Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX‐2 inhibitor

Riendeau, Denis; Percival, M. David; Boyce, Susan; Brideau, Christine; Charleson, S.; Cromlish, Wanda; Ethier, Diane; Evans, Jilly F.; Falgueyret, Jean‐Pierre; Ford-Hutchinson, A W; Gordon, Robert J.; Greig, Gillian; Gresser, Michael J.; Guay, Jocelyne; Kargman, Stacia; Léger, Serge; Mancini, Joseph A.; O’Neill, Gary P.; Ouellet, Marc; Rodger, Ian W.; Thérien, Michel; Wang, Z; Webb, J.K.; Wong, Elizabeth; Xu, Lijing; Young, Robert N.; Zamboni, Robert; Prasit, Petpiboon; Chan, Chi Chung

doi:10.1038/sj.bjp.0701076

Cited by 302 publications

(221 citation statements)

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“…* Ratio of IC50 for COX-1 to IC50 for COX-2 (positively correlated with COX-2 selectivity such that a ratio < 1 indicates COX-1 selectivity and a ratio > 1 indicates COX-2 selectivity). Based on references [33][34][35][36] Biochem Pharmacol. Author manuscript; available in PMC 2012 February 1.…”

Section: Discussionmentioning

confidence: 99%

“…The experiments performed utilized NSAIDs with variable effects on intestinal restitution and variable COX-selectivity, as shown in Table 1 [33][34][35][36]. Drug effects were evaluated over the following ranges of concentrations, as indicated in the text or figure legends: indomethacin (1-100uM); phenylbutazone (1-100uM); NS-398 (1-100uM), SC-560 (10 nM-1uM).…”

Section: Treatment Protocolsmentioning

confidence: 99%

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Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Freeman

Narváez

McCoy

et al. 2007

Biochemical Pharmacology

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Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential (E m ) and altered surface expression of K + channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 μM), phenylbutazone (100 μM) and NS-398 (100 μM) but not by SC-560 (1 μM). NSAIDinhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of E m , whereas treatment with SC-560 had no effect on E m . The E m of IEC-Cdx2 cells was: −38.5±1.8 mV under control conditions; −35.9±1.6 mV after treatment with SC-560; −18.8±1.2 mV after treatment with indomethacin; and −23.7±1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of K v 1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of K v 1.4, but also the cell surface expression of both K v 1.4 and K v 1.6 channel subunits in IEC-Cdx2. Both K v 1.4 and K v 1.6 channel proteins were immunoprecipitated by K v 1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric K v channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of E m and decreased surface expression of heteromeric K v 1 channels.

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Section: Discussionmentioning

confidence: 99%

Section: Treatment Protocolsmentioning

confidence: 99%

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Freeman

Narváez

McCoy

et al. 2007

Biochemical Pharmacology

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“…In some experiments, mice were treated daily for 4 days with 5, 5-Dimethyl-3(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU) (5 mg/kg body weight) to inhibit COX-2 29 or with indomethacin (50 mg/kg body weight) as a nonselective COX-2 inhibitor. Animals were treated in accordance with Institutional Care Instructions.…”

Section: Methodsmentioning

confidence: 99%

Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes

et al. 2007

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Cyclooxygenase-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE 2 found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals.

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“…18 To evaluate the NO availability, concentration-response curves to ACh were constructed in the presence of the NO synthase inhibitor…”

Section: Influence Of Cox-1 and Cox-2 Activity And No Availability Onmentioning

confidence: 99%

Cyclooxygenase-1 Is Involved in Endothelial Dysfunction of Mesenteric Small Arteries From Angiotensin II–Infused Mice

et al. 2007

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Abstract-Angiotensin II induces endothelial dysfunction by reducing NO availability and increasing reactive oxygen species. We assessed whether cyclooxygenase (COX)-1 or COX-2 participate in the angiotensin II-induced endothelial dysfunction in murine mesenteric small arteries and examined the role of reduced nicotinamide-adenine dinucleotide phosphate-dependent reactive oxygen species production. Mice received angiotensin II (600 ng/kg per minute, SC), saline (controls), angiotensin II ϩ apocynin (reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, 2.5 mg/day), or apocynin alone for 2 weeks. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In controls, acetylcholine-induced relaxation was inhibited by N G -monomethyl-L-arginine and unaffected by DFU (COX-2 inhibitor), SC-560 (COX-1 inhibitor), or ascorbic acid. In angiotensin II-infused animals, the attenuated response to acetylcholine was less sensitive to N G -monomethyl-L-arginine, unaffected by DFU, and enhanced by SC-560 and, similarly, by SQ-29548, a thromboxane-prostanoid receptor antagonist. Moreover, response to acetylcholine was unchanged by ozagrel, a thromboxane synthase inhibitor, and normalized by ascorbic acid. Apocynin prevented the angiotensin II-induced vascular dysfunctions. In angiotensin II-infused mice, RT-PCR analysis showed a significant COX-2 downregulation, whereas COX-1 expression was upregulated. These changes were unaffected by apocynin. Modulation of COX isoform by angiotensin II was also documented by immunohistochemistry. In small mesenteric vessels, the reduced NO availability and oxidant excess, which characterize endothelial dysfunction secondary to angiotensin II, are associated with a reduced COX-2 and an increased COX-1 function and expression. Angiotensin II causes an oxidative stress-independent COX-1 overexpression, whereas angiotensin II-mediated oxidant excess production stimulates COX-1 activity to produce a contracting prostanoid endowed with agonist activity on thromboxane-prostanoid receptors. Key Words: angiotensin II Ⅲ microcirculation, cyclooxygenase Ⅲ endothelium Ⅲ oxidative stress I t is widely accepted that angiotensin (Ang) II is greatly implicated in the development of endothelial dysfunction in small resistance arteries, 1,2 mainly through an increased generation of reactive oxygen species (ROS) via vascular reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase activation. [3][4][5][6] Mesenteric arteries from Ang II-infused mice are characterized by a blunted endothelium-dependent relaxation, as a consequence of a reduced NO availability because of oxidant excess. 5 Recent evidence indicates that another pathway involved in endothelial dysfunction is cyclooxygenase (COX) activity. Thus, prostaglandins (PGs) have been shown to play a major role in modulating vascular tone, and COX represents a key enzyme in PG synthesis. Indeed, COX metabolizes arachidonic acid into the unstable intermediate PGH 2 , which, in turn, is converted by an array...

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Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX‐2 inhibitor

Cited by 302 publications

References 44 publications

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes

Cyclooxygenase-1 Is Involved in Endothelial Dysfunction of Mesenteric Small Arteries From Angiotensin II–Infused Mice

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