti-inflammatory and lipase inhibitory peptides generated by in vitro gastrointestinal hydrolysis of heat treated millet grains

Jakubczyk

Szymanowska

Karaś

et al. 2019

CyTA - Journal of Food

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The influence of heat treatment (65°C and 100°C) on the activities of potential anti-inflammatory peptides obtained from a millet protein fraction was investigated. The molecular mass of proteins was found to be in the range of 6.5-100 kDa. The protein fractions were in vitro hydrolyzed in gastrointestinal-like conditions. The highest peptide content was noted for albumin in the control sample (2.03 mg/mL). The peptide fraction obtained from globulin 7S derived from grains heated at 65°C was characterized by the highest COX-1 and COX-2 inhibitory activity (IC 50 = 0.08 and 0.12 mg/mL, respectively). The peptide fraction obtained from the prolamin treatment at 100°C exhibited the highest LOX inhibitory activity (IC 50 = 0.14 mg/mL). Peptides from the prolamin treatment at 65°C were characterized by the highest pancreatic lipase inhibitory activity (IC 50 = 0.03 mg/mL). Peptide fractions with highest anti-inflammatory activity were rich in Gly. Posibles péptidos antiinflamatorios e inhibidores de la lipasa generados por hidrólisis gastrointestinal in vitro de granos de mijo tratados térmicamente RESUMEN Se investigó la influencia del tratamiento con calor (65°C y 100°C) en la actividad de posibles péptidos antiinflamatorios obtenidos de una fracción de proteína de mijo. Al respecto, se constató que la masa molecular de las proteínas estaba en el rango de 6.5-100 kDa. Las fracciones de proteínas se hidrolizaron in vitro en condiciones similares a las gastrointestinales. La albúmina de la muestra de control exhibió el mayor contenido de péptidos (2.03 mg/ml). La fracción peptídica obtenida de la globulina 7S derivada de granos calentados a 65°C presentó la actividad inhibidora de COX-1 y COX-2 más alta (IC 50 = 0.08 y 0.12 mg/mL, respectivamente). La fracción peptídica obtenida del tratamiento con prolamina a 100°C mostró la mayor actividad inhibidora de LOX (IC 50 = 0.14 mg/mL). Los péptidos del tratamiento con prolamina a 65°C exhibieron la actividad inhibidora de la lipasa pancreática más alta (IC 50 = 0.03 mg/mL). Las fracciones peptídicas con mayor actividad antiinflamatoria mostraron abundante Gly.

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“…Concerning CV system, two in vivo studies in rabbit models have shown that licofelone may have an interesting CV profile . First, it has efficiently protected rabbits from peptide‐induced CV derangements . Second, licofelone has exhibited a greater protective effect than rofecoxib in a rabbit model of atherosclerosis .…”

Section: Identification Of Novel Targets In the Arachidonic Acid Cascadementioning

confidence: 99%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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The lipoxygenase–cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit

Cited by 9 publications

References 27 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

Potential anti-inflammatory and lipase inhibitory peptides generated by in vitro gastrointestinal hydrolysis of heat treated millet grains

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

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The lipoxygenase–cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit

Cited by 9 publications

References 27 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

Potential anti-inflammatory and lipase inhibitory peptides generated by in vitro gastrointestinal hydrolysis of heat treated millet grains

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

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Product

Resources

About

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