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1

Cox2 is needed but not sufficient for apoptosis induced by Cox2 selective inhibitors in colon cancer cells  

Microsoft Academic Search

The role of Cox-2 in NSAID-induced apoptosis is debated. We studied the role of Cox-2 inhibition in apoptosis induced by a selective Cox-2 inhibitor, SC236 (a structural analogue of celecoxib) in two colon cancer cell lines, HT29 (expressing Cox-2 protein) and HCT116 (not expressing Cox-2 protein). Apoptosis was quantified by flow cytometry. SC236 0–75 µM decreased cell numbers and induced

B. Agarwal; P. Swaroop; P. Protiva; S. V. Raj; H. Shirin; P. R. Holt

2003-01-01

2

Characterization of Etoricoxib, a Novel, Selective COX2 Inhibitor  

Microsoft Academic Search

Etoricoxib is a potent selective COX-2 inhibitor in man. Ex vivo whole-blood assays assessed COX-2 inhibition after oral administration of etoricoxib in single (5-500 mg) and multiple (25-150 mg) once-daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE2synthesis after etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect

Aimee Dallob; Christopher J. Hawkey; Howard Greenberg; Nicholas Wight; Paul De Schepper; Scott Waldman; Peggy Wong; Lisa De Tora; Barry Gertz; Nancy Agrawal; John Wagner; Keith Gottesdiener

2003-01-01

3

Cyclooxygenase2 (COX2) in Carcinogenesis and Selective COX2 Inhibitors for Chemoprevention in Gastrointestinal Cancers  

Microsoft Academic Search

Introduction  Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have a property to inhibit tumor development in some cancers\\u000a while it shows various side effects such as gastrointestinal bleeding and renal disorder. Selective cyclooxygenase (COX)-2\\u000a inhibitors (coxibs) were originally developed as one of anti-inflammatory drugs to avoid side effect of NSAIDs. Fortunately,\\u000a the coxibs was also proved to have an inhibiting

Takashi Fujimura; Tetsuo Ohta; Katsunobu Oyama; Tomoharu Miyashita; Kochi Miwa

2007-01-01

4

Radiosensitivity Enhancement by Celecoxib, a Cyclooxygenase (COX)-2 Selective Inhibitor, via COX2Dependent Cell Cycle Regulation on Human Cancer Cells Expressing Differential COX2 Levels  

Microsoft Academic Search

To characterize the radiation-enhancing effects on human cancer cells and underlying mechanisms of celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, and to ascertain whether its effects are COX-2 dependent. Clonogenic cytotox- icity assays and radiation survival assays after treatment with celecoxib F radiation were done on four human cancer cell lines that expressed differential COX-2 levels. Stably COX-2 knocked down or

You Keun Shin; Ji Sun Park; Hyun Seok Kim; Hyun Jung Jun; Gwi Eon Kim; Chang Ok Suh; Yeon Sook Yun; Hongryull Pyo

5

Selective COX2 Inhibitors and Risk of Myocardial Infarction  

Microsoft Academic Search

Selective inhibitors of cyclooxygenase-2 (COX-2, ‘coxibs’) are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non-steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myo cardial infarction and atherothrombotic events. This has led

Florian Krötz; Thomas M. Schiele; Volker Klauss; Hae-Young Sohn

2005-01-01

6

Preparation of 3-arylmethylindoles as selective COX2 inhibitors  

Microsoft Academic Search

The 3-arylmethylation of indoles using TMSOTf\\/Et3SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO2 and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this

Jeffrey A Campbell; Viola Bordunov; Chris A Broka; John Dankwardt; Robert T Hendricks; James M Kress; Keith A. M Walker; Jin-Hai Wang

2004-01-01

7

N-Caffeoyl serotonin as selective COX-2 inhibitor.  

PubMed

The inhibitory effects of the synthetic serotonin analogues (1-8) on COX (1 and 2) were evaluated. Two serotonin derivatives (4 and 8) showed inhibitory effect of COX (1 and 2). Especially, 4 exhibited excellent inhibitions on COX-2 with extremely high potency (IC(50)=42.5 ?M). The inhibitory activities of cinnamic acid derivatives and serotonin were evaluated to clarify whether inhibitory activities of compound 4 and 8 are due to cinnamic acid moiety or serotonin moiety. Caffeic acid and N-caffeoyl serotonin (4) exhibited selective inhibition of COX-2 compared to aspirin. Comparison caffeic acid with 4 suggested that the linkage of caffeic acid and serotonin enhance COX-2 inhibition. Comparison of structures of caffeic acid and sinapic acid implied that catechol moiety of cinnamic acid derivatives is a major contributing factor for selective inhibition of COX-2. The selective COX-2 inhibitory activity of compound 4 is significant and could be employed as drugs against inflammatory and allergy. PMID:22386242

Takahashi, Toshiyuki; Miyazawa, Mitsuo

2012-02-09

8

Gastrointestinal Tolerability of the Selective Cyclooxygenase2 (COX2) Inhibitor Rofecoxib Compared With Nonselective COX1 and COX2 Inhibitors in Osteoarthritis  

Microsoft Academic Search

Background: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective cyclooxygenase (COX-1 and COX-2) inhibitors and are associated with a variety of upper gastrointestinal (GI) tract symptoms. The roles of COX-1 and COX-2 in the pathogenesis of these symp- toms are unclear. To test whether COX-2 inhibition with rofecoxib would have greater GI tolerability than non- selective COX-1 and COX-2 inhibition, we

Douglas J. Watson; Sean E. Harper; Peng-Liang Zhao; Hui Quan; James A. Bolognese; Thomas J. Simon

2000-01-01

9

Design and synthesis of 1,3-diarylurea derivatives as selective cyclooxygenase (COX-2) inhibitors.  

PubMed

A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC(50)=0.11 microM) with a high COX-2 selectivity index (SI=203.6) comparable to the reference drug celecoxib (COX-2 IC(50)=0.06 microM; COX-2 SI=405). The structure-activity data acquired indicate that the urea moiety constitutes a suitable scaffold to design new acyclic 1,3-diarylurea derivatives with selective COX-2 inhibitory activity. PMID:18226898

Zarghi, Afshin; Kakhgi, Samaneh; Hadipoor, Atefeh; Daraee, Bahram; Dadrass, Orkideh G; Hedayati, Mehdi

2008-01-11

10

Design and synthesis of 1,3-diarylurea derivatives as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1\\/COX-2 isozyme inhibition structure–activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC50=0.11?M) with a high COX-2

Afshin Zarghi; Samaneh Kakhgi; Atefeh Hadipoor; Bahram Daraee; Orkideh G. Dadrass; Mehdi Hedayati

2008-01-01

11

Radiosensitizing potential of the selective cyclooygenase-2 (COX2) inhibitor meloxicam on human glioma cells  

Microsoft Academic Search

The COX-2 protein is frequently overexpressed in human malignant gliomas. This expression has been associated with their aggressive\\u000a growth characteristics and poor prognosis for patients. Targeting the COX-2 pathway might improve glioma therapy. In this\\u000a study, the effects of the selective COX-2 inhibitor meloxicam alone and in combination with irradiation were investigated\\u000a on human glioma cells in vitro. A panel

Irene V. Bijnsdorp; Jaap van den Berg; Gitta K. Kuipers; Laurine E. Wedekind; Ben J. Slotman; Johannes van Rijn; M. Vincent M. Lafleur; Peter Sminia

2007-01-01

12

Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors  

PubMed Central

All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.

Kalgutkar, Amit S.; Crews, Brenda C.; Rowlinson, Scott W.; Marnett, Alan B.; Kozak, Kevin R.; Remmel, Rory P.; Marnett, Lawrence J.

2000-01-01

13

Regulation of cell growth by selective COX2 inhibitors in oral carcinoma cell lines  

Microsoft Academic Search

Evidence indicates that NSAIDs that inhibit prostaglandin (PG) synthesis can reduce the incidence of colorectal cancers and that inhibition of cyclooxygenase-2 (COX-2) may be the underlying mechanism. The objective of this study was to investigate this putative mechanism by examining the effect of selective COX-2 inhibitors (Celebrex, DFU, NS-398) and COX-1 inhibitors (Aspirin) on the growth of two human oral

C. Y Yang; C. L Meng; C. L Liao; P. Y.-K Wong

2003-01-01

14

Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2  

PubMed Central

Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses.

Li, Haitao; Zhu, Feng; Sun, Yanwen; Li, Bing; Oi, Naomi; Chen, Hanyong; Lubet, Ronald A.; Bode, Ann M.; Dong, Zigang

2013-01-01

15

Gastrointestinal safety of novel nonsteroidal antiinflammatory drugs: selective COX-2 inhibitors and beyond.  

PubMed

Nonsteroidal antiinflammatory drugs (NSAIDs) are frequently associated with adverse reactions, related to inhibition of cyclooxygenase (COX) in tissues where prostaglandins exert physiological effects, such as gastric mucosal defense and renal homeostasis. The discovery of two COX isoforms, namely COX-1 constitutively expressed in most tissues and COX-2 induced at sites of inflammation, led to the development of selective COX-2 inhibitors ("coxibs"), with the hope of significantly reducing the gastrointestinal toxicity associated with acute and chronic NSAID use. However, the increased knowledge of physiological roles of COX-2 enzyme in a variety of tissues, including stomach and kidney, together with the withdrawal from the market of rofecoxib and valdecoxib because of cardiovascular toxicity, have challenged the benefits of selective COX-2 inhibition. As a consequence, the interest for novel approaches has re-emerged; new therapeutic options, still under clinical evaluation, are represented by dual COX and 5-lipooxygenase (5-LOX) inhibitors, synthetic lipoxins, nitric oxide (NO)-releasing NSAIDs and, more recently, by NSAIDs releasing hydrogen sulphide (H2S). This review focuses upon the gastrointestinal (GI) safety of selective COX-2 inhibitors and of novel therapeutic strategies, in comparison with traditional NSAIDs. PMID:17933277

Coruzzi, Gabriella; Venturi, Nicola; Spaggiari, Silvana

2007-08-01

16

The 2?-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor  

PubMed Central

Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2?-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2?-methyl group of indomethacin with trifluoromethyl produces CF3–indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 ?M). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3–indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin.

2013-01-01

17

Effect of the selective COX2 inhibitors, celecoxib and rofecoxib in rat acute models of inflammation  

Microsoft Academic Search

Objective: This study evaluates the action of celecoxib and rofecoxib, two selective cyclooxygenase-2 (COX-2) inhibitors in two acute models of inflammation, carrageenan (Cg)-induced rat pleurisy, and paw oedema formation.¶Material: Male Wistar rats (N = 4-10 per group) were used. A fixed volume of PBS or carrageenan was injected into the pleural cavity or into the paw. Furthermore, the myeloperoxidase (MPO)

R. M. Pinheiro; J. B. Calixto

2002-01-01

18

A new synthesis of 3-arylthioindoles as selective COX2 inhibitors using PIFA  

Microsoft Academic Search

The direct 3-arylthiolation of 2-substituted indoles using phenyliodine(III)bis trifluoroacetate (PIFA) in (CF3)2CHOH with a wide variety of benzenethiols has been accomplished. In particular, indoles bearing a 6-MeSO2 and either a 2-methyl or 2-carboxymethyl substituent could be 3-arylthiolated in good to excellent yields to afford the corresponding 3-arylthioindoles as selective COX-2 inhibitors. In a study varying the electronic nature of the

Jeffrey A Campbell; Chris A Broka; Leyi Gong; Keith A. M Walker; Jin-Hai Wang

2004-01-01

19

Synthesis and biological acitivity of annulated pyrazoles as selective COX-2 inhibitors. I.  

PubMed

A series of disubstituted 4,5-polymethylenepyrazoles were synthesized and evaluated their inhibitory activities against COX-2. Some compounds showed strong (0.3 nM) inhibitory activity on COX-2 and were found somewhat selective (up to 16) on COX-2 over COX-1. PMID:10489876

Kim, H H; Park, J G; Moon, T C; Chang, H W; Jahng, Y

1999-08-01

20

Design and synthesis of new 1,3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1\\/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one (7b) as a potent (IC50=0.05?M) and selective (selectivity index=259) COX-2 inhibitor.

Afshin Zarghi; Tannaz Zebardast; Bahram Daraie; Mehdi Hedayati

2009-01-01

21

Design and synthesis of new 1,3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors.  

PubMed

A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one (7b) as a potent (IC(50)=0.05 microM) and selective (selectivity index=259) COX-2 inhibitor. PMID:19596198

Zarghi, Afshin; Zebardast, Tannaz; Daraie, Bahram; Hedayati, Mehdi

2009-06-27

22

Design and synthesis of new 2,4,5-triarylimidazole derivatives as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A new group of 2,4,5-triarylimidazole derivatives, possessing a methyl sulfonyl pharmacophore, were synthesized and their\\u000a biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1\\/COX-2 structure–activity\\u000a relationships were determined by varying the substituents at the para position of C-2 phenyl ring. Among the 2,4,5-triarylimidazoles, 2-(4-hydroxy phenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-1H imidazole (11f) was identified as a selective COX-2 inhibitor (COX-2 IC50 = 0.15 ?M; selectivity

A. Zarghi; S. Arfaei; R. Ghodsi

23

Amelioration of cisplatin-induced mouse renal lesions by a cyclooxygenase (COX)-2 selective inhibitor.  

PubMed

In this study, we investigated the effects of the cyclooxygenase (COX)-2 selective inhibitor, meloxicam, on cisplatin-induced inflammation, oxidative stress and renal lesions in BALB/c mice. A single cisplatin injection (13mg/kg, i.p.) significantly increased plasma creatinine, blood urea nitrogen and urinary glucose accompanied by a concomitant increase in COX-2 mRNA and COX-2 protein levels. These changes in renal lesion parameters were diminished by simultaneous treatment of meloxicam (0.7mg/kg/day in drinking water). The expression of oxidative stress markers, p47(phox), p67(phox), hemoxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and 4-hydroxy-2-nonenal (4-HNE)-modified protein were increased with cisplatin injection. Simultaneous treatment of meloxicam with cisplatin significantly inhibited the increase in p47(phox), HO-1 and 4-HNE-modified protein. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) were increased with cisplatin injection, but these changes were inhibited by meloxicam. Moreover, concomitant meloxicam treatment also prevented the cisplatin-induced infiltration of macrophages to the tubulointerstitial area. These results suggest that meloxicam can ameliorate cisplatin-induced mouse renal lesions, potentially through the inhibition of inflammatory and oxidative stress responses. PMID:23747596

Honma, Shigeyoshi; Takahashi, Naho; Shinohara, Masahiro; Nakamura, Kazuki; Mitazaki, Satoru; Abe, Sumiko; Yoshida, Makoto

2013-06-04

24

Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791  

PubMed Central

Recent findings suggest that modulation of ion channels might be implicated in some of the clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2). Celecoxib and its inactive analog 2,5-dimethyl-celecoxib, but not rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human Kv2.1 channels by a highly selective COX-2 inhibitor SC-791. In this study we have further explored the SC-791 action on ion channels and heartbeat in Drosophila, which lacks cyclooxygenases and thus can serve as a convenient model to study COX-2-independent mechanisms of coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that SC-791 inhibited voltage-activated K+ and L-type Ca2+ channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike celecoxib and several other K+ channel blockers, SC-791 did not induce arrhythmia. Instead, application of SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat. Isradipine, a selective blocker of L-type Ca2+ channels, showed a similar pattern of heart arrest, though no prolongation of contractions was observed. Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like SC-791, ryanodine reduced heart rate without arrhythmia. However, it could not stop heartbeat completely even at 500 µM, the highest concentration used. The magnitude of heart rate reduction, when SC-791 and ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that SC-791 might be interfering with excitation-contraction coupling in Drosophila heart.

Frolov, Roman V.; Singh, Satpal

2012-01-01

25

Inhibition of ion channels and heart beat in Drosophila by selective COX-2 inhibitor SC-791.  

PubMed

Recent findings suggest that modulation of ion channels might be implicated in some of the clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2). Celecoxib and its inactive analog 2,5-dimethyl-celecoxib, but not rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human K(v)2.1 channels by a highly selective COX-2 inhibitor SC-791. In this study we have further explored the SC-791 action on ion channels and heartbeat in Drosophila, which lacks cyclooxygenases and thus can serve as a convenient model to study COX-2-independent mechanisms of coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that SC-791 inhibited voltage-activated K(+) and L-type Ca(2+) channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike celecoxib and several other K(+) channel blockers, SC-791 did not induce arrhythmia. Instead, application of SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat. Isradipine, a selective blocker of L-type Ca(2+) channels, showed a similar pattern of heart arrest, though no prolongation of contractions was observed. Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like SC-791, ryanodine reduced heart rate without arrhythmia. However, it could not stop heartbeat completely even at 500 µM, the highest concentration used. The magnitude of heart rate reduction, when SC-791 and ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that SC-791 might be interfering with excitation-contraction coupling in Drosophila heart. PMID:22701705

Frolov, Roman V; Singh, Satpal

2012-06-06

26

NSAID inhibition of RGM1 gastric monolayer wound re-epithelialization: comparison of selective Cox2 versus non-selective Cox inhibitors  

Microsoft Academic Search

Clinical studies indicate that specific cyclooxygenase-2 (Cox-2) inhibitors are less ulcerogenic than their non-selective predecessors (e.g. indomethacin). However, Cox-2 inhibitors may also interfere with ulcer healing. Re-epithelialization is a crucial factor in both gastrointestinal mucosal injury and ulcer healing. This study was aimed to compare the effects of selective Cox-2 inhibitor (NS398) versus non-selective Cox inhibitor (indomethacin) on basal and

Andrew Q Giap; Andrzej Tarnawski; Neil T Hoa; Vimesh Akotia; Thomas Y Ma

2002-01-01

27

Design and synthesis of new 1,3-benzdiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors.  

PubMed

A new group of regioisomeric 2,3-diaryl-1,3-benzdiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were tested for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluorophenyl)-2-(4-methylsulfonylphenyl)-1,3-benzdiazinane-4-one (2b) as a potent and highly selective (IC(50) = 0.07 µM; selectivity index = 572.8) COX-2 inhibitor. PMID:22076641

Zarghi, Afshin; Zebardast, Tannaz; Hajighasemali, Fatemeh; Alipoor, Eskandar; Daraie, Bahram; Hedayati, Mehdi

2011-11-11

28

Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity  

PubMed Central

Aims Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. Main Methods We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Key Findings Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. Significance These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer.

Srivastava, Janmejai K; Pandey, Mitali; Gupta, Sanjay

2009-01-01

29

The Gastrointestinal Safety and Effect on Disease Activity of Etoricoxib, a Selective Cox2 Inhibitor in Inflammatory Bowel Diseases  

Microsoft Academic Search

BACKGROUND:While traditional nonsteroidal antiinflammatory drugs (t-NSAIDs) are relatively contraindicated in patients with inflammatory bowel disease (IBD) for fear of disease aggravation, controlled clinical trials showed that cyclo-oxygenase-2 inhibitors have fewer gastrointestinal side effects than the t-NSAIDs. Etoricoxib is a new antiinflammatory inhibitor that has high Cox-2 selectivity.OBJECTIVES:To assess the safety of etoricoxib and effect on disease activity in patients with

Yasser El Miedany; Sally Youssef; Ihab Ahmed; Maha El Gaafary

2006-01-01

30

Administration of the selective cyclooxygenase (COX)-2 inhibitor etodolac prolongs cardiac allograft survival in a mouse model.  

PubMed

Etodolac, a selective cyclooxygenase-2 (COX-2) inhibitor, is a non-steroidal anti-inflammatory drug. COX-2 is a key factor in the progression of inflammation. Although inflammation is an essential pathologic feature of cardiac allograft rejection, the role of COX-2 in this process remains unclear. The aim of this study was to investigate the expression of COX and the effects of etodolac in a mouse cardiac allograft model. Balb/c mice (H-2d) were used as recipients and C57BL/6 (H-2b) mice as heart donors. Heart function was evaluated daily after transplantation by regular abdominal palpation of the heart and by laparotomy in cases where the beating became weak. Rejection was defined as total cessation of cardiac muscle contraction. COX-2 expression was analyzed by immunohistochemistry. Cardiac isograft was well tolerated (>150 days, n=5), while non-treated cardiac allograft was rapidly rejected (mean 10.9±2.4, n=7). In the etodolac-treated cardiac allograft (10 mg/kg/day by hypodermic injection), survival was extended to 18.53±2.1 days (n=7). The necrotic area and the grade of COX-2 immunostaining were more significantly reduced in the etodolac-treated cardiac allograft than in the non-treated cardiac allograft at day 14. These results indicate that etodolac contributes to protection against rejection after heart transplantation. Etodolac could therefore be used to suppress graft rejection by means of its anti-inflammatory properties. PMID:21472312

Matsuyama, Masahide; Yoshimura, Rikio; Hase, Taro; Chargui, Jamel; Yoshimura, Norio; Touraine, Jean-Louis

2010-07-26

31

Design, synthesis and biological evaluation of new ( E)- and ( Z)-1,2,3-triaryl-2-propen-1-ones as selective COX2 inhibitors  

Microsoft Academic Search

A group of (E)-and (Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-1 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1\\/COX-2 structure–activity relationships were determined by varying the substituents on the C-3 propenone moiety. Among the 1,2,3-triaryl-2-propen-1-ones, (Z)-1-(4-(methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-one (3b) showed the most potency and selectivity on COX-2 inhibition (COX-2 IC50 = 0.07 ?M;

Sara Arfaie; Afshin Zarghi

2010-01-01

32

The Gastrointestinal and Cardiovascular Safety of COX2 selective inhibitors in general practice: the contribution of Prescription-Event Monitoring  

Microsoft Academic Search

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for many conditions, especially in the elderly. Whilst effective, they also have side-effects, most commonly on the stomach. Advances in the understanding of how NSAIDs work in the body led to newer NSAIDs (COX-2 selective inhibitors which are commonly known as 'coxibs') being developed with the potential for equivalent benefit to traditional NSAIDs

D. Layton

2007-01-01

33

Enhancement of glioblastoma radioresponse by a selective COX2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis  

Microsoft Academic Search

Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. Methods and Materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of

Khong Bee. Kang; Ting Ting Wang; Chow Thai Woon; Elizabeth S. Cheah; Xiao Lei Moore; Congju Zhu; Meng Cheong Wong

2007-01-01

34

Do steroids, conventional non-steroidal anti-inflammatory drugs and selective Cox-2 inhibitors adversely affect fracture healing?  

PubMed

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs worldwide. They are prescribed for orthopaedic conditions such as osteoarthritis, soft-tissue injuries and fractures. The new generation of NSAIDs, selective cyclooxygenase-2 (COX-2) inhibitors, exhibit analgesic and anti-inflammatory effects equivalent or superior to conventional NSAIDs, while reducing the prevalence of adverse gastrointestinal events. Several reports from animal and in vitro studies have demonstrated impaired bone healing in the presence of conventional NSAIDs, as measured by a variety of different parameters. More recently, initial studies investigating the effects of selective COX-2 inhibitors on bone healing have yielded similar results, while other reports showed minor or no impairment of the healing process. The purpose of the present review article is the thorough review and analysis of the past 50-year literature and the attempt to get some conclusions about the effect of NSAIDs and selective COX-2 inhibitors on fracture healing and the clinical significance of their use in the management of postoperative and post-fracture pain. PMID:19240368

Boursinos, L A; Karachalios, T; Poultsides, L; Malizos, K N

35

Design and synthesis of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A new group of 3-alkyl-2-aryl-1,3-thiazinan-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1\\/COX-2 inhibition studies identified 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazinan-4-one (11a) as a potent (IC50=0.06?M) and selective (selectivity index >285) COX-2 inhibitor.

Tannaz Zebardast; Afshin Zarghi; Bahram Daraie; Mehdi Hedayati; Orkideh G. Dadrass

2009-01-01

36

Design and synthesis of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors.  

PubMed

A new group of 3-alkyl-2-aryl-1,3-thiazinan-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazinan-4-one (11a) as a potent (IC(50)=0.06 microM) and selective (selectivity index >285) COX-2 inhibitor. PMID:19447036

Zebardast, Tannaz; Zarghi, Afshin; Daraie, Bahram; Hedayati, Mehdi; Dadrass, Orkideh G

2009-05-03

37

Antitumor effect of the selective COX-2 inhibitor celecoxib on endometrial adenocarcinoma in vitro and in vivo  

PubMed Central

The aim of this study was to investigate the antitumor effect of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib on endometrial adenocarcinoma in mice. Various amounts of celecoxib were added to HEC-1B cells in vitro for different durations. Cell cycle and apoptosis were analyzed using flow cytometry. HEC-1B cytostasis, invasiveness and COX-2 expression were examined by MTT, transwell cabin and western blot assays, respectively. An in vivo human endometrial adenocarcinoma model was established in BALB/c nude mice using HEC-1B cells. For two weeks, the celecoxib groups were treated with celecoxib 2 or 4 mg/day via oral administration and the control group was treated with saline. Tumor volume, growth curves and the inhibition rate (IR) were recorded. COX-2 expression levels and microvessel density (MVD) were investigated using an immunohistochemical technique. In the celecoxib groups, cell proliferation was significantly inhibited in a concentration- and time-dependent manner. The proportion of cells in the G0/G1 phase increased within 24 h after the addition of celecoxib whereas those in the S and G2/M phases decreased with an increasing apoptosis peak (sub-G1) and apoptosis rate. The microporous Matrigel-coated polycarbonate membrane of the Transwell cabin was traversable for the HEC-1B cells. The invasiveness was attenuated when the celecoxib concentration was increased. The tumor growth was also greatly inhibited when the celecoxib concentration was increased. The tumor IRs were 32.4 and 48.6% following treatment with 2 and 4 mg/day celecoxib, respectively. COX-2 was mainly expressed in the cytoplasm of the tumor cells. In the celecoxib groups, the COX-2 expression levels were concentration-dependent. The COX-2 expression level and MVD decreased when the celecoxib concentration was increased. The results of dependability analysis revealed that the COX-2 expression level was positively correlated with MVD (r=0.921; P<0.01). The antitumor effect of celecoxib on endometrial adenocarcinoma in nude mice may be related to the inhibition of COX-2 expression and microangiogenesis.

XIAO, YITAO; TENG, YINCHENG; ZHANG, RUI; LUO, LAIMIN

2012-01-01

38

Chamomile, a novel and selective COX2 inhibitor with anti-inflammatory activity  

Microsoft Academic Search

AimsInducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway.

Janmejai K. Srivastava; Mitali Pandey; Sanjay Gupta

2009-01-01

39

COX2 inhibitors: are they good, bad or ugly?  

Microsoft Academic Search

Arthritis and Hypertension are common co-morbid conditions affecting elderly adults. Hypertensive patients on antihypertensive medications can have destabilization of BP control and other cardiorenal events with the use of NSAIDs. The potential for similar interactions with COX-2 inhibitors is being explored. This study involves the effects of selective COX-2 inhibitor (Celecoxib) on renal functions and blood pressure. This is a

Munavvar Izhar; Elena Hung; George Bakris

2003-01-01

40

Effects of a non-selective COX inhibitor and selective COX-2 inhibitors on contractility of human and porcine ureters in vitro and in vivo  

PubMed Central

Background and purpose: Anti-inflammatory drugs are used in the treatment of acute renal colic. The aim of this study was to investigate the effects of selective COX-2 inhibitors and the non-selective COX inhibitor diclofenac on contractility of human and porcine ureters in vitro and in vivo, respectively. COX-1 and COX-2 receptors were identified in human ureter and kidney. Experimental approach: Human ureter samples were used alongside an in vivo pig model with or without partial ureteral obstruction. COX-1 and COX-2 receptors were located in human ureters by immunohistochemistry. Key results: Diclofenac and valdecoxib significantly decreased the amplitude of electrically-stimulated contractions in human ureters in vitro, the maximal effect (Vmax) being 120 and 14%, respectively. Valdecoxib was more potent in proximal specimens of human ureter (EC50=7.3 × 10?11?M) than in distal specimens (EC50=7.4 × 10?10?M), and the Vmax was more marked in distal specimens (22.5%) than in proximal specimens (8.0%) in vitro. In the in vivo pig model, parecoxib, when compared to the effect of its solvent, significantly decreased the maximal amplitude of contractions (Amax) in non-obstructed ureters but not in obstructed ureters. Diclofenac had no effect on spontaneous contractions of porcine ureter in vivo. COX-1 and COX-2 receptors were found to be expressed in proximal and distal human ureter and in tubulus epithelia of the kidney. Conclusions and implications: Selective COX-2 inhibitors decrease the contractility of non-obstructed, but not obstructed, ureters of the pig in vivo, but have a minimal effect on electrically-induced contractions of human ureters in vitro.

Chaignat, V; Danuser, H; Stoffel, M H; z'Brun, S; Studer, U E; Mevissen, M

2008-01-01

41

Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling.  

PubMed

Increasing evidence has suggested that high expression level of cyclooxygenase-2 (Cox-2) is associated with the malignancies of non-small cell lung cancer (NSCLC), leading to a rationale of applying Cox-2 inhibitors as adjuvant therapy in the treatment of NSCLC. However, the addition of celecoxib, a selective Cox-2 inhibitor, to chemotherapy in clinical trials failed to benefit the survival of NSCLC patients, which urges the investigation to re-evaluate this strategy for NSCLC treatment. In this study, we observed that celecoxib treatment at clinically relevant concentrations induced epithelial-mesenchymal transition (EMT) in NSCLC cells regardless of Cox-2 status, which, however, was not recapitulated using another Cox-2 inhibitor, etodolac. Celecoxib-stimulated EMT in turn promoted cell invasion and rendered cells resistant to chemotherapy. Further mechanistic investigation by disrupting the integrity of signaling pathways using specific inhibitors or RNA interference revealed that celecoxib-induced EMT in NSCLC cells is indispensable of transforming growth factor-?1/Smad signaling. Instead, the activated MEK/ERK/SNAIL1 signaling largely accounted for celecoxib-induced EMT. Taken together, our study reveals the diverse impacts of Cox-2 inhibitors on EMT in NSCLC cells independent of Cox-2 inhibition, where celecoxib treatment leads to metastasis and chemoresistance via EMT induction. These findings reveal the increased risks of cancer metastasis and chemoresistance by applying Cox-2 inhibitors, celecoxib in particular, in clinical trials of NSCLC treatment and urge intensive preclinical assessment before proceeding to clinical application. PMID:23172668

Wang, Zi-li; Fan, Zhi-qiang; Jiang, Han-dong; Qu, Jie-ming

2012-11-21

42

QSAR analysis of diaryl COX2 inhibitors: Comparison of feature selection and train-test data selection methods  

Microsoft Academic Search

QSAR analyses were performed on a series of trans-stilbenoid diaryl compounds for modeling their COX-2 inhibitory activities. The multivariate regression equations were developed with the selected independent variables using various feature selection methods. In addition, model training was done using different test-train data selection methods. The applicability of each variable and the test-train selection methods was investigated through the type

Somaieh Soltani; Hoda Abolhasani; Afshin Zarghi; Abolghasem Jouyban

2010-01-01

43

Wound collagen deposition in rats: effects of an NO-NSAID and a selective COX-2 inhibitor  

PubMed Central

Selective cyclo-oxygenase (COX)-2 inhibitors and nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit reduced toxicity in the gastrointestinal tract, but may affect wound healing in other tissues. In this study, we have compared the effects of a selective COX-2 inhibitor (celecoxib), a nitric-oxide releasing derivative of naproxen (HCT-3012) and naproxen in a model of wound collagen deposition in the rat. Polyvinyl alcohol sponges were implanted subcutaneously in rats. The rats were treated daily for 5 days with the test drugs at equieffective anti-inflammatory doses. Naproxen (10?mg?kg?1) significantly decreased (45%) collagen deposition at the wound site relative to the vehicle-treated control group. In contrast, HCT-3012 (14.5?mg?kg?1) significantly increased (62%) collagen deposition, while celecoxib (10?mg?kg?1) had no effect. Naproxen and HCT-3012 suppressed prostaglandin (PG) E2 levels at the wound site and whole blood thromboxane synthesis to similar degrees. Celecoxib had no significant effect on wound fluid PGE2 levels, but slightly reduced whole blood thromboxane synthesis (by 17%). COX-1 mRNA and protein were expressed in the wound exudate, the skin surrounding the wound and in normal skin. In contrast, COX-2 mRNA, but not protein, was expressed in wound and normal skin. These results demonstrate that HCT-3012 can significantly enhance collagen deposition at a wound site, despite inhibiting prostaglandin synthesis to the same extent as the parent drug. Nitric oxide-releasing NSAIDs may represent a safer alternative to standard NSAIDs for use as anti-inflammatory and analgesic agents by post-surgery patients.

Muscara, Marcelo N; McKnight, Webb; Asfaha, Samuel; Wallace, John L

2000-01-01

44

QSAR analysis of diaryl COX-2 inhibitors: comparison of feature selection and train-test data selection methods.  

PubMed

QSAR analyses were performed on a series of trans-stilbenoid diaryl compounds for modeling their COX-2 inhibitory activities. The multivariate regression equations were developed with the selected independent variables using various feature selection methods. In addition, model training was done using different test-train data selection methods. The applicability of each variable and the test-train selection methods was investigated through the type and number of the selected significant descriptors as well as the statistical criteria of the developed model for each pair of feature and test-train selection methods. The goodness of fit and the statistical significance of 15 developed equations were evaluated using the correlation coefficient (R), the variance ratio (F), and the standard error of estimate (S.E.). The models were validated using the leave many out and the leave one out cross-validation methods. The mean percentage deviation (MPD(+/-SD)) was used as an accuracy criterion for checking the predicted activities. It was found that the developed models could predict the COX-2 and COX-1 inhibitory activities as well as the COX-2/COX-1 selectivity ratios producing the MPD values of 1.6(+/-0.8)%, 7.7(+/-5.6)%, and 16.9(+/-9.6)%, respectively. PMID:20332057

Soltani, Somaieh; Abolhasani, Hoda; Zarghi, Afshin; Jouyban, Abolghasem

2010-03-01

45

New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.  

PubMed

The synthesis and pharmacological evaluation of new water-soluble phosphoramidate derivatives of the COX-2 selective inhibitor cimicoxib (4) are described. The sulfonylphosphoramidic acid derivative 10 was converted to 4 in human plasma and showed excellent in vivo activity in the rat carrageenan-edema test. Pharmacokinetic evaluation in dogs indicated that 10 behaved as a prodrug, immediately converting to 4 and giving an identical profile to that of the parent compound. These results represent the first description of phosphoramidic acids as prodrugs for the sulfonamido group. Compound 10 also exhibited an important and sustained analgesic effect in the hyperalgesia test in rats and a high aqueous solubility at pH higher than 7. This profile led to the selection of 10 (UR-14048) for further development in the parenteral treatment of acute pain. PMID:15481993

Almansa, Carmen; Bartrolí, Javier; Belloc, Jordi; Cavalcanti, Fernando L; Ferrando, Rosa; Gómez, Luis A; Ramis, Isabel; Carceller, Elena; Merlos, Manuel; García-Rafanell, Julián

2004-10-21

46

NSAID inhibition of RGM1 gastric monolayer wound re-epithelialization: comparison of selective Cox-2 versus non-selective Cox inhibitors.  

PubMed

Clinical studies indicate that specific cyclooxygenase-2 (Cox-2) inhibitors are less ulcerogenic than their non-selective predecessors (e.g. indomethacin). However, Cox-2 inhibitors may also interfere with ulcer healing. Re-epithelialization is a crucial factor in both gastrointestinal mucosal injury and ulcer healing. This study was aimed to compare the effects of selective Cox-2 inhibitor (NS398) versus non-selective Cox inhibitor (indomethacin) on basal and basic fibroblast growth factor (bFGF) - stimulated gastric wound re-epithelialization. In-vitro epithelial wounds were created in confluent monolayers of RGM1 rat gastric epithelial cells by a razor blade scrape. Following wounding there was a significant re-epithelialization by 24 hrs. Indomethacin (0.25 mM and 0.5 mM) significantly inhibited basal wound re-epithelialization in a dose dependent manner. In contrast, selective Cox-2 inhibitor NS398 did not inhibit the basal re-epithelialization process. Basic FGF treatment produced significant enhancement of wound re-epitheliazation at the various concentrations [10, 20, 30, 40, 50 and 70 ng/ml] studied. Both indomethacin and NS398 inhibited bFGF stimulated wound re-epithelialization, with indomethacin having a greater inhibitory effect. The extent of NS398 inhibition was limited to the bFGF-stimulated component, whereas indomethacin inhibition extended to both the bFGF-stimulated and the basal re-epithelialization components. These findings indicate that specific Cox-2 inhibitor (NS398) does not interfere with the basal re-epithelialization but significantly inhibits the bFGF - stimulated re-epithelialization, whereas indomethacin interferes with both the basal as well as the bFGF-stimulated wound re-epithelialization. PMID:12138016

Giap, Andrew Q; Tarnawski, Andrzej; Hoa, Neil T; Akotia, Vimesh; Ma, Thomas Y

2002-05-10

47

Role of cytokines in experimentally induced lung cancer and chemoprevention by COX-2 selective inhibitor, etoricoxib.  

PubMed

This study explored the role of pro- and anti-inflammatory cytokines in dimethyl benz(a)anthracene (DMBA)-induced lung cancer and its subsequent correction with a COX-2 inhibitory NSAID, etoricoxib. A single dose of DMBA (20 mg/kg body weight) in 0.9 % NaCl administered intratracheally was used to induce tumors in the rat lungs in 20 weeks. The study of pro-inflammatory cytokines like IL-1?, TNF-?, and IFN-? revealed their upregulation by DMBA administration and restoration of their levels toward normal by the treatment with etoricoxib, while the anti-inflammatory cytokine IL-2 was found to be down-regulated with carcinogen administration and corrected with etoricoxib treatment. Apoptosis was studied by mitochondrial Bcl-2/Bax ratio and staining with fluorescent dyes acridine orange/ethidium bromide. The results showed a decreased apoptotic level with DMBA which was corrected with etoricoxib. Also, mitochondrial membrane potential was studied using JC-1 and rhodamine-123, which are membrane permeant fluorescent dyes, and generate information about cells at lower and higher mitochondrial membrane potential (??(M)). The results showed the presence of maximum number of cells with higher ??(M) in the DMBA group and their number was considerably lowered in the other three groups. PMID:22991065

Nadda, Neeti; Setia, Shruti; Vaish, Vivek; Sanyal, Sankar Nath

2012-09-19

48

Design, synthesis and biological evaluation of new (E)- and (Z)-1,2,3-triaryl-2-propen-1-ones as selective COX-2 inhibitors.  

PubMed

A group of (E)-and (Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-1 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 propenone moiety. Among the 1,2,3-triaryl-2-propen-1-ones, (Z)-1-(4-(methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-one (3b) showed the most potency and selectivity on COX-2 inhibition (COX-2 IC(50) = 0.07 microM; selectivity index = 201). The Z-propenones were also found to be more potent and selective than their E-isomers for COX-2 inhibitory activity. The structure-activity data acquired indicate that the geometry of propenone and also the type of substituents on the C-3 propenone are important for COX-2 inhibitory activity. PMID:20691338

Arfaie, Sara; Zarghi, Afshin

2010-06-02

49

COX2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX2 inhibitor celecoxib  

Microsoft Academic Search

The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX- independent mechanisms

Sabine Grösch; Irmgard Tegeder; Ellen Niederberger; Lutz Bräutigam; Gerd Geisslinger

2001-01-01

50

Meloxicam: Selective COX2 inhibition in clinical practice  

Microsoft Academic Search

Nonsteroidal antiinflammatory drugs (NSAIDs) exert their actions by inhibitingcyclooxygenase (COX). It has recently been postulated that NSAIDs' antiinflammatory efficacy arises from inhibition of the COX-2 isoform of cyclooxygenase, whereas inhibition of the COX-1 isoform produces the troublesome and sometimes serious gastric and renal side effects of NSAIDs. A relatively selective COX-2 inhibitor, such as meloxicam, may combine antiinflammatory efficacy with

Daniel E. Furst

1997-01-01

51

Targeting KSHV/HHV-8 Latency with COX-2 Selective Inhibitor Nimesulide: A Potential Chemotherapeutic Modality for Primary Effusion Lymphoma  

PubMed Central

The significance of inflammation in KSHV biology and tumorigenesis prompted us to examine the role of COX-2 in primary effusion lymphoma (PEL), an aggressive AIDS-linked KSHV-associated non-Hodgkin's lymphoma (NHL) using nimesulide, a well-known COX-2 specific NSAID. We demonstrate that (1) nimesulide is efficacious in inducing proliferation arrest in PEL (KSHV+/EBV-; BCBL-1 and BC-3, KSHV+/EBV+; JSC-1), EBV-infected (KSHV-/EBV+; Raji) and non-infected (KSHV-/EBV-; Akata, Loukes, Ramos, BJAB) high malignancy human Burkitt's lymphoma (BL) as well as KSHV-/EBV+ lymphoblastoid (LCL) cell lines; (2) nimesulide is selectively toxic to KSHV infected endothelial cells (TIVE-LTC) compared to TIVE and primary endothelial cells (HMVEC-d); (3) nimesulide reduced KSHV latent gene expression, disrupted p53-LANA-1 protein complexes, and activated the p53/p21 tumor-suppressor pathway; (4) COX-2 inhibition down-regulated cell survival kinases (p-Akt and p-GSK-3?), an angiogenic factor (VEGF-C), PEL defining genes (syndecan-1, aquaporin-3, and vitamin-D3 receptor) and cell cycle proteins such as cyclins E/A and cdc25C; (5) nimesulide induced sustained cell death and G1 arrest in BCBL-1 cells; (6) nimesulide substantially reduced the colony forming capacity of BCBL-1 cells. Overall, our studies provide a comprehensive molecular framework linking COX-2 with PEL pathogenesis and identify the chemotherapeutic potential of nimesulide in treating PEL.

George Paul, Arun; Sharma-Walia, Neelam; Chandran, Bala

2011-01-01

52

Design and synthesis of new 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo[d] imidazoles as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A new series of 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo[d]imidazoles, possessing a methylsulfonyl pharmacophore, were synthesized\\u000a to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme\\u000a inhibition studies were carried out to acquire structure–activity relationship data with respect to the point that molecular\\u000a modeling studies showed that designed compounds bind in the primary binding site such that the SO2Me

A. Zarghi; H. Reihanfard; S. Arfaei; B. Daraei; M. Hedayati

53

Design and synthesis of new 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-ones as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A new series of 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-ones, possessing a methylsulfonyl pharmacophore,\\u000a were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1\\u000a and COX-2 isozyme inhibition studies were performed to acquire structure-activity relationship data with respect to the point\\u000a that molecular modeling studies showed that designed compounds bind in the primary binding site such that

A. Zarghi; H. Arefi; O. G. Dadrass; S. Torabi

2010-01-01

54

Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumor angiogenesis with extensive tumor necrosis  

SciTech Connect

Purpose: Toward improved glioblastoma multiforme treatment, we determined whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, could enhance glioblastoma radiosensitivity by inducing tumor necrosis and inhibiting tumor angiogenesis. Methods and Materials: U-87MG cells treated with celecoxib, irradiation, or both were assayed for clonogenic survival and angiogenic factor protein analysis (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor [VEGF]). In vivo, survival of mice intracranially implanted with U-87MG cells and treated with celecoxib and/or irradiation was monitored. Isolated tumors were assessed for tumor necrosis and tumor microvascular density by von Williebrand's factor (vWF) immunohistochemical staining. Results: Celecoxib (4 and 30 {mu}M; 24, 48, and 72 h) enhanced U-87MG cell radiosensitivity by significantly reducing clonogenic survival of irradiated cells. Angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 expression increased after 72 h of celecoxib alone and when combined with irradiation. In vivo, median survival of control mice intracranially implanted with U-87MG cells was 18 days. Celecoxib (100 mg/kg/day, 2 weeks) significantly extended median survival of irradiated mice (24 Gy total) from 34 to 41 days, with extensive tumor necrosis [24.5 {+-} 8.6% of tumor region, compared with irradiation alone (2.7 {+-} 1.8%)]. Tumor microvascular density was significantly reduced in combined celecoxib and irradiated tumors (52.5 {+-} 2.9 microvessels per mm{sup 2} tumor region), compared with irradiated tumors alone (65.4 {+-} 4.0 microvessels per mm{sup 2}). Conclusion: Celecoxib significantly enhanced glioblastoma radiosensitivity, reduced clonogenic survival, and prolonged survival of glioblastoma-implanted mice by inhibition of tumor angiogenesis with extensive tumor necr0010os.

Kang, Khong Bee [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre (Singapore)]. E-mail: dmskkb@nccs.com.sg; Wang, Ting Ting [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre (Singapore); Woon, Chow Thai [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre (Singapore); Cheah, Elizabeth S. [Department of Pathology, Singapore General Hospital (Singapore); Moore, Xiao Lei [Baker Heart Research Institute, Melbourne (Australia); Zhu Congju [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre (Singapore); Wong, Meng Cheong [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre (Singapore) and National Neuroscience Institute, Singapore General Hospital Campus (Singapore)

2007-03-01

55

Superiority of the gastroduodenal safety profile of licofelone over rofecoxib, a COX-2 selective inhibitor, in dogs.  

PubMed

This study assessed the gastroduodenal safety profile of licofelone, a new nonsteroidal anti-inflammatory drug with dual inhibitory activity against 5-lipoxygenase and cyclo-oxygenase (COX), by using endoscopic evaluations and by comparing licofelone to rofecoxib, a selective COX-2 inhibitor. Twenty-one dogs underwent blinded gastroduodenoscopies, during which the mucosa of the gastroduodenal tract was assessed and scored. Blood analyses were monitored on days 0 (baseline), 14, 28, 42, and 56. Examinations to detect fecal occult blood were performed daily. Dogs were randomly assigned to three groups that received either a placebo, licofelone at a dose of 2.5 mg/kg twice daily, or rofecoxib at a dose of 0.5 mg/kg daily, respectively. Significant differences between the groups in gastric (P = 0.003), duodenal (P = 0.009), and gastroduodenal (P = 0.002) endoscopic lesion scores were observed at day 56. Rofecoxib-treated dogs had more lesions in all areas when compared with placebo-treated dogs, more duodenal lesions when compared with licofelone-treated dogs and more lesions than they had at baseline. In contrast to licofelone, rofecoxib was found to induce significant gastric and gastroduodenal lesions in dogs that lacked pre-existing lesions at baseline. Blood analyses and fecal examinations did not reveal abnormalities in any of the experimental groups. Treatment with licofelone was well tolerated and was shown to be safer than rofecoxib in terms of upper gastrointestinal damage. In this way, this study demonstrates the gastroduodenal safety profile of licofelone for chronic treatment. PMID:15720519

Moreau, M; Daminet, S; Martel-Pelletier, J; Fernandes, J; Pelletier, J-P

2005-02-01

56

Glycosylation of human cyclooxygenase-2 (COX-2) decreases the efficacy of certain COX-2 inhibitors.  

PubMed

Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenase-2 (COX-2). COX-2 exists as two glycoforms, 72 and 74 kDa, the latter resulting from an additional glycosylation at Asn(580). In this study, Asn(580) was mutated, and the mutant and wild-type COX-2 genes were expressed in COS-1 cells to determine how glycosylation affects the inhibition of COX-2 activity by aspirin, flurbiprofen, ibuprofen, celecoxib, and etoricoxib. Results indicate that certain inhibitors were 2-5 times more effective at inhibiting COX-2 activity when the glycosylation site was eliminated, indicating that glycosylation of COX-2 at Asn(580) decreases the efficacy of some inhibitors. PMID:22245433

Sevigny, Mary B; Graham, Kamara; Ponce, Esmeralda; Louie, Maggie C; Mitchell, Kylie

2012-01-08

57

Cox-2 inhibitors and the risk of cardiovascular thrombotic events.  

PubMed

In 1971, Vane showed that the analgesic action of traditional NSAIDs relies on inhibition of the cyclo-oxygenase (COX) enzyme, which in turn results in reduced synthesis of proalgesic prostaglandins. Two decades later COX was shown to exist as two distinct isoforms. The constitutive isoform COX-1, supports the beneficial homeostatic functions whereas the inducible isoform, COX-2 becomes up regulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis. Despite the benefits of NSAIDs for acute and chronic pain one of the most clinically significant and well characterized adverse effect is on GI mucosa. The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. The COX-2 selective (COX-1 sparing) inhibitors are associated with reduced GI mucosal damage as demonstrated in several trials. In light of the overwhelming and sometimes contradictory information for patients and physicians regarding the safety of COX-2 agents this article will summarize the available evidence regarding cardiovascular (CV) safety data and contemporary recommendations for prescribing of COX-2-selective NSAIDs. PMID:22708229

Khan, M; Fraser, A

2012-04-01

58

30Day Mortality After Peptic Ulcer Perforation Among Users of Newer Selective Cox2 Inhibitors and Traditional NSAIDs: A Population-Based Study  

Microsoft Academic Search

OBJECTIVES:Nonsteroidal anti-inflammatory drug (NSAID) use is a strong risk factor for peptic ulcer perforation, yet little is known about the outcome of this condition among NSAID users. We examined 30-day mortality after peptic ulcer perforation associated with the use of traditional NSAIDs and newer selective cyclo-oxygenase-2 (COX-2) inhibitors.METHODS:We conducted a cohort study of patients with the first hospitalization for peptic

Reimar W. Thomsen; Anders Riis; Estrid M. Munk; Mette Nørgaard; Steffen Christensen; Henrik T. Sørensen

2006-01-01

59

Aspirin, but not the more selective cyclooxygenase (COX)-2 inhibitors meloxicam and SC 58125, aggravates postischaemic cardiac dysfunction, independent of COX function  

Microsoft Academic Search

Inhibition of cyclooxygenase (COX) might favour non-enzymatic formation of cardiodepressive isoprostanes from arachidonic acid by radicals generated during reperfusion. This could explain deleterious effects of acetylsalicylic acid (ASA) on cardiac function. We examined the influence of COX inhibition on myocardial function after low-flow ischaemia and reperfusion, employing either ASA (100 µmol\\/l), the partially selective COX-2 inhibitor meloxicam (0.3 µmol\\/l and

Bernhard Heindl; Bernhard F. Becker

2001-01-01

60

QSAR analysis of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives as selective COX-2 inhibitors.  

PubMed

Quantitative structure-activity relationship (QSAR) analysis was performed on a series of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindole for their cyclooxygenase-2 (COX-2) inhibition. QSAR investigations were based on Hansch's extra thermodynamic multi-parameter approach and receptor surface analysis (RSA). QSAR investigations reveal that steric and electrostatic interactions are primarily responsible for COX-2 enzyme-ligand interaction. QSAR model derived from Hansch analysis demonstrated that COX-2 inhibitory activity is correlated with sum of atomic polarizability (Apol), number of hydrogen-bond donor groups (HBD), energy of the highest occupied molecular orbital (HOMO), desolvation free energy for water (F(H(2)O)) and fraction of areas of molecular shadow in the XY and ZX planes over area of enclosing rectangle (Sxyf and Sxzf) with r ranges 0.870-0.904. The best model was obtained from RSA model having r = 0.940 with good predictive ability (predicted compounds in training set and test set within +/- 1.0 unit of pIC(50)) and can be used in designing better selective COX-2 inhibitors among the congeners in future. PMID:18023931

Silakari, Pratigya; Shrivastava, Savitri Devi; Silakari, Gyati; Kohli, Dharm Veer; Rambabu, Gundla; Srivastava, Soumya; Shrivastava, Santosh Kumar; Silakari, Om

2007-10-11

61

Effect of nonselective and selective COX-2 inhibitors on memory dysfunction, glutathione system, and tumor necrosis factor alpha level against cerebral ischemia reperfusion injury.  

PubMed

Involvement of the glutathione system is well established in stroke-induced memory dysfunction. The aim of the present study was to investigate the effects of celecoxib (a selective cyclooxygenase-2 [COX-2] inhibitor), nimesulide (a preferential COX-2 inhibitor), and ibuprofen (a nonselective COX-2 inhibitor) against bilateral common carotid artery occlusion (BCCAO)-induced memory dysfunction. BCCAO for 30 minutews, followed by 24-hour reperfusion, significantly delayed transfer latency in the plus-maze performance task and shortened fall-off time in the hanging-wire experimental test. Besides significant alterations in glutathione defense (i.e., glutathione S-transferase and redox ratio), increased acetylcholinesterase activity and proinflammatory marker (tumor necrosis factor alpha TNF-?) in the hippocampus was seen. Seven days of treatment with celecoxib (3 and 10?mg/kg, p.o.), nimesulide (10?mg/kg, p.o.), and ibuprofen (30?mg/kg, p.o.) significantly improved behavioral alterations and glutathione defense and attenuated acetylcholinesterase activity and TNF-? levels, as compared to the control (i.e., ischemic reperfusion) group. The present study highlights the neuroprotective effect of celecoxib and nimesulide against ischemia reperfusion injury-induced memory dysfunction, neuroinflammation, and oxidative damage. PMID:21995864

Gaur, Vaibhav; Kumar, Anil

2011-10-14

62

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.  

PubMed Central

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE2. PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.

Anderson, G D; Hauser, S D; McGarity, K L; Bremer, M E; Isakson, P C; Gregory, S A

1996-01-01

63

Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors.  

PubMed

A group of 2,3-diaryl-1,3-thiazolidine-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. PMID:17822894

Zarghi, Afshin; Najafnia, Leila; Daraee, Bahram; Dadrass, Orkideh G; Hedayati, Mehdi

2007-08-22

64

Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives as selective cyclooxygenase (COX2) inhibitors  

Microsoft Academic Search

A group of 2,3-diaryl-1,3-thiazolidine-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity.

Afshin Zarghi; Leila Najafnia; Bahram Daraee; Orkideh G. Dadrass; Mehdi Hedayati

2007-01-01

65

The gastrointestinal safety of the COX2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events  

Microsoft Academic Search

ObjectiveEtoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).

Richard H Hunt; Sean Harper; Douglas J Watson; Chang Yu; Hui Quan; Michael Lee; Judith K Evans; Bettina Oxenius

2003-01-01

66

Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors.  

PubMed

A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC(50) values of 6 and 7 ?M for COX-2. All compounds showed IC(50) values greater 100 ?M for COX-1 inhibition. PMID:22341941

Al-Hourani, Baker Jawabrah; Sharma, Sai Kiran; Suresh, Mavanur; Wuest, Frank

2012-02-02

67

The gastrointestinal safety of the COX2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events  

Microsoft Academic Search

OBJECTIVE:Etoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).METHODS:Upper GI endoscopy

Richard H. Hunt; Sean Harper; Douglas J. Watson; Chang Yu; Hui Quan; Michael Lee; Judith K. Evans; Bettina Oxenius

2003-01-01

68

QSAR and classification models of a novel series of COX-2 selective inhibitors: 1,5-diarylimidazoles based on support vector machines.  

PubMed

The support vector machine, which is a novel algorithm from the machine learning community, was used to develop quantitation and classification models which can be used as a potential screening mechanism for a novel series of COX-2 selective inhibitors. Each compound was represented by calculated structural descriptors that encode constitutional, topological, geometrical, electrostatic, and quantum-chemical features. The heuristic method was then used to search the descriptor space and select the descriptors responsible for activity. Quantitative modelling results in a nonlinear, seven-descriptor model based on SVMs with root mean-square errors of 0.107 and 0.136 for training and prediction sets, respectively. The best classification results are found using SVMs: the accuracy for training and test sets is 91.2% and 88.2%, respectively. This paper proposes a new and effective method for drug design and screening. PMID:15663000

Liu, H X; Zhang, R S; Yao, X J; Liu, M C; Hu, Z D; Fan, B T

2004-06-01

69

COX-2 inhibitors and their role in gynecology.  

PubMed

This review summarizes current knowledge about the roles of cyclooxygenases and prostaglandins in reproductive medicine. With the development of COX-2 specific inhibitors, new therapeutic options are available to obstetricians and gynecologists, offering better-tolerated alternatives to conventional NSAIDs. The analgesic effectiveness of COX-2 specific inhibitors is well established, and they are already in use in a range of painful conditions. Both celecoxib and valdecoxib are indicated for the treatment of primary dysmenorrhea, and may be effective in postoperative pain, including hysterectomy, and pain associated with endometriosis. There is also speculation that COX-2 specific inhibitors may be effective tocolytic agents without the risks to the fetus seen with conventional NSAIDs. The role of COX-2 in oncogenesis is also under investigation, and COX-2 specific inhibitors may eventually be used in the prevention and treatment of gynecologic malignancies. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to describe the two types of cylooxygenase enzymes (COX), to list the effects and side effects of NSAIDs and COX-2 medications, and to outline the various changes in COX expression during pregnancy. PMID:12447099

Hayes, Ellen C; Rock, John A

2002-11-01

70

The Cox2Specific Inhibitor Celecoxib Inhibits Adenylyl Cyclase  

Microsoft Academic Search

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known causes of acute renal insufficiency and gastropathy in patients with chronic inflammatory diseases. This action is presumed to result from nonselective inhibition of both constitutive and inducible forms of prostaglandin H synthases, also known as the cyclooxygenase enzymes (i.e., COX-1 amd COX-2). Celecoxib (Celebrex®) is a COX-2 enzyme inhibitor and has emerged as a

Shamsher S. Saini; Deborah L. Gessell-Lee; Johnny W. Peterson

2003-01-01

71

Kinetics and docking studies of a COX-2 inhibitor isolated from Terminalia bellerica fruits.  

PubMed

Triphala is an Ayurvedic herbal formulation consisting of equal parts of three myrobalans: Terminalia chebula, Terminalia bellerica and Emblica officinalis. We recently reported that chebulagic acid (CA) isolated from Terminalia chebula is a potent COX-2/5-LOX dual inhibitor. In this study, compounds isolated from Terminalia bellerica were tested for inhibition against COX and 5-LOX. One of the fractionated compounds showed potent inhibition against COX enzymes with no inhibition against 5-LOX. It was identified as gallic acid (GA) by LC-MS, NMR and IR analyses. We report here the inhibitory effects of GA, with an IC(50) value of 74 nM against COX-2 and 1500 nM for COX-1, showing ?20 fold preference towards COX-2. Further docking studies revealed that GA binds in the active site of COX-2 at the non-steroidal anti-inflammatory drug (NSAID) binding site. The carboxylate moiety of GA interacts with Arg120 and Glu524. Based on substrate dependent kinetics, GA was found to be a competitive inhibitor of both COX-1 and COX-2, with more affinity towards COX-2. Taken together, our studies indicate that GA is a selective inhibitor of COX-2. Being a small natural product with selective and reversible inhibition of COX-2, GA would form a lead molecule for developing potent anti-inflammatory drug candidates. PMID:20441561

Reddy, Tamatam Chandramohan; Aparoy, Polamarasetty; Babu, Neela Kishore; Kumar, Kotha Anil; Kalangi, Suresh Kumar; Reddanna, Pallu

2010-10-01

72

Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib  

PubMed Central

Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings.

Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

2013-01-01

73

Multifocal Fixed Drug Eruption with COX-2 Inhibitor-Celecoxib.  

PubMed

Cyclooxygenase-2 (COX-2) inhibitors are rapidly becoming the first choice nonsteroidal anti-inflammatory drugs (NSAIDs) for various rheumatological and other painful conditions. However, they might not be as safe or free of side effects as they are considered to be. These COX-2inhibitors may cause a variety of dermatological and systemic side effects of which we should be aware to avoid their indiscriminate use. We hereby report a case of multifocal fixed drug eruption (FDE) with celecoxib which has not yet been reported in Indian settings. PMID:23716804

Chugh, Shikha; Sarkar, Rashmi; Garg, Vijay K; Singh, Avninder; Keisham, Chitralekha

2013-03-01

74

The double-edged sword of COX2 selective NSAIDs  

Microsoft Academic Search

THE LAUNCH OF THE CYCLOOXYGENASE-2 (COX-2) selective NSAIDs was based on 2 hypotheses: (1) the major adverse effects limiting the usefulness of nonselective NSAIDs are gastrointestinal in nature and (2) COX-2 selective NSAIDs are associ- ated with fewer gastrointestinal adverse effects than nonselective NSAIDs. At the time of the launch, neither of these hypotheses had been proven and, as docu-

James M. Wright

75

In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX2 inhibitor etoricoxib (MK-0663)  

Microsoft Academic Search

Characterization of the metabolites of the COX-2 inhibitor etoricoxib (MK-0663 and L-791,456) produced in vitro indicate formation of an N-oxide pyridine and hydroxymethyl pyridine that can further be glucuronidated or oxidized to an acid. Significant turnover is observed in human hepatocytes. Several CYPs are involved in the oxidative biotranformations and, from in vitro studies, etoricoxib is not a potent CYP3A4

Nathalie Chauret; James A Yergey; Christine Brideau; Richard W Friesen; Joseph Mancini; Denis Riendeau; José Silva; Angela Styhler; Laird A Trimble; Deborah A Nicoll-Griffith

2001-01-01

76

COX2 inhibitors: a story of greed, deception and death  

Microsoft Academic Search

In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over

Georges M. Halpern

2005-01-01

77

COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells.  

PubMed

Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We selected U937 cells as a model of sensitive cells for further studies. Here, we provide evidence that the protective effect is COX-independent. No suppression of the low basal prostaglandin (PG)E(2) production may be observed upon treatment by COX-2 inhibitors. Besides, the non-active celecoxib analog 2,5-dimethyl-celecoxib is able to protect from apoptosis as well. We demonstrate early prevention of the stress-induced apoptotic signaling, prior to Bax/Bak activation. This preventive effect fits with an impairment of the ability of chemotherapeutic agents to trigger apoptogenic stress. Accordingly, etoposide-induced DNA damage is strongly attenuated in the presence of COX-2 inhibitors. In contrast, COX-2 inhibitors do not exert any anti-apoptotic activity when cells are challenged with physiological stimuli (anti-Fas, TNF? or Trail) or with hydrogen peroxide, which do not require internalization and/or are not targeted by chemoresistance proteins. Altogether, our findings show a differential off-target anti-apoptotic effect of COX-2 inhibitors on intrinsic vs. extrinsic apoptosis at the very early steps of intracellular signaling, prior to commitment. The results imply that an exacerbation of the chemoresistance phenomena may be implicated. PMID:21745461

Cerella, Claudia; Sobolewski, Cyril; Chateauvieux, Sébastien; Henry, Estelle; Schnekenburger, Michael; Ghelfi, Jenny; Dicato, Mario; Diederich, Marc

2011-06-24

78

Different COXindependent effects of the COX2 inhibitors etoricoxib and lumiracoxib  

Microsoft Academic Search

Etoricoxib and lumiracoxib are both highly selective COX-2 inhibitors. This drug class has recently been linked to severe side effects in particular within the cardiovascular system. The underlying signal transduction pathway is not clarified at the moment but different COX-independent mechanisms might contribute to wanted and unwanted effects of these drugs. Here, we investigated COX-2-independent effects of etoricoxib and lumiracoxib.

Ellen Niederberger; Christine Manderscheid; Gerd Geisslinger

2006-01-01

79

Selective COX2 inhibition and cardiovascular effects: a review of the rofecoxib development program  

Microsoft Academic Search

Cyclo-oxygenase-2 (COX-2) inhibitors appear to alter the balance of vasoactive eicosanoids (prostacyclin and thromboxane) and to suppress the inflammatory mediators implicated in the progression of atherogenesis and ischemic myocardial injury. Neutral, harmful, and beneficial cardiovascular (CV) effects have all been postulated to result from these changes. Investigations conducted with rofecoxib, a selective COX-2 inhibitor, have substantially contributed to our understanding

Matthew R Weir; Rhoda S Sperling; Alise Reicin; Barry J Gertz

2003-01-01

80

Sulfone COX2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX2 inhibitors and NSAIDs  

Microsoft Academic Search

Clinical investigations have demonstrated a link between use of the sulfone cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, and increased risk for atherothrombotic events. This increased risk was not observed for a sulfonamide COX-2 inhibitor (celecoxib), indicating a potential non-enzymatic mechanism for rofexocib. To test this hypothesis, we compared the independent effects of COX-2 inhibitors on human LDL oxidation, an important contributor to

Mary F. Walter; Robert F. Jacob; Charles A. Day; Rachel Dahlborg; Yujia Weng; R. Preston Mason

2004-01-01

81

Efficacy and Safety of COX-2 Inhibitors in the Clinical Management of Arthritis: Mini Review  

PubMed Central

In the clinical management of arthritis, the choice of nonsteroidal anti inflammatory drug (NSAID) remains confusing and controversial. A common practice on the choice of NSAID in clinical management of arthritis is the risk benefit ratio. The main objective of this review is to addresses the main arguments for the pharmacological and clinical use of COX-2 inhibitors in relation to nonselective NSAIDs for the clinical management of arthritis. This review concluded that, both NSAIDs and COX-2 inhibitors are equally effective and are associated with increased risk of GI, renal, and CV, adverse effects. Complete understanding of the patient's comorbid conditions and concomitant medications, coupled with precise monitoring during the treatment, may help to decrease the threat of adverse effects induced by nonselective NSAIDs and selective COX-2 inhibitors.

Mathew, Sam T.; Devi S, Gayathri; Prasanth, V. V.; Vinod, B.

2011-01-01

82

QSAR analysis of 1,3-diaryl-4,5,6,7-tetrahydro-2 H-isoindole derivatives as selective COX2 inhibitors  

Microsoft Academic Search

Quantitative structure–activity relationship (QSAR) analysis was performed on a series of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindole for their cyclooxygenase-2 (COX-2) inhibition. QSAR investigations were based on Hansch's extra thermodynamic multi-parameter approach and receptor surface analysis (RSA). QSAR investigations reveal that steric and electrostatic interactions are primarily responsible for COX-2 enzyme–ligand interaction. QSAR model derived from Hansch analysis demonstrated that COX-2 inhibitory activity is correlated

Pratigya Silakari; Savitri Devi Shrivastava; Gyati Silakari; Dharm Veer Kohli; Gundla Rambabu; Soumya Srivastava; Santosh Kumar Shrivastava; Om Silakari

2008-01-01

83

COX2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells  

Microsoft Academic Search

Enzymatic inhibitors of pro-inflammatory cyclooxygenase-2 (COX-2) possess multiple anti-cancer effects, including chemosensitization. These effects are not always linked to the inhibition of the COX-2 enzyme. Here we analyze the effects of three COX-2 enzyme inhibitors (nimesulide, NS-398 and celecoxib) on apoptosis in different hematopoietic cancer models. Surprisingly, COX-2 inhibitors strongly prevent apoptosis induced by a panel of chemotherapeutic agents. We

Claudia Cerella; Cyril Sobolewski; Sébastien Chateauvieux; Estelle Henry; Michael Schnekenburger; Jenny Ghelfi; Mario Dicato; Marc Diederich

2011-01-01

84

COX2 Inhibitors for the Prevention of Breast Cancer  

Microsoft Academic Search

The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is normally expressed predominantly in kidney and brain, and also has important roles in reproduction and inflammation. COX-2 misexpression has been observed in numerous human cancers, including the majority of colorectal cancers. Recently, COX-2 overexpression has been described in human breast cancer. COX-2 is present in about 40% of invasive breast carcinomas, particularly those

Louise R. Howe; Andrew J. Dannenberg

2003-01-01

85

Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors  

PubMed Central

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 203 possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

Vernieri, Ermelinda; Gomez-Monterrey, Isabel; Grieco, Paolo; Musella, Simona; Bertamino, Alessia; Scognamiglio, Ilaria; Alcaro, Stefano; Ortuso, Francesco; Novellino, Ettore; Campiglia, Pietro

2013-01-01

86

Synthesis and selective cyclooxygenase-2 (COX2) inhibitory activity of a series of novel bicyclic pyrazoles  

Microsoft Academic Search

Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in human whole blood (HWB). Several of the compounds were found to be novel and selective COX-2 inhibitors, the most potent and selective being 1-(5-cyclohexyl (2H,3H-pyrazolo[5,1-b]-1,3-oxazolidin-6-yl)-4-(methylsulfonyl)benzene, 7a (IC5o for COX-1>100 ?M; for COX-2=1.3 ?M).

Ramani R. Ranatunge; David S. Garvey; David R. Janero; L. Gordon Letts; Allison M. Martino; Madhavi G. Murty; Stewart K. Richardson; Delano V. Young; Irina S. Zemetseva

2004-01-01

87

Neoplasms escape selective COX2 inhibition in an animal model of breast cancer  

Microsoft Academic Search

Background  Cyclo-oxygenase-2 (COX-2) is up-regulated in malignant tumours rendering it an attractive target for cancer therapeutics.\\u000a However, whether long-term antagonism maintains its initial efficacy on established tumours is unclear.\\u000a \\u000a \\u000a \\u000a Methods  4T1 cells were injected into the mammary fat pad of BALB\\/c mice (n = 8). Once tumour deposits were established, animals were randomized into two equal groups to receive either a selective\\u000a COX-2 inhibitor

M. Barry; R. A. Cahill; G. Roche-Nagle; T. G. Neilan; A. Treumann; J. H. Harmey; D. J. Bouchier-Hayes

2009-01-01

88

Selective inhibition of COX2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen  

Microsoft Academic Search

BACKGROUNDSelective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs.AIMSWe compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity.SUBJECTSThirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind,

A A Shah; B Thjodleifsson; F E Murray; E Kay; M Barry; G Sigthorsson; H Gudjonsson; E Oddsson; A B Price; D J Fitzgerald; I Bjarnason

2001-01-01

89

Celecoxib Exhibits the Greatest Potency amongst Cyclooxygenase (COX) Inhibitors for Growth Inhibition of COX2-negative Hematopoietic and Epithelial Cell Lines1  

Microsoft Academic Search

Cyclooxygenase-2 (COX-2) is an important cellular target for both therapy and\\/or prevention of inflammatory disorders and cancer. The advent of selective COX-2 inhibitors now allows a more precise and safer treatment approach. The screening of an array of cancer cell lines for growth inhibitory effects of COX-2-selective and -nonselective inhibitors, including celecoxib (Celebrex) and rofecoxib (Vioxx), produced two un- anticipated

Chris Waskewich; Rosalyn D. Blumenthal; Honglan Li; Rhona Stein; David M. Goldenberg; Jack Burton

2002-01-01

90

Information, Learning, and Drug Diffusion: the Case of Cox2 Inhibitors  

Microsoft Academic Search

The recent withdrawal of Cox-2 Inhibitors has generated debate on the role of information in drug diffusion: can the market learn the efficacy of new drugs, or does it depend solely on manufacturer advertising and FDA updates? In this study, we use a novel data set to study the diffusion of three Cox-2 Inhibitors ? Celebrex, Vioxx and Bextra ?

Pradeep Chintadunta; Renna Jiang; Ginger Z. Jin

2008-01-01

91

Primary Virtual and in vitro Bioassay Screening of Natural Inhibitors from Flavonoids against COX2  

Microsoft Academic Search

In this study, we reported the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2 092 flavonoids) using the iGEMDOCK software tool against the COX-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of COX-2. Centaureidin and luteolin were found to be the potential inhibitors of COX-2

Ya-Di LI; Christopher M. Frenz; Mian-Hua CHEN; Yu-Rong WANG; Feng-Juan LI; Cheng LUO; Ning LIANG; Hua YANG; Lars bohlin; Chang-Lu WANG

2011-01-01

92

Cyclooxygenase2 (COX2), aromatase and breast cancer: a possible role for COX2 inhibitors in breast cancer chemoprevention  

Microsoft Academic Search

breast. The main target of NSAID activity is the cyclooxygenase (COX) enzyme. Two isoforms of COX have been identified: COX-1, the constitutive isoform; and COX-2, the inducible form of the enzyme. COX-2 can undergo rapid induction in response to many factors such as bacterial lipopolysaccharides, growth factors, cytokines and phorbol esters. COX-2 is overexpressed in some malignancies including carcinoma of

G. Davies; L.-A. Martin; N. Sacks; M. Dowsett

2002-01-01

93

Trends in the Use and Expenditures for COX-2 Inhibitors and Traditional Nonsteroidal Anti-inflammatory Drugs, 1997-2003. Statistical Brief No. 139.  

National Technical Information Service (NTIS)

Since their approval by the Food and Drug Administration (FDA) in 1998, selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) have accounted for a growing proportion of prescriptions for the class containing all nonsteroidal anti-inflammatory drugs (NS...

J. Banthin M. Zodet

2006-01-01

94

Information, learning, and drug diffusion: The case of Cox2 inhibitors  

Microsoft Academic Search

The recent withdrawal of Cox-2 Inhibitors has generated debate on the role of information in drug diffusion: can the market\\u000a learn the efficacy of new drugs, or does it depend solely on manufacturer advertising and FDA updates? In this study, we use\\u000a a novel data set to study the role of learning in the diffusion of three Cox-2 Inhibitors—Celebrex, Vioxx

Pradeep K. Chintagunta; Renna Jiang; Ginger Z. Jin

2009-01-01

95

Going against the flow: the impact of PHARMAC not funding COX2 inhibitors for chronic arthritis  

Microsoft Academic Search

COX-2 inhibitors have come under a lot of scrutiny lately, with questions raised regarding class effects and the risk-benefit of these pharmaceuticals. From 1999 to 2003 the New Zealand Pharmaceutical Management Agency (PHARMAC) evaluated the evidence on COX-2 inhibitors, including their efficacy, cost-effectiveness and budgetary impact. In September 2003 PHARMAC decided not to list celecoxib, rofecoxib and meloxicam on the

Rachel Grocott; Scott Metcalfe

2005-01-01

96

The efficacy of rebamipide add-on therapy in arthritic patients with COX-2 selective inhibitor-related gastrointestinal events: a prospective, randomized, open-label blinded-endpoint pilot study by the GLORIA study group.  

PubMed

OBJECTIVE: We aimed to confirm the effect of combined treatment with celecoxib and rebamipide would be more effective than celecoxib alone for prevention of upper gastrointestinal (GI) events. METHODS: Patients with rheumatoid arthritis, osteoarthritis, and low back pain were enrolled in this study. Patients were randomized to two groups: a monotherapy group (100 mg celecoxib twice daily) and a combination therapy group (add on100 mg of rebamipide three times a day). The GI mucosal injury was evaluated by endoscopic examination before treatment and at 3 months. The primary endpoint was to evaluate the preventive effect of the combination therapy group for GI events, endoscopic upper GI ulcers and intolerable GI symptoms, compared with the monotherapy group. RESULTS: Seventy-five patients were enrolled. Sixty-five patients were analyzed (16 males, 49 females; mean age: 67 ± 13 years). The prevalence of upper GI events, five of endoscopic GI ulcers and one of intolerable GI symptoms, were 6/34 (17.6 %) in the monotherapy group and 0/31 in the combination therapy group, p = 0.0252. CONCLUSIONS: The combination therapy group was more effective than the monotherapy group for prevention of upper GI events in this study. Rebamipide might be a candidate for an option to prevent COX-2 selective inhibitor-induced upper GI events. PMID:23306427

Hasegawa, Masahiro; Horiki, Noriyuki; Tanaka, Kyosuke; Wakabayashi, Hiroki; Tano, Shunsuke; Katsurahara, Masaki; Uchida, Atsumasa; Takei, Yoshiyuki; Sudo, Akihiro

2013-01-10

97

Overcoming paclitaxel resistance in uterine endometrial cancer using a COX-2 inhibitor.  

PubMed

Cyclooxygenase (COX)-2 inhibitors have been reported to potentially modulate the resistance of cancer cells to chemotherapeutic drugs by affecting multidrug resistance 1 (MDR1) expression. In the present study, we investigated the association between COX-2 and MDR1 expression in endometrial cancers and evaluated the effects of the COX-2 inhibitor, etodolac, in combination with paclitaxel on paclitaxel-resistant endometrial cancer cells. The relationship between COX-2 and MDR1 mRNA expression was examined by quantitative PCR in 36 endometrial cancer specimens. The paclitaxel-resistant cell line OMC-2P was established from OMC-2 cells. Paclitaxel (1 µg/ml) with or without etodolac (10 µg/ml) was added to OMC-2 and OMC-2P cells, and COX-2 and MDR1 mRNA expression levels were examined. The concentration of prostaglandin E2 (PGE2) in the supernatant of each cell line was examined by enzyme-linked immunosorbent assay. The function of MDR1 was determined by intracellular accumulation of rhodamine 123 using flow cytometry, and the concentration of intracellular paclitaxel was determined by high-performance liquid chromatography. We found a positive relationship between COX-2 and MDR1 mRNA expression in endometrial cancer. Both COX-2 mRNA expression and PGE2 production were elevated in resistant OMC-2P cells when compared to non-resistant OMC-2 cells. Additionally, MDR1 mRNA expression was markedly upregulated in OMC-2P cells. In OMC-2 cells, COX-2 and MDR1 mRNA levels were significantly upregulated by paclitaxel treatment and downregulated by co-administration with etodolac. In OMC-2P cells, COX-2 mRNA expression was also significantly upregulated by paclitaxel treatment and tended to be downregulated by co-administration with etodolac. Moreover, co-administration of paclitaxel and etodolac suppressed the induction of MDR1 mRNA. Rhodamine 123 efflux was increased in OMC-2P cells when compared to the efflux in the OMC-2 cells and was increased in response to paclitaxel treatment. Co-administration of paclitaxel and etodolac in both cell lines resulted in decreased rhodamine 123 efflux. The actual concentration of intracellular paclitaxel in OMC-2P cells was significantly lower than that in OMC-2 cells treated with paclitaxel alone and was significantly increased after co-administration of paclitaxel and etodolac. These findings suggest that paclitaxel resistance may be associated with COX-2 and MDR1 expression in cancer cells. Co-administration of COX-2 inhibitors and paclitaxel may have a key role in modulating or overcoming paclitaxel resistance in endometrial cancers. PMID:24100466

Hasegawa, Kiyoshi; Ishikawa, Kunimi; Kawai, Satoshi; Torii, Yutaka; Kawamura, Kyoko; Kato, Rina; Tsukada, Kazuhiko; Udagawa, Yasuhiro

2013-10-08

98

What are the risks of long-term NSAIDs and COX-2 inhibitors?  

PubMed

This review presents an interesting new analysis of cyclo-oxygenase-2 (COX-2) inhibitor safety, concluding that long-term use results in more serious adverse events than traditional nonsteroidal anti-inflammatory drugs (NSAIDs). The nonsystematic and retrospective properties of this analysis limit its validity. However, the fact that an evaluation of long-term data found some small harm to COX-2 inhibitors relative to traditional NSAIDs (number needed to harm=78 over 9 months) should give clinicians pause. Until better meta-analyses or new safety data are published, clinicians should prescribe COX-2 inhibitors long-term only for those patients deemed to be at high risk of ulcer complications. PMID:12620173

DeBisschop, Michael

2003-03-01

99

COX-2 inhibitors and cardiovascular risk. Inferences based on biology and clinical studies.  

PubMed

Even though non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for a long time, the search continues for anti-inflammatory drugs with few side-effects. COX-2 inhibitors are currently most debated, because they have less gastrointestinal side effects but have been linked to increased cardiovascular morbidity and mortality, presumably related to thrombotic events. This has brought about the withdrawal of rofecoxib and other COX-2 inhibitors from the market. Although the results of several large studies with prospective, randomized design and meta-analysis of different trials have led to the demise of many popular COX-2 inhibitors, yet the conclusion seems to be rather simplistic. This review presents evidence from basic biology and clinical studies with the expectation that a balanced position, particularly in relation to increase in cardiovascular events, may be elucidated. PMID:17003914

Marwali, Muhammad R; Mehta, Jawahar L

2006-10-01

100

Population impact of regulatory activity restricting prescribing of COX-2 inhibitors: ecological study  

PubMed Central

AIMS To investigate impacts of withdrawal and regulatory advice regarding cyclooxygenase-2 (COX-2) inhibitors on UK population rates of gastrointestinal haemorrhage and acute myocardial infarction (MI). METHODS Ecological time series study of prescribing, mortality and hospital admission trends in people aged ?55 years. RESULTS Withdrawal and regulatory advice limiting COX-2 inhibitor availability from 2004 were temporally associated with reversal of previously unfavourable trends in emergency MI admissions among people aged ?65 years. Annual admission rate trends changed from +4.6% to ?3.1% (P < 0.001) among women and from +2.1% to ?3.8% (P= 0.003) among men. Absolute changes in average annual trend in the number of individuals aged ?65 years admitted following MI were from +981 (1999–2004) to ?819 (2004–2006) per year for women and from +713 to ?995 for men. No change in trend was apparent among people aged 55–64 years, or in MI mortality trends. There was some suggestion of an unfavourable change in admission trends for gastrointestinal haemorrhage among 55?64-year-olds, although this appeared to occur prior to COX-2 inhibitor withdrawal/regulation by up to 2 years. These trends were not apparent in older people, or in gastrointestinal haemorrhage mortality rates. CONCLUSIONS Withdrawal/regulation of COX-2 inhibitors was temporally associated with a favourable reversal of population-level hospital admission trends in MI among people aged ?65 years. Unfavourable reversal of previous declines in gastrointestinal haemorrhage admissions probably occurred before changes in COX-2 inhibitor availability. Withdrawal/ regulation of COX-2 inhibitors did not appear to have any adverse impact on population health and may have been beneficial.

Wheeler, Benedict W; Metcalfe, Chris; Gunnell, David; Stephens, Peter; Martin, Richard M

2009-01-01

101

Antiinflammatory and neuroprotective actions of COX2 inhibitors in the injured brain  

PubMed Central

Overexpression of COX2 appears to be both a marker and an effector of neural damage after a variety of acquired brain injuries, and in natural or pathological aging of the brain. COX2 inhibitors may be neuroprotective in the brain by reducing prostanoid and free radical synthesis, or by directing arachidonic acid down alternate metabolic pathways. The arachidonic acid shunting hypothesis proposes that COX2 inhibitors' neuroprotective effects may be mediated by increased formation of potentially beneficial eicosanoids. Under conditions where COX2 activity is inhibited, arachidonic acid accumulates or is converted to eicosanoids via lipoxygenases and cytochrome P450 (CYP) epoxygenases. Several P450 eicosanoids have been demonstrated to have beneficial effects in the brain and/or periphery. We suspect that arachidonic acid shunting may be as important to functional recovery after brain injuries as altered prostanoid formation per se. Thus, COX2 inhibition and arachidonic acid shunting have therapeutic implications beyond the suppression of prostaglandin synthesis and free radical formation.

Strauss, Kenneth I.

2008-01-01

102

The Economic Benefits of Pharmaceutical Innovations: The Case of Cox2 Inhibitors  

Microsoft Academic Search

Despite dramatic improvements in medical technology, little attention has been paid to the role of these innovations in improving economic outcomes. This study estimates the labor supply effects of Cox-2 inhibitors, a widely prescribed class of pharmaceuticals used for the treatment of chronic pain and inflammation and primarily marketed under the brand names Vioxx, Celebrex, and Bextra. This paper exploits

Craig L. Garthwaite

2012-01-01

103

A new class of COX2 inhibitor, rutaecarpine from Evodia rutaecarpa  

Microsoft Academic Search

Objective and Design: We investigated the effect of a new class of COX-2 inhibitor, rutaecarpine, on the production of PGD2 in bone marrow derived mast cells (BMMC) and PGE2 in COX-2 transfected HEK293 cells. Inflammation was induced by l-carrageenan in male Splague-Dawley (SD) rats. Material: Rutaecarpine (8,13-Dihydroindolo(2¢,3¢:3,4)pyri- dol(2,1-b)quinazolin-5(7H)-one) was isolated from the fruits of Evodia rutaecarpa. BMMC were cultured with

T. C. Moon; M. Murakami; I. Kudo; K. H. Son; H. P. Kim; S. S. Kang; H. W. Chang

1999-01-01

104

In -silico molecular docking analysis of prodigiosin and cycloprodigiosin as COX-2 inhibitors.  

PubMed

Prodigiosin and cycloprodigiosin are tripyrrole red pigmented compounds with medical importance for their anticancer property. In the present investigation, molecular docking studies were performed for both prodigiosin and cycloprodigiosins to evaluate the in- silico anti-inflammatory activity against Cycloxigenase-2 (COX-2) protein as model compound and the data compared with rofecoxib and celcoxid. Cycloprodigiosin showed higher initial potential, initial RMS gradient and potential energy values compared to prodigiosin. Analysis of COX-2 protein and ligand binding revealed that cyclprodigiosin interacted with COX-2 protein amino acid residues of Tyr(324), Phe(487) and Arg(89) while prodigiosin interaction was observed with two amino acids i.e. Leu(321) and Tyr(324). The computational ligand binding interaction suggested > 45% higher fitness score value for prodigiosin to that of cycloprodigiosin with COX-2 protein while the standard compounds rofecoxib and celecoxid revealed fitness score of 44 and 62, respectively. The prodigiosin ligand revealed the best fitness score compared with the standard drug rofecoxib suggesting the prodigiosin could be effective as the potential inhibitor compound against COX-2 protein and can be evaluated as anti-inflammatory drug molecule using clinical trials. PMID:23741639

Krishna, Pabba Shiva; Vani, Kompally; Prasad, Metuku Ram; Samatha, Burra; Bindu, Nidadavolu Shesha Venkata Sathya Siva Surya Laxmi Hima; Charya, Maringanti Alaha Singara; Reddy Shetty, Prakasham

2013-04-19

105

Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans.  

PubMed

Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11betaHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity. PMID:19307727

Zhang, Ming-Zhi; Xu, Jie; Yao, Bing; Yin, Huiyong; Cai, Qiuyin; Shrubsole, Martha J; Chen, Xiwu; Kon, Valentina; Zheng, Wei; Pozzi, Ambra; Harris, Raymond C

2009-03-23

106

COX2 inhibitors and arterial hypertension: an analysis of spontaneous case reports in the Pharmacovigilance database  

Microsoft Academic Search

Objective: To evaluate the main characteristics of case reports of arterial hypertension (AH) related to COX-2 inhibitor (coxib) use in real-life practice. Methods: This study was based on spontaneous reports of adverse drug reactions (ADRs) submitted to the French Pharmacovigilance system. Associations be- tween AH and the different groups of those using non- steroidal anti-inflammatory drugs (NSAIDs: rofecoxib, celecoxib and

G. Durrieu; P. Olivier; J. L. Montastruc

2005-01-01

107

A randomized trial of the peri-operative use of COX2 inhibitors in Lichtenstein herniorrhaphy  

Microsoft Academic Search

Introduction  We present a randomized controlled trial to evaluate the value of the cyclo-oxygenase-2 (COX-2) inhibitor, rofecoxib, as an\\u000a adjuvant for pain management for patients undergoing a conventional Lichtenstein inguinal herniorrhaphy. The drug was removed\\u000a from the market coincidentally with the conclusion of the trial due to thrombotic complications. We believe that the data\\u000a remains important, however, because of the imminent

K. Turaga; A. Wright; R. Lee; W. P. C. Dias; C. Destache; R. Christian; R. J. Fitzgibbons

2008-01-01

108

Pifithrin-?, an Inhibitor of p53 Transactivation, Up-Regulates COX2 Expression through an MAPK-Dependent Pathway  

Microsoft Academic Search

Cyclooxygenase-2 (COX-2) has been reported to be elevated in many cancers, including breast and colorectal cancers, resulting in accumulation of prostaglandin E2 in the cancer cell environment. In this study, we investigated the effect of pifithrin (PFT)-?, an inhibitor of p53 transactivation, on COX-2 expression in breast and fibrosarcoma cells. Our results showed that COX-2 expression was dose-dependently increased by

Sangmin Kim; Jeonghun Han; Se Kyung Lee; Sung Mo Hur; Minyoung Koo; Dong Hui Cho; Soo Youn Bae; Min-Young Choi; Incheol Shin; Jung-Hyun Yang; Seok Jin Nam; Jeong Eon Lee

2010-01-01

109

COX-2 chronology  

PubMed Central

The role of selective cyclooxygenase (COX)-2 inhibitors in medical practice has become controversial since evidence emerged that their use is associated with an increased risk of myocardial infarction. Selective COX-2 inhibitors were seen as successor to non-selective non-steroidal anti-inflammatory drugs, in turn successors to aspirin. The importance of pain relief means that such drugs have always attracted attention. The fact that they work through inhibition of cyclooxygenase, are widespread, and have multiple effects also means that adverse effects that were unanticipated (even though predictable) have always emerged. In this paper I therefore present an historical perspective so that the lessons of the past may be applied to the present.

Hawkey, C J

2005-01-01

110

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen  

PubMed Central

BACKGROUND—Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs.?AIMS—We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity.?SUBJECTS—Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments.?METHODS—Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase.?RESULTS—Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B2 (TXB2) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB2 by 29%. Production of prostaglandin E2 and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E2 formation in plasma, was markedly suppressed by both treatments.?INTERPRETATION—Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.???Keywords: cyclooxygenase; prostaglandins; platelet aggregation; non-steroidal anti-inflammatory drug enteropathy

Shah, A; Thjodleifsson, B; Murray, F; Kay, E; Barry, M; Sigthorsson, G; Gudjonsson, H; Oddsson, E; Price, A; Fitzgerald, D; Bjarnason, I

2001-01-01

111

Apricoxib, a Novel Inhibitor of COX-2, Markedly Improves Standard Therapy Response in Molecularly Defined Models of Pancreatic Cancer  

PubMed Central

Purpose COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/ erlotinib in preclinical models of pancreatic cancer. Experimental Design Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined. Results COX-2 inhibition reduced the IC50 of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression. Conclusions Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer.

Kirane, Amanda; Toombs, Jason E.; Ostapoff, Katherine; Carbon, Juliet G.; Zaknoen, Sara; Braunfeld, Jordan; Schwarz, Roderich E.; Burrows, Francis J.; Brekken, Rolf A.

2013-01-01

112

Pharmacophore Elucidation and Molecular Docking Studies on 5-Phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic Acid Derivatives as COX-2 Inhibitors  

PubMed Central

A set of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (16–32) showing anti-inflammatory activity was analyzed using a three-dimensional qualitative structure-selectivity relationship (3D QSSR) method. The CatalystHipHop approach was used to generate a pharmacophore model for cyclooxygenase-2 (COX-2) inhibitors based on a training set of 15 active inhibitors (1–15). The degree of fitting of the test set compounds (16–32) to the generated hypothetical model revealed a qualitative measure of the more or less selective COX-2 inhibition of these compounds. The results indicate that most derivatives (16, 18, 20–25, and 30–32) are able to effectively satisfy the proposed pharmacophore geometry using energy accessible conformers (Econf < 20 kcal/mol). In addition, the triazole derivatives (16–32) were docked into COX-1 and COX-2 X-ray structures, using the program GOLD. Based on the docking results it is suggested that several of these novel triazole derivatives are active COX inhibitors with a significant preference for COX-2. In principle, this work presents an interesting, comprehensive approach to theoretically predict the mode of action of compounds that showed anti-inflammatory activity in an in vivo model.

Lindner, Marc; Sippl, Wolfgang; Radwan, Awwad A.

2010-01-01

113

Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX inhibiting Therapies (SELECT) trial in osteoarthritis  

Microsoft Academic Search

SUMMARY Select is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with

J. DEQUEKER; C. HAWKEY; A. KAHAN; K. STEINBRUCK; C. ALEGRE; E. BAUMELOU; B. BEGAUD; H. ISOMAKI; G. LITTLEJOHN; J. MAU; S. PAPAZOGLOU

1998-01-01

114

Insights from the docking analysis of biologically active compounds from plant Litsea Genus as potential COX-2 inhibitors  

PubMed Central

Litsea spp of Laural family are traditionally used as herbal medicine for treating inflammation including gastroenterologia, oedema and rheumatic arthritis. Therefore, it is of interest to investigate and understand the molecular principles for such actions. Here, we have illustrated the binding of thirteen Litsea derived biologically active compounds against the inflammation associated target COX (cyclo-oxygenase) -2 enzymes. We compared the binding information of these compounds with a selected number of already known COX-2 inhibitors. The comparison reflected that some of these compounds such as linderol, catechin, 6'-hydroxy-2',3',4' - trimethoxy-chalcone and litseaone have better or equivalent binding features compared to already known inhibitory compounds namely celecoxib, acetylsalicylic acid, rofecoxib. Therefore, all these small compounds reported from plant Litsea spp were found to possess potential medicinal values with anti-inflammatory properties.

Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan; Bordoloi, Manabjyoti; Sarmah, Rajeev; Bora, Tarun Chandra

2012-01-01

115

Insights from the docking analysis of biologically active compounds from plant Litsea Genus as potential COX-2 inhibitors.  

PubMed

Litsea spp of Laural family are traditionally used as herbal medicine for treating inflammation including gastroenterologia, oedema and rheumatic arthritis. Therefore, it is of interest to investigate and understand the molecular principles for such actions. Here, we have illustrated the binding of thirteen Litsea derived biologically active compounds against the inflammation associated target COX (cyclo-oxygenase) -2 enzymes. We compared the binding information of these compounds with a selected number of already known COX-2 inhibitors. The comparison reflected that some of these compounds such as linderol, catechin, 6'-hydroxy-2',3',4' - trimethoxy-chalcone and litseaone have better or equivalent binding features compared to already known inhibitory compounds namely celecoxib, acetylsalicylic acid, rofecoxib. Therefore, all these small compounds reported from plant Litsea spp were found to possess potential medicinal values with anti-inflammatory properties. PMID:23139590

Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan; Bordoloi, Manabjyoti; Sarmah, Rajeev; Bora, Tarun Chandra

2012-09-11

116

Anti-hyperalgesic activity of the cox-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat  

Microsoft Academic Search

Chronic pain resulting from metastatic bone cancer remains poorly understood and resistant to treatment. Here we have examined the effect of the novel COX-2 enzyme inhibitor lumiracoxib in a model of bone cancer pain in the rat. Lumiracoxib was administered orally twice daily from day 10 to day 20 after injection of MRMT-1 tumour cells into one tibia. Mechanical hyperalgesia,

Alyson Fox; Stephen Medhurst; Jean-Philippe Courade; Marcus Glatt; Janet Dawson; Laszlo Urban; Stuart Bevan; Isabel Gonzalez

2004-01-01

117

Effect of COX-2 Inhibitors on the Aromatase Gene Expression in Human Breast Cancer.  

National Technical Information Service (NTIS)

Aromatase (CYP-19) is responsible for estrogen biosynthesis within breast tumor tissue. Aromatase and cyclooxygenase-2 (COX-2) are both overexpressed in human breast cancer, and increased levels of prostaglandin (PG) activates the CYP19 promotor and incre...

C. L. Shapiro W. Burak R. Brueggemeier

2003-01-01

118

Pharmacoeconomic Modeling of Prior-Authorization Intervention for COX2 Specific Inhibitors in a 3Tier Copay Plan  

Microsoft Academic Search

OBJECTIVE: To determine from a health plan perspective the cost-effectiveness of cyclooxygenase-2 (COX-2) specific inhibitors, with and without a prior-authoriza- tion (PA) process. METHODS: A modeling exercise was employed, based on prescription drug claims for a managed care organization with 3.8 million health maintenance organization (HMO) and preferred provider organization (PPO) members. Drug claims revealed 96,154 members (2.9% of the

JANE STACY; ELIZABETH SHAW; MICHELE D. ARLEDGE; DONNA HOWELL-SMITH

2003-01-01

119

The use of force plate measurements to titrate the dosage of a new cox-2 inhibitor in lame horses  

Microsoft Academic Search

Reasons for performing study: Lameness is a highly prevalent\\u000acondition in horses and the principal cause of removal from\\u000aathletic activity. In clinical studies to evaluate nonsteroidal\\u000aanti-inflammatory drug therapies, force plates are commonly\\u000aused to assess improvement of lameness objectively.\\u000aHypothesis: To use a force plate to determine the optimal dose\\u000aof a new COX-2 inhibitor (firocoxib) that will

W. Back; C. G. MacAllister; M. C. V. van Heel; M. Pollmeier; P. D. Hanson

2009-01-01

120

Specific NF-kappaB blockade selectively inhibits tumour necrosis factor-alpha-induced COX-2 but not constitutive COX-1 gene expression in HT-29 cells.  

PubMed Central

Cyclo-oxygenase (COX) is the key regulatory enzyme of the prostaglandin/eicosanoid pathway. While COX-1 is mostly constitutively expressed, the COX-2 isoform is inducible by proinflammatory cytokines. We used an adenoviral vector containing an NF-kappaB super-repressor (Ad5IkappaB) to investigate the role of NF-kappaB in tumour necrosis factor-alpha (TNF-alpha)-mediated COX-2 gene expression in a colonic epithelial cell line. COX-1 mRNA and protein were constitutively expressed in uninfected, control Ad5LacZ- or Ad5IkappaB-infected HT-29 cells with no apparent change following TNF-alpha exposure. COX-2 mRNA and protein expression was undetectable in unstimulated cells but was strongly up-regulated after TNF-alpha stimulation in uninfected and Ad5LacZ-infected HT-29 cells. This induction was prevented in Ad5IkappaB cells. TNF-alpha increased prostaglandin E2 production by 20-fold in Ad5LacZ-infected HT-29 cells compared with uninfected cells and was significantly inhibited in Ad5IkappaB-infected cells in agreement with the COX-2 mRNA findings. We conclude that NF-kappaB activation is critical in mediating COX-2, but not COX-1 gene expression in HT-29 cells. Selective inhibition of COX-2 expression with the NF-kappaB super-repressor may be useful in distinguishing the role of inducible versus constitutive prostaglandins in intestinal function and provides greater specificity than pharmacological inhibitors. Images Figure 1 Figure 2 Figure 3

Jobin, C; Morteau, O; Han, D S; Balfour Sartor, R

1998-01-01

121

COX-2: friend or foe?  

PubMed

It wasn't until 1990, when the existence of two different cyclooxygenases was hypothesized, based on the evidence that steroids inhibited the increase in COX activity induced by bacterial lipopolysaccharides in macrophages, without any effects on the basal production of prostaglandins or leukotrienes. The first isoform, COX-1 is responsible for the production of "housekeeping" prostaglandins critical to the maintenance of normal renal function, gastric mucosal integrity, platelet aggregation, and the autocrine response to circulating hormones. COX-2 on the other hand is an inducible enzyme, upregulated 20-fold in macrophages, monocytes, synoviocytes, chondrocytes, fibroblasts, osteoblasts and endothelial cells by various inflammatory stimuli and cytochines. Classical findings shown that the therapeutics effects of NSAIDs are largely dependent on COX-2 inhibition, whereas some undesirable side effects are bound to COX-1 blockade, such as gastrointestinal bleeding and renal failure. Therefore, agents that selectively inhibit COX-2 over COX-1 are desirable for the treatment of inflammation. However, since September 2004 reports of increased risk of thrombotic cardiovascular events had accumulated for coxibs, the COX-2 inhibitors. Our goal is to provide an overview of the relevant biology and pharmacology of this enzyme in atherosclerosis. PMID:17584101

Iezzi, Annalisa; Ferri, Claudio; Mezzetti, Andrea; Cipollone, Francesco

2007-01-01

122

Effect of 5-LOX/COX-2 common inhibitor DHDMBF30 on pancreatic cancer cell Capan2  

PubMed Central

AIM: To study the effect of 5-lipoxygenase/cyclooxy-genase-2 (5-LOX/COX-2) dual inhibitor 7-tert-butyl-2, 3-dihydro-3, 3-dimethyl substituted dihydrofuran 30 (DHDMBF30) on proliferation and apoptosis of the pancreatic cancer cell line Capan-2 and the effect of DHDMBF30 on human pancreatic cancer in a nude mouse model. METHODS: Investigate the effect of 5-LOX/COX-2 dual inhibitor DHDMBF30 on proliferation and apoptosis of the pancreatic cancer cell line Capan-2 by RT-PCR, MTT assay, FCM and electron microscope. Cell line Capan-2 was inoculated percutaneously on the outer thigh of 12 nude mice. The VEGF mRNA of transplantation tumor was detected by RT-PCR. RESULTS: DHDMBF30 inhibits the proliferation of cell line Capan2, reduces the expression of 5-LOX, COX-2 and VEGF. After Capan2 was treated with DHDMBF30, we found that the apoptosis peak of the experimental group was significantly higher than that of the contrast group (3.08 ± 1.89 vs 27.67 ± 0.52, P < 0.001). The tumor weight of the DHDMBF30 group was significantly lower than PBS control groups (1.35 ± 0.47 vs 2.92 ± 0.73, P < 0.01). Expression of VEGF in the DHDMBF30 group was significantly decreased. CONCLUSION: DHDMBF30 inhibits the proliferation of the pancreatic cell line Capan2, and induces apoptosis and inhibits the growth of pancreatic cancer in nude mice.

Zhang, Bo; Wang, Chang-Liang; Zhao, Wen-Hua; Lv, Ming; Wang, Chun-Ying; Zhong, Wei-Xia; Zhou, Wu-Yuan; Yu, Wen-Sheng; Zhang, Yan; Li, Sheng

2008-01-01

123

Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates TNF-Induced NF-B Activation through Inhibition of Activation of IB Kinase and Akt in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of COX2 Synthesis1  

Microsoft Academic Search

The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-B. In the present study, we investigated the effect of

Shishir Shishodia; Dimpy Koul; Bharat B. Aggarwal

124

Computer aided discovery of potential anti-inflammatory (S)-naproxen analogs as COX-2 inhibitors.  

PubMed

A series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential. In silico studies (molecular modeling and docking) were carried out to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing Maestro (Version 9.1, Schrodinger, LLC.) software. 2-(1-(2(2-methoxynaphthalen-6-yl)propanoyl)-1H-indol-2-yl) acetic acid (3k) was found to be the most active compound amongst the series with inhibition of paw edema volume by 62.1%, in silico sitemap score of -0.40kcal/mol and ulcerogenic index as least as 1.19. PMID:22946530

Raghavendra, Nulgumnalli Manjunathaiah; Ramakrishna, Kota; Sirisha, Vippula; Divya, Pingli; Rao, Alapati Venkateswara

2013-06-01

125

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain  

PubMed Central

Objective: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious. Materials and Methods: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period. Results: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (±5 years), gender, and admission TFIM score (± 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance. Conclusions: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

Rabadi, Meheroz H.; Rabadi, Freny M; Hallford, Gene; Aston, Christopher E.

2013-01-01

126

Overexpression of cyclooxygenase-2 (COX2) in human primitive neuroectodermal tumors: effect of celecoxib and rofecoxib  

Microsoft Academic Search

In this study the role of cyclooxygenase-2 (COX-2) in primitive neuroectodermal tumor (PNET) the most malignant brain tumors of childhood was investigated. COX-2 expression in human brain tumor biopsy samples (seven\\/seven) was about 6–8-fold higher than normal brain tissue and several PNET cell lines also express COX-2. The effect of selective COX-2 inhibitors, celecoxib and rofecoxib on the growth of

Ratnakar Patti; Kiranmai Gumired; Pallu Reddanna; Leslie N. Sutton; Peter C. Phillips; C. Damodar Reddy

2002-01-01

127

Antiproliferative Diarylpyrazole Derivatives as Dual Inhibitors of the ERK Pathway and COX-2.  

PubMed

A series of 3,4-diarylpyrazole-1-carboxamide derivatives was designed and synthesized. A selected group of the target compounds was tested for in vitro antiproliferative activities over a panel of 60 cancer cell lines at the National Cancer Institute (NCI, Bethesda, MD, USA) at a single-dose concentration of 10 ?m, and the four most active compounds 9a, 9l, 9n, and 10o were further tested in a five-dose testing mode to determine their IC50 values over the 60 cell lines. In addition, a selected group of target compounds were tested for inhibitory effect over cyclooxygenase isozymes. Compounds 9a, 9l, 9n, and 10o were also tested for MEK and ERK kinase inhibitory activity using Western blot assay. Compound 10o was selective toward melanoma cell line subpanel, and its antiproliferative activity may be attributed to selective cyclooxygenase-2 inhibition and ERK pathway inhibition. PMID:23834707

El-Gamal, Mohammed I; Choi, Hong Seok; Yoo, Kyung Ho; Baek, Daejin; Oh, Chang-Hyun

2013-08-10

128

An overview of the recent developments in analytical methodologies for determination of COX2 inhibitors in bulk drugs, pharmaceuticals and biological matrices  

Microsoft Academic Search

An extensive survey of the literature published in various analytical and pharmaceutical chemistry related journals has been conducted and the instrumental analytical methods which were developed and used for determination of COX-2 inhibitors in bulk drugs, formulations and biological fluids have been reviewed. This review covers the time period from 1995 to 2004 during which 138 analytical methods including all

R. Nageswara Rao; S. Meena; A. Raghuram Rao

2005-01-01

129

Design and synthesis of ( Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes and ( Z)-1-(4-azidophenyl)-1,2-diphenylalk-1-enes: novel inhibitors of cyclooxygenase-2 (COX2) with anti-inflammatory and analgesic activity  

Microsoft Academic Search

A group of novel (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1\\/COX-2 enzyme inhibition studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)oct-1-ene (8d) as a highly potent (IC50=0.03?M), and an extremely selective [COX-2 SI (selectivity index)>3,333], COX-2 inhibitor that showed good anti-inflammatory (AI) activity (ID50=2.8mg\\/kg). A molecular modeling (docking) study showed that the p-MeSO2NH group present in (Z)-8d inserts deep

P. N. Praveen Rao; Edward E. Knaus

2005-01-01

130

Prophylactic and therapeutic benefits of COX-2 inhibitor on motility dysfunction in bowel obstruction: roles of PGE2 and EP receptors  

PubMed Central

We reported previously that mechanical stretch in rat colonic obstruction induces cyclooxygenase (COX)-2 expression in smooth muscle cells. The aims of the present study were to investigate whether in vivo treatment with COX-2 inhibitor has prophylactic and therapeutic effects on motility dysfunction in colon obstruction, and if so what are the underlying mechanisms. Partial colon obstruction was induced with a silicon band in the distal colon of 6–8-wk-old Sprague-Dawley rats; obstruction was maintained for 3 days or 7 days. Daily administration of COX-2 inhibitor NS-398 (5 mg/kg) or vehicle was started before or after the induction of obstruction to study its prophylactic and therapeutic effects, respectively. The smooth muscle contractility was significantly suppressed, and colonic transit rate was slower in colonic obstruction. Prophylactic treatment with NS-398 significantly prevented the impairments of colonic transit and smooth muscle contractility and attenuated fecal collection in the occluded colons. When NS-398 was administered therapeutically 3 days after the initiation of obstruction, the muscle contractility and colonic transit still improved on day 7. Obstruction led to marked increase of COX-2 expression and prostaglandin E2 (PGE2) synthesis. Exogenous PGE2 decreased colonic smooth muscle contractility. All four PGE2 E-prostanoid receptor types (EP1 to EP4) were detected in rat colonic muscularis externa. Treatments with EP1 and EP3 antagonists suppressed muscle contractility in control tissue but did not improve contractility in obstruction tissue. On the contrary, the EP2 and EP4 antagonists did not affect control tissue but significantly restored muscle contractility in obstruction. We concluded that our study shows that COX-2 inhibitor has prophylactic and therapeutic benefits for motility dysfunction in bowel obstruction. PGE2 and its receptors EP2 and EP4 are involved in the motility dysfunction in obstruction, whereas EP1 and EP3 mediate PGE2 regulation of colonic smooth muscle contractile function in normal state.

Lin, You-Min; Sarna, Sushil K.

2012-01-01

131

Comparative Study for Preventive Effects of Intra-Abdominal Adhesion Using Cyclo-Oxygenase-2 Enzyme (COX-2) Inhibitor, Low Molecular Weight Heparin (LMWH), and Synthetic Barrier  

PubMed Central

Purpose Postoperative adhesion is the most frequent complication of abdominal surgery. Therefore, we investigated the individual effects of synthetic barrier [hyaluronic acid/carboxymethylcellulose (HA/CMC)] and pharmacologic agents [low molecular weight heparin (LMWH) cyclo-oxygenase-2 inhibitor (COX-2 inhibitor)] using animal model of intra-abdominal adhesion. Materials and Methods The cecum was rubbed with sterile alcohol wet gauze until subserosal haemorrhage and punctate bleeding developed under the general anesthesia. Five animal groups were prepared using the film HA/CMC, gel HA/CMC, LMWH and COX-2 inhibitor. Results The grade of adhesion by modified Leach method for group I (control), II (film type HA/CMC), III (gel type HA/CMC), IV (LMWH) and V (COX-2 inhibitor) were 5.35±1.8, 6.15±1.3, 4.23±2.6, 5.05±0.7 and 5.50±0.9, respectively. Group III showed the least grade of adhesion and it is statistically significant in adhesion formation (p=0.028). The numbers of lymphocytes were significantly low in group III and group V compared to the control group (lymphocyte: p=0.004). The mast cell counts were generally low except for the control group (I: 1.05, II: 0.35, III: 0.38, IV: 0.20, V: 0.37), however, it was not statistically significant (p=0.066). Conclusion The gel barriers were shown to be partly efficient in inhibiting the formation of postoperative adhesions and might provide an option for abdominal surgery to reduce postoperative adhesions. The LMWH and COX-2 inhibitor had been known for their inhibitor effect of fibrin formation and anti-angiogenic/anti-fibroblastic activity, respectively. However, their preventive effects of adhesion and fibrosis were found to be obscure.

2013-01-01

132

Comparative Study for Preventive Effects of Intra-Abdominal Adhesion Using Cyclo-Oxygenase-2 Enzyme (COX-2) Inhibitor, Low Molecular Weight Heparin (LMWH), and Synthetic Barrier.  

PubMed

Purpose: Postoperative adhesion is the most frequent complication of abdominal surgery. Therefore, we investigated the individual effects of synthetic barrier [hyaluronic acid/carboxymethylcellulose (HA/CMC)] and pharmacologic agents [low molecular weight heparin (LMWH) cyclo-oxygenase-2 inhibitor (COX-2 inhibitor)] using animal model of intra-abdominal adhesion. Materials and Methods: The cecum was rubbed with sterile alcohol wet gauze until subserosal haemorrhage and punctate bleeding developed under the general anesthesia. Five animal groups were prepared using the film HA/CMC, gel HA/CMC, LMWH and COX-2 inhibitor. Results: The grade of adhesion by modified Leach method for group I (control), II (film type HA/CMC), III (gel type HA/CMC), IV (LMWH) and V (COX-2 inhibitor) were 5.35±1.8, 6.15±1.3, 4.23±2.6, 5.05±0.7 and 5.50±0.9, respectively. Group III showed the least grade of adhesion and it is statistically significant in adhesion formation (p=0.028). The numbers of lymphocytes were significantly low in group III and group V compared to the control group (lymphocyte: p=0.004). The mast cell counts were generally low except for the control group (I: 1.05, II: 0.35, III: 0.38, IV: 0.20, V: 0.37), however, it was not statistically significant (p=0.066). Conclusion: The gel barriers were shown to be partly efficient in inhibiting the formation of postoperative adhesions and might provide an option for abdominal surgery to reduce postoperative adhesions. The LMWH and COX-2 inhibitor had been known for their inhibitor effect of fibrin formation and anti-angiogenic/ anti-fibroblastic activity, respectively. However, their preventive effects of adhesion and fibrosis were found to be obscure. PMID:24142656

Kim, Yong Il

2013-11-01

133

Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib.  

PubMed

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Among different structurally related COX-2 inhibitors, only celecoxib was found to cause apoptosis and cell death of human lung cancer cells (IC50 values of 19.96 µM [A549], 12.48 µM [H460], and 41.39 µM [H358]) that was paralleled by a time- and concentration-dependent upregulation of COX-2 and peroxisome proliferator-activated receptor ? (PPAR?) at mRNA and protein levels. Apoptotic death of celecoxib-treated cancer cells was suppressed by the PPAR? antagonist GW9662 and by siRNA targeting PPAR? and, surprisingly, also by the selective COX-2 inhibitor NS-398 and siRNA targeting COX-2. NS-398 (1 µM) was shown to suppress celecoxib-induced COX-2 activity. Among the COX-2-dependent prostaglandins (PG) induced upon celecoxib treatment, PGD2 and 15-deoxy-?(12,14)-PGJ2 were found to induce a cytosol-to-nucleus translocation of PPAR? as well as a PPAR?-dependent apoptosis. Celecoxib-elicited PPAR? translocation was inhibited by NS-398. Finally, a COX-2- and PPAR?-dependent cytotoxic action of celecoxib was proven for primary human lung tumor cells. Together, our data demonstrate a proapoptotic mechanism of celecoxib involving initial upregulation of COX-2 and PPAR? and a subsequent nuclear translocation of PPAR? by COX-2-dependent PGs. PMID:23943857

Ramer, Robert; Walther, Udo; Borchert, Philipp; Laufer, Stefan; Linnebacher, Michael; Hinz, Burkhard

2013-08-12

134

Healing of chronic gastric ulcers in diabetic rats treated with native aspirin, nitric oxide (NO)-derivative of aspirin and cyclooxygenase (COX)-2 inhibitor.  

PubMed

Previous studies have demonstrated that the gastric mucosa of diabetic rats is highly vulnerable to acute injury but the influence of nonsteroidal anti-inflammatory drugs (NSAID) and their new nitric oxide (NO) releasing derivatives of aspirin (NO-ASA) on the ulcer healing under diabetic conditions has been little studied. In this study streptozocin (STZ, 70 mg/kg injected intraperitoneally) was used to induce diabetes mellitus in rats. Four weeks after STZ injection, gastric ulcers were induced using the acetic acid method and rats with gastric ulcers received the treatment with 1) aspirin (ASA, 30 mg/kg-d i.g.), 2) NO-ASA applied in equimolar dose of 50 mg/kg-d i.g., 3) rofecoxib (5 mg/kg-d i.g.), the selective cyclooxygenase-(COX)-2 inhibitor and 4) SNAP (5 mg/kg-d i.g.), a donor of NO, combined with ASA (30 mg/kg-d i.g.). Ten days after the induction of the ulcers, the healing rate and the gastric blood flow (GBF) were measured by planimetry and hydrogen (H(2))-gas clearance method, respectively and the plasma cytokine such as IL-1beta, TNF-alpha and IL-10 were determined. In addition, the effect of insulin (4 IU/day/rat i.p.) with or without the blockade of NO-synthase by L-NNA (20 mg/kg-d i.p.) on the ulcer healing and the GBF in non-diabetic and diabetic rats was determined. In the diabetic rats, a significant delay in ulcer healing (approximately by 300%) was observed with an accompanied decrease in the GBF at ulcer margin. The prolongation of the healing in diabetic animals was associated with an increase in the plasma cytokine (IL-1beta, TNF-alpha and IL-10) levels. ASA and rofecoxib, that significantly suppressed the mucosal prostaglandin (PG) E(2) generation in ulcer area, delayed significantly the rate of ulcer healing and decreased the GBF at ulcer margin, while elevating plasma IL-1beta, TNF-alpha and IL-10 concentrations in non-diabetic rats and these alterations were significantly augmented in diabetic animals. In contrast to ASA, the treatment with NO-ASA failed to influence both, the ulcer healing and GBF at ulcer margin and significantly attenuated the plasma levels of IL-1beta, TNF-alpha and IL-10 as compared to those recorded in ASA- or rofecoxib-treated animals. Co-treatment of SNAP with native ASA abolished the deleterious effect of ASA on ulcer healing, GBF at ulcer margin and luminal NO release in diabetic rats. Administration of insulin in rats with diabetes, opposed the delay in ulcer healing, and the fall in the GBF at ulcer margin and these effects were counteracted by the concurrent treatment with L-NNA. We conclude that: 1) ulcer healing is dramatically impaired in experimental diabetes and this effect involves the fall in the gastric microcirculation at the ulcer margin and increased release of proinflammatory cytokines; 2) classic NSAID such as ASA and selective COX-2 inhibitors such as rofecoxib, prolong ulcer healing under diabetic conditions probably due to suppression of endogenous PG and the fall in the GBF at the ulcer margin suggesting that both COX isoforms, namely, COX-1 and COX-2, are important sources of PG during ulcer healing in diabetes; and 3) NO-ASA counteracts the impairment of ulcer healing in diabetic rats induced by ASA, mainly due to the release of NO that compensates for PG deficiency resulting in enhancement in the GBF at ulcer margin and suppression of cytokine release in the ulcer area. PMID:15613743

Brzozowska, I; Targosz, A; Sliwowski, Z; Kwiecien, S; Drozdowicz, D; Pajdo, R; Konturek, P C; Brzozowski, T; Pawlik, M; Konturek, S J; Pawlik, W W; Hahn, E G

2004-12-01

135

Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates Activation of Cigarette Smoke-Induced Nuclear Factor (NF)B by Suppressing Activation of IB Kinase in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of Cyclin D1, COX2, and Matrix Metalloproteinase-9  

Microsoft Academic Search

Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, blad- der, and lung; all are known to overexpress the nuclear factor-B (NF- B)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 inhibitor, celecoxib, ap- proved for the treatment of

Shishir Shishodia; Bharat B. Aggarwal

136

Rational design of 6-methylsulfonylindoles as selective cyclooxygenase-2 inhibitors  

Microsoft Academic Search

The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the

Jeffrey A. Campbell; Viola Bordunov; Chris A. Broka; Michelle F. Browner; James M. Kress; Tara Mirzadegan; Chakk Ramesha; Bong F. Sanpablo; Russell Stabler; Patricia Takahara; Armando Villasenor; Keith A. M. Walker; Jin-Hai Wang; Mary Welch; Paul Weller

2004-01-01

137

The impact of the cox-2 inhibitor issue on perceptions of the pharmaceutical industry: content analysis and communication implications.  

PubMed

The field of risk communication has its roots in the environmental, chemical, space, and nuclear arenas. As a number of these sectors have now vastly improved their communication strategies, attention is being placed on sectors that have been more problematic as of late. Examples of such sectors, include the food industries and the pharmaceutical/health sector. This article focuses on how large, multinational pharmaceutical companies can better communicate risks by analysis of one specific case, namely, that of the Cox-2 controversy.(1) For purposes of this article, risk communication is best described as "the flow of information and risk evaluations back and forth between academic experts, regulatory practitioners, interest groups and the general public," and "big pharma" refers to the more traditional R & D-based, innovative pharmaceutical companies. PMID:17710597

Lofstedt, Ragnar E

138

Stretch-induced myoblast proliferation is dependent on the COX2 pathway  

SciTech Connect

Skeletal muscle increases in size due to weight bearing loads or passive stretch. This growth response is dependent in part upon myoblast proliferation. Although skeletal muscles are responsive to mechanical forces, the effect on myoblast proliferation remains unknown. To investigate the effects of mechanical stretch on myoblast proliferation, primary myoblasts isolated from Balb/c mice were subjected to 25% cyclical uniaxial stretch for 5 h at 0.5 Hz. Stretch stimulated myoblast proliferation by 32% and increased cell number by 41% 24 and 48 h after stretch, respectively. COX2 mRNA increased 3.5-fold immediately poststretch. Prostaglandin E2 and F{sub 2{alpha}} increased 2.4- and 1.6-fold 6 h after stretch, respectively. Because COX2 has been implicated in regulating muscle growth and regeneration, we hypothesized that stretched myoblasts may proliferate via a COX2-dependent mechanism. We employed two different models to disrupt COX2 activity: (1) treatment with a COX2-selective drug, and (2) transgenic mice null for COX2. Treating myoblasts with a COX2-specific inhibitor blocked stretch-induced proliferation. Likewise, stretched COX2{sup -/-} myoblasts failed to proliferate compared to controls. However, supplementing stretched, COX2{sup -/-} myoblasts with prostaglandin E2 or fluprostenol increased proliferation. These data suggest that the COX2 pathway is critical for myoblast proliferation in response to stretch.

Otis, Jeffrey S. [Emory University School of Medicine, Department of Pharmacology, O.W. Rollins Research Building, Room 5027, Atlanta, GA 30322 (United States); Burkholder, Thomas J. [Georgia Institute of Technology, School of Applied Physiology, Atlanta, GA 30332 (United States); Pavlath, Grace K. [Emory University School of Medicine, Department of Pharmacology, O.W. Rollins Research Building, Room 5027, Atlanta, GA 30322 (United States)]. E-mail: gpavlat@emory.edu

2005-11-01

139

The Complex Interplay between COX-2 and Angiotensin II in Regulating Kidney Function  

PubMed Central

Purpose of Review Cyclooxygenase-2 (COX-2) plays a critical role in modulating deleterious actions of angiotensin II (Ang II) where there is an inappropriate activation of the renin-angiotensin system (RAS). This review discusses recent developments regarding the complex interactions by which COX-2 modulates the impact of an activated RAS on kidney function and blood pressure. Recent Findings Normal rats with increased COX-2 activity but with different intrarenal Ang II activity due to sodium restriction or chronic treatment with angiotensin converting enzyme (ACE) inhibitors showed similar responses to COX-2 selective inhibition (nimesulide) indicating independence from the intrarenal Ang II activity. COX-2 dependent maintenance of medullary blood flow was consistent and not dependent on dietary salt or ACE inhibition. In contrast, COX-2 influences on sodium excretion were contingent on the prevailing RAS activity. In chronic hypertensive models, COX-2 inhibition elicited similar reductions in kidney function but COX-2 metabolites contribute to rather than ameliorate the hypertension. Summary The maintenance of renal hemodynamics reflects direct and opposing effects of Ang II and COX-2 metabolites. The antagonism in water and electrolyte reabsorption is dependent on the prevailing intrarenal Ang II activity. The recent functional experiments demonstrate a beneficial modulation of Ang II by COX-2 except in the presence of inflammation promoted by hypertension, hyperglycemia and oxidative stress.

Green, Torrance; Gonzalez, Alexis A.; Mitchell, Kenneth D.; Navar, L. Gabriel

2012-01-01

140

Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action.  

PubMed

Enzyme cyclooxygenase (COX) is reported to play a significant role in neurodegeneration and may play a significant role in the pathogenesis of epilepsy. Bicuculline (4 mg/kg; ip), picrotoxin (8 mg/kg; ip) and electroshock (60 mA for 0.2 sec) significantly induced convulsions in male Laka mice. COX-inhibitors viz. nimesulide (2.5 mg/kg; ip) and rofecoxib (2 mg/kg, ip) administered 45 minutes prior to an epileptic challenge prolonged mean onset time of convulsions, decreased duration of clonus and decreased % mortality rate against bicuculline- and picrotoxin-induced convulsions in mice. COX-2 inhibitors were ineffective towards maximal electroshock-induced convulsions. Nimesulide (1 mg/kg) and rofecoxib (1 mg/kg) also enhanced the effect of subprotective dose of muscimol against picrotoxin-induced convulsions. The result of the present study strongly suggests for a possible role of cyclooxygenase isoenzymes particularly, COX-2 in the pathophysiology of epilepsy and its GABAergic modulation. PMID:16629370

Dhir, Ashish; Naidu, Pattipati S; Kulkarni, Shrinivas K

2006-04-01

141

Transactivation of EGFR by LPS Induces COX-2 Expression in Enterocytes  

PubMed Central

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC.

McElroy, Steven J.; Hobbs, Stuart; Kallen, Michael; Tejera, Noemi; Rosen, Michael J.; Grishin, Anatoly; Matta, Poojitha; Schneider, Claus; Upperman, Jeffrey; Ford, Henri; Polk, D. Brent; Weitkamp, Jorn-Hendrik

2012-01-01

142

COX2 and beyond: approaches to prostaglandin inhibition in human disease  

Microsoft Academic Search

Selective inhibitors of cyclooxygenase (COX)-2 afford relief from pain and inflammation. They could also prove useful in the chemoprevention of cancer and are being investigated in a range of neurological diseases. This novel class of drug is less likely to cause gastric ulceration than traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, plausible mechanisms have been proposed whereby COX-2 inhibitors could cause

Garret A. FitzGerald

2003-01-01

143

An analysis from clinico-epidemiological data of the principal adverse events from the COX2 selective NSAID, nimesulide, with particular reference to hepatic injury  

Microsoft Academic Search

The safety of the cyclo-oxygenase-2 (COX-2) selective NSAID, nimesulide, has been evaluated from information (a) in clinical\\u000a trials in osteoarthritis that have been performed in Europe as well as in earlier pilot studies that were performed in patients\\u000a with rheumatoid arthritis in the USA, and (b) in post-marketing studies (PMS) that have been performed by the manufacturer\\u000a since the introduction

K. D. Rainsford

1998-01-01

144

The sphingosine kinase 1\\/sphingosine-1-phosphate pathway mediates COX2 induction and PGE2 production in response to TNF  

Microsoft Academic Search

In this study we addressed the role of sphingolipid metabolism in the inflammatory response. In a L929 fibroblast model, tumor necrosis factor- (TNF) induced prostaglandin E2 (PGE2) production by 4 h and cyclooxygenase-2 (COX-2) induction as early as 2 h. This TNF-induced PGE2 production was inhibited by NS398, a COX-2 selective inhibitor. GC-MS analysis revealed that only COX-2-generated prostanoids were

BENJAMIN J. PETTUS; JACEK BIELAWSKI; ANNA M. PORCELLI; DAVIS L. REAMES; KOREY R. JOHNSON; JASON MORROW; CHARLES E. CHALFANT; LINA M. OBEID; YUSUF A. HANNUN

2003-01-01

145

Detection of overexpressed COX2 in precancerous lesions of hamster pancreas and lungs by molecular imaging: implications for early diagnosis and prevention  

Microsoft Academic Search

The enzyme cyclooxygenase-2 (COX-2) is overexpressed in many cancers, cardiovascular disease, neurodegenerative disorders, and arthritis. Selective inhibitors of COX-2 have been developed as therapeutics or preventive agents for these diseases. However, recent reports have revealed a significant increase in cardiovascular mortality in long-term users of the COX-2 inhibitors Vioxx and Celebrex, emphasizing the need for noninvasive tests that allow the

George Kabalka; Gary Smith; Arjun Mereddy; Murthy Akula; Cekanova Maria

2006-01-01

146

Pharmacokinetics, COX2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans  

Microsoft Academic Search

Objective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2).\\u000a It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1\\/COX-2\\u000a inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state\\u000a pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (VioxxTM), characterized in vitro

M. Depré; E. Ehrich; A. Van Hecken; I. De Lepeleire; A. Dallob; P. Wong; A. Porras; B. J. Gertz; P. J. De Schepper

2000-01-01

147

In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems. Comparison with non-selective and COX-2 selective NSAIDs.  

PubMed

1. The in vivo effects of the non-steroid anti-inflammatory drug (NSAID) amtolmetin guacyl, a pro-drug of the NSAID tolmetin, on lipid peroxidation, glutathione levels and activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) in rat gastric mucosa, colon mucosa and liver, were compared with the effects of non-selective (indomethacin, diclofenac) and COX-2 selective (celecoxib) NSAIDs. 2. Indomethacin treatment led to an increase in lipid peroxidation, glutathione peroxidase and glucose-6-phosphate dehydrogenase activities and to a decrease in catalase activity and glutathione levels in gastric mucosa. In contrast, amtolmetin guacyl treatment was without effects in gastric and colon mucosa, or liver from control animals. Like amtolmetin guacyl, celecoxib had no effect on the lipid peroxidation, or on enzyme and non-enzyme antioxidant defence systems in gastric mucosa. 3. It is suggested that the lack of pro-oxidant effects in vivo associated with amtolmetin guacyl treatment contribute improved gastric tolerability. PMID:17391279

Kirkova, M; Alexandova, A; Kesiova, M; Todorov, S

2007-04-01

148

Increased COX2 in the trigeminal nucleus caudalis is involved in orofacial pain induced by experimental tooth movement.  

PubMed

Pain is among the major problems during orthodontic treatment. Recent studies have shown that central Cyclooxygenase2 (COX2) pathway was involved in several pain models. The present study investigated whether inducible COX2 within the trigeminal nucleus caudalis (Vc) contributed to experimental tooth movement pain in freely moving rats. Elastic rubber bands were inserted between the first and second maxillary molars bilaterally to establish tooth movement model. The directed mouth wiping behavior was used to evaluate the pain during tooth movement. COX2 distribution in Vc was studied by immunohistochemistry and the changes of COX2 expression were detected by Western blot at different time point after rubber band insertion. Our results showed that tooth movement significantly increased COX2 expression in Vc and the time spent on mouth wiping, reaching a maximum at 1 day and then decreasing gradually. Furthermore, the rhythm change of COX2 expression in Vc and the mouth wiping behavior were much correlative with each other. All of the COX2-immunoreactive structures in Vc exhibited NeuN-immunopositive staining and most of these COX2-immunoreactive neurons were Fos-immunopositive. Importantly, the mouth wiping behavior could be attenuated by intracisternal injection of NS-398 (a selective COX2 inhibitor) but not by periodontal administration of NS-398. All these results suggested that increased COX2 in Vc was involved in tooth movement pain and thus may be a central target for orthodontic pain treatment. PMID:20091889

Gao, Yuan; Duan, Yin-Zhong

2010-03-01

149

Prognostic significance of cyclooxygenase-2 (COX-2) and expression of cell cycle inhibitors p21 and p27 in human pleural malignant mesothelioma  

PubMed Central

Background: A study was undertaken to analyse the potential prognostic value of the immunohistochemical expression of cyclooxygenase-2 (COX-2) and p27 in 29 malignant mesotheliomas already screened for the expression of p21 and p53. Methods: Immunohistochemistry was used to determine the expression of COX-2 and p27. The correlation with survival of these factors and of p21 and p53 expression was assessed by univariate and multivariate analyses. Results: A positive statistically significant correlation was found between p27 and p21 expression (p<0.0001), but there was a negative correlation between COX-2 expression and both p27 (p = 0.001) and p21 (p<0.0001). No statistically significant correlation was recorded between p53 and all the other immunohistochemical parameters. Univariate analysis showed that overall survival was strongly influenced by p21, p27, and COX-2 expression, but multivariate Cox regression analysis showed that the only immunohistochemical parameter to influence overall survival of patients with mesothelioma was COX-2. Conclusions: These findings suggest that COX-2 expression may be a useful prognostic parameter for mesothelioma.

Baldi, A; Santini, D; Vasaturo, F; Santini, M; Vicidomini, G; Di, M; Esposito, V; Groeger, A; Liuzzi, G; Vincenzi, B; Tonini, G; Piccoli, M; Baldi, F; Scarpa, S

2004-01-01

150

Design, synthesis and biological evaluation of new 5,5-diarylhydantoin derivatives as selective cyclooxygenase-2 inhibitors.  

PubMed

A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.077 ?M; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC(50) = 0.060 ?M; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO(2) COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity. PMID:21886896

Zarghi, Afshin; Javid, Farin Sattary; Ghodsi, Razieh; Dadrass, Orkideh G; Daraei, Bahram; Hedayati, Mehdi

2011-07-25

151

Design, Synthesis and Biological Evaluation of New 5,5-Diarylhydantoin Derivatives as Selective Cyclooxygenase-2 Inhibitors  

PubMed Central

A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC50 = 0.077 ?M; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC50 = 0.060 ?M; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity.

Zarghi, Afshin; Javid, Farin Sattary; Ghodsi, Razieh; Dadrass, Orkideh G.; Daraei, Bahram; Hedayati, Mehdi

2011-01-01

152

Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib  

Microsoft Academic Search

2,5-dimethyl-celecoxib (DMC) is a close structural analog of the selective cycloox- ygenase-2 (COX-2) inhibitor celecoxib that lacks COX-2 inhibitory function. We and others have demonstrated that DMC, de- spite its inability to block COX-2, is able to potently mimic the antitumor effects of celecoxib in vitro and in vivo. In this current study, we investigated whether DMC would also be

Adel Kardosh; Nathaniel Soriano; Yen-Ting Liu; Jasim Uddin; Nicos A. Petasis; Florence M. Hofman; Thomas C. Chen; Axel H. Schonthal

2005-01-01

153

Evaluation of Selective COX2 Inhibitors for the Treatment of Alzheimer's Disease  

Microsoft Academic Search

Alzheimer's disease (AD) is a worldwide problem that affects 5 million people in the United States alone. Until the approval of tacrine in the mid-1990s, there was no effective therapy for the cognitive symptoms of AD. Although cholinergic therapy provides modest but significant symptomatic relief, the development of effective disease-modifying therapy is essential. It has been demonstrated that a number

Paul S Aisen

2002-01-01

154

COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice.  

PubMed

A cardinal feature of peripheral inflammation is pain. The most common way of managing inflammatory pain is to use nonsteroidal antiinflammatory agents (NSAIDs) that reduce prostanoid production, for example, selective inhibitors of COX2. Prostaglandins produced after induction of COX2 in immune cells in inflamed tissue contribute both to the inflammation itself and to pain hypersensitivity, acting on peripheral terminals of nociceptors. COX2 is also induced after peripheral inflammation in neurons in the CNS, where it aids in developing a central component of inflammatory pain hypersensitivity by increasing neuronal excitation and reducing inhibition. We engineered mice with conditional deletion of Cox2 in neurons and glial cells to determine the relative contribution of peripheral and central COX2 to inflammatory pain hypersensitivity. In these mice, basal nociceptive pain was unchanged, as was the extent of peripheral inflammation, inflammatory thermal pain hypersensitivity, and fever induced by lipopolysaccharide. By contrast, peripheral inflammation-induced COX2 expression in the spinal cord was reduced, and mechanical hypersensitivity after both peripheral soft tissue and periarticular inflammation was abolished. Mechanical pain is a major symptom of most inflammatory conditions, such as postoperative pain and arthritis, and induction of COX2 in neural cells in the CNS seems to contribute to this. PMID:19127021

Vardeh, Daniel; Wang, Dairong; Costigan, Michael; Lazarus, Michael; Saper, Clifford B; Woolf, Clifford J; Fitzgerald, Garret A; Samad, Tarek A

2009-01-05

155

Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities  

PubMed Central

Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs — adverse effects attributed to suppression of COX-1–derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2–derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a “balance” between COX-2–derived PGI2 and COX-1–derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.

Grosser, Tilo; Fries, Susanne; FitzGerald, Garret A.

2006-01-01

156

Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors.  

PubMed

A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity (COX-2 IC(50)=0.07 microM; selectivity index=687.1) that was more selective than the reference drug celecoxib (COX-2 IC(50)=0.06 microM; selectivity index=405). A molecular modeling study where 8 was docked in the binding site of COX-2 indicated that the p-MeSO(2) COX-2 pharmacophore group on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg(513), Phe(518) and Val(523)) and the carboxylic acid substituent can interact with Ser(530). The structure activity data acquired indicate that the size and nature of the C-4 quinoline substituent are important for COX-2 inhibitory activity. PMID:20061161

Ghodsi, Razieh; Zarghi, Afshin; Daraei, Bahram; Hedayati, Mehdi

2010-01-04

157

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.  

PubMed Central

Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxin-activated J774.2 macrophages) in intact cells, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different. Ibuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW 755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action. Images Fig. 1

Mitchell, J A; Akarasereenont, P; Thiemermann, C; Flower, R J; Vane, J R

1993-01-01

158

Efficacy and safety of the COX2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen  

Microsoft Academic Search

Objective Non-steroidal antiinflammatory agents are commonly used to treat pain and inflammation associated with osteoarthritis (OA), but have poor gastrointestinal (GI) tolerability. This study compared the efficacy of the COX-2 specific inhibitor valdecoxib with naproxen and placebo, in treating symptomatic OA of the hip.Design This multicenter, randomized, double-blind 12-week study compared the efficacy and tolerability of single daily doses of

W. Makarowski; William W. Zhao; Terry Bevirt; David P. Recker

2002-01-01

159

In-vitro test system for the evaluation of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) inhibitors based on a single HPLC run with UV detection using bovine aortic coronary endothelial cells (BAECs)  

Microsoft Academic Search

Objective and Design: The aim of this study was to develop a new, whole-cell test system which is easy to handle and requires a standard equipment for the parallel screening of COX-1 and COX-2 inhibitors.¶ Materials: Bovine aortic endothelial cells (BAECs).¶ Treatment and methods: Unstimulated bovine aortic coronary endothelial cells (BAECs) were used as a source of COX-1 and BAECs

G. Dannhardt; H. Ulbrich

2001-01-01

160

Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors  

Microsoft Academic Search

A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1\\/COX-2 structure–activity relationships were determined by varying the substituents on the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity

Razieh Ghodsi; Afshin Zarghi; Bahram Daraei; Mehdi Hedayati

2010-01-01

161

The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning  

PubMed Central

Background Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. Objective To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. Methods COX-2 knockout (KO) mice (COX-2?/?), prostacyclin receptor KO (IP?/?) mice, and respective wildtype (WT, COX-2+/+ and IP+/+) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. Results There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2+/+, COX-2?/?, IP+/+, and IP?/? mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2?/? or IP?/? mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. Conclusions This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC.

Guo, Yiru; Tukaye, Deepali Nivas; Wu, Wen-Jian; Zhu, Xiaoping; Book, Michael; Tan, Wei; Jones, Steven P.; Rokosh, Gregg; Narumiya, Shuh; Li, Qianhong; Bolli, Roberto

2012-01-01

162

Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure–activity relationship  

Microsoft Academic Search

Resveratrol (3,5,4?-trihydroxy-trans-stilbene) is found in grapes and various medical plants. Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1

Marek Murias; Norbert Handler; Thomas Erker; Karin Pleban; Gerhard Ecker; Philipp Saiko; Thomas Szekeres; Walter Jäger

2004-01-01

163

Cyclooxygenase-2 (COX-2) expression in high-risk premalignant oral lesions.  

PubMed

Emerging data indicate a link between genetic instability and up-regulation of cyclooxygenase-2 (COX-2). To see if individuals at high risk of oral cancer are candidates for treatment with selective COX-2 inhibitors (coxibs), levels of COX-2 expression in healthy, premalignant and cancerous oral mucosa were compared with the occurrence of DNA ploidy status as a genetic risk marker of oral cancer. COX-2 gene product was evaluated immunohistochemically in 30 healthy persons, in 22 patients with dysplastic lesions without previous or concomitant carcinomas, and in 29 patients with oral carcinomas. The immunohistochemical findings were verified by western blotting. COX-2 expression was correlated to DNA content as a genetic risk marker of oral cancer. COX-2 was up-regulated from healthy to premalignant to cancerous oral mucosa. Thus, COX-2 expression was found in 1 case of healthy oral mucosa (3%). All specimens from healthy mucosa had a normal DNA content. In patients with premalignancies. In 29 patients with oral carcinomas, cyclooxygenase-2 expression was observed in 26 (88%), and aneuploidy was observed in 25 cases (94%, P=0.04). Notably, of 22 patients with dysplastic lesions, COX-2 was exclusively expressed in a subgroup of nine patients (41%) identified to be at high risk of cancer by the aberrant DNA content of their lesions. Seven of these patients were followed for 5 years or more. An oral carcinoma developed in six of them (85%; P=0.02). These findings emphasize the need to determine whether coxibs can reduce the risk of oral cancer in patients with high-risk precancerous lesions. PMID:12747975

Sudbø, Jon; Ristimäki, Ari; Sondresen, Jan Erik; Kildal, Wanja; Boysen, Morten; Koppang, Hanna S; Reith, Albrecht; Risberg, Björn; Nesland, Jahn M; Bryne, Magne

2003-07-01

164

An observational study of the discrediting of COX-2 NSAIDs in Australia: Vioxx or class effect?  

PubMed Central

Background When a medicine such as rofecoxib (Vioxx) is withdrawn, or a whole class of medicines discredited such as the selective COX-2 inhibitors (COX-2s), follow-up of impacts at consumer level can be difficult and costly. The Australian Longitudinal Study on Women's Health provides a rare opportunity to examine individual consumer medicine use following a major discrediting event, the withdrawal of rofecoxib and issuing of safety warnings on the COX-2 class of medicines. The overall objective of this paper was to examine the impact of this discrediting event on dispensing of the COX-2 class of medicines, by describing medicine switching behaviours of older Australian women using rofecoxib in September 2004; the uptake of other COX-2s; and the characteristics of women who continued using a COX-2. Methods Participants were concessional beneficiary status women from the Older cohort (born 1921-26) of the Australian Longitudinal Study on Women's Health who consented to linkage to Pharmaceutical Benefits Scheme data, with at least one rofecoxib prescription dispensed in the 12 months before rofecoxib withdrawal. A prescription was defined as one dispensing occasion. Women were grouped by rofecoxib pattern of use: continuous (nine or more prescriptions dispensed in the 12 months prior to rofecoxib withdrawal) or non-continuous (eight or less prescriptions dispensed in the 12 months prior to rofecoxib withdrawal) users. Incidence rate per 100,000 person days and incidence risk ratio described uptake of alternate medicines, following rofecoxib withdrawal. Kaplan-Meier curves described differences in uptake patterns by medicine and pattern of rofecoxib use. Patterns of use of COX-2s in the next 100 days after first COX-2 uptake were described. Results Medicine switches and pattern of medicines uptake differed significantly depending upon whether a woman was a continuous or non-continuous rofecoxib user prior to rofecoxib discrediting. Continuous rofecoxib users overwhelmingly switched to another COX-2 and remained continuing COX-2 users for at least 100 days post-switch. Conclusions The typical switching behaviour of this group of women suggests that the issues leading to the discrediting of rofecoxib were not seen as a COX-2 class effect by prescribers to this high use group of consumers.

2011-01-01

165

The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases  

Microsoft Academic Search

Background & Aims: Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial. Methods: Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib

Stephen W. Fenwick; Giles J. Toogood; J. Peter A. Lodge; Mark A. Hull

2003-01-01

166

Expression of cyclooxygenase-2 (COX-2) in pituitary tumours  

PubMed Central

Summary Background Microvessel density in angiogenesis is regarded as a prognostic factor of tumour invasiveness, independent of cell proliferation. In recent studies of pituitary tumours, correlation between the expression of cyclooxygenase-2 (COX-2) and micro-vascularization density and microvessel surface density has been established. We studied the expression of COX-2 in different types of pituitary adenomas to determine the usefulness of COX-2 expression as a prognostic factor of tumour progression or recurrence in patients with hypophyseal tumours. Material/Methods We retrospectively studied a group of 60 patients of mean age 46.7±17.6 (range, 18 to 85) years who underwent pituitary tumour surgery. Expression of COX-2, as determined by immunohistochemistry, was analyzed in relation to histopathology features of tumour, clinical symptoms, MR imaging and post-operative recurrence/progression of disease. Results COX-2 was expressed in adenomas of 87% of patients, with a median index value of 57.5% [IQR=60.5]. Highest COX-2 expression was observed in hormonally inactive adenomas and gonadotropinomas and lowest in prolactinomas. We found no differences in COX-2 expression with respect to patient age, gender, tumour size, degree of tumour invasiveness, or whether tumours were immunopositive or immunonegative for pituitary hormones, nor have we found any relation between COX-2 expression and recurrence or progression of tumour size. Conclusions COX-2 does not appear to be a predictive factor for recurrence or progression of tumour size. Nevertheless, due to the observed relatively high expression of COX-2 in pituitary adenomas, further studies with COX-2 inhibitors are justified in these tumours.

Sokolowski, Grzegorz; Baldys-Waligorska, Agata; Trofimiuk, Malgorzata; Adamek, Dariusz; Hubalewska-Dydejczyk, Alicja; Golkowski, Filip

2012-01-01

167

Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death  

PubMed Central

Chemopreventive agents generate oxidative stress, which culminates in cell death and may be part of a general mechanism of chemoprevention. The redox-responsive cyclooxygenase (COX)-2, overexpressed during carcinogenesis, has been a target for cancer prevention. To assess the potential link between chemopreventive agents, oxidative stress and COX-2, we studied the chemopreventive sulindac and nitric oxide-donating aspirin (NO-ASA). Both generated oxidative stress and induced COX-2 in various cell lines, more prominently in dying cells. Two antioxidants and an inhibitor of NADPH oxidase abrogated the induction of COX-2 and cell death. Exogenous xanthine/xanthine oxidase, which produce O2?·, had the same effect. Inhibition of caspases and cox-2 knockdown showed that COX-2 did not participate in reactive oxygen species (ROS) generation or cell death induction in response to NO-ASA. Our results support three potentially useful ideas: (i) the concept that ROS are a critical component of the action of chemopreventive agents; (ii) the notion that COX-2 may not be an ideal target for chemoprevention and (iii) the possibility that COX-2 may be overexpressed in cancer cells due to their state of oxidative stress. It is conceivable that, if further substantiated, these findings may inform the rational design of chemotherapeutic strategies, in particular the choice of agents in combination approaches.

Sun, Yu; Chen, Jie; Rigas, Basil

2009-01-01

168

Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death.  

PubMed

Chemopreventive agents generate oxidative stress, which culminates in cell death and may be part of a general mechanism of chemoprevention. The redox-responsive cyclooxygenase (COX)-2, overexpressed during carcinogenesis, has been a target for cancer prevention. To assess the potential link between chemopreventive agents, oxidative stress and COX-2, we studied the chemopreventive sulindac and nitric oxide-donating aspirin (NO-ASA). Both generated oxidative stress and induced COX-2 in various cell lines, more prominently in dying cells. Two antioxidants and an inhibitor of NADPH oxidase abrogated the induction of COX-2 and cell death. Exogenous xanthine/xanthine oxidase, which produce O(2)(-)., had the same effect. Inhibition of caspases and cox-2 knockdown showed that COX-2 did not participate in reactive oxygen species (ROS) generation or cell death induction in response to NO-ASA. Our results support three potentially useful ideas: (i) the concept that ROS are a critical component of the action of chemopreventive agents; (ii) the notion that COX-2 may not be an ideal target for chemoprevention and (iii) the possibility that COX-2 may be overexpressed in cancer cells due to their state of oxidative stress. It is conceivable that, if further substantiated, these findings may inform the rational design of chemotherapeutic strategies, in particular the choice of agents in combination approaches. PMID:18952595

Sun, Yu; Chen, Jie; Rigas, Basil

2008-10-24

169

Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue  

PubMed Central

Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE2, PGF2?, 6-keto-PGF1?, PGD2, and thromboxane (Tx) B2 concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE2, 6-keto-PGF1?, and PGF2? was increased at 6 h BUO, and PGE2 and PGF2? increased further at 12 h BUO. TxB2 increased after 12 h BUO. 6-keto-PGF1? remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE2, TxB2, 6-keto-PGF1?, and PGF2? below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE2, PGF2?, and PGD2 in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE2 and 6-keto-PGF1? concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF1? and TxB2 concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE2 and PGF2? with minor, but significant, contributions from COX-1. PGD2 synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.

N?rregaard, Rikke; Jensen, Boye L; Topcu, Sukru Oguzkan; Wang, Guixian; Schweer, Horst; Nielsen, S?ren

2010-01-01

170

Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue.  

PubMed

Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE(2), PGF(2alpha), 6-keto-PGF(1alpha), PGD(2), and thromboxane (Tx) B(2) concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE(2), 6-keto-PGF(1alpha), and PGF(2alpha) was increased at 6 h BUO, and PGE(2) and PGF(2alpha) increased further at 12 h BUO. TxB(2) increased after 12 h BUO. 6-keto-PGF(1alpha) remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE(2,) TxB(2), 6-keto-PGF(1alpha), and PGF(2alpha) below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE(2), PGF(2alpha), and PGD(2) in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE(2) and 6-keto-PGF(1alpha) concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF(1alpha) and TxB(2) concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE(2) and PGF(2alpha) with minor, but significant, contributions from COX-1. PGD(2) synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2. PMID:20147610

Nørregaard, Rikke; Jensen, Boye L; Topcu, Sukru Oguzkan; Wang, Guixian; Schweer, Horst; Nielsen, Søren; Frøkiaer, Jørgen

2010-02-10

171

Compensatory hypertrophy induced by ventricular cardiomyocyte-specific COX2 expression in mice  

Microsoft Academic Search

Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases owing to the finding that highly specific COX-2 inhibitors (i.e., Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact

John M. Streicher; Kenichiro Kamei; Tomo-o Ishikawa; Harvey Herschman; Yibin Wang

2010-01-01

172

Suppression of Intestinal Polyposis in Apc ?716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX2)  

Microsoft Academic Search

Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc?716knockout mice, a model of human familial adenomatous polyposis. A Ptgs2null mutation reduced the number and size of the intestinal

Masanobu Oshima; Joseph E Dinchuk; Stacia L Kargman; Hiroko Oshima; Bruno Hancock; Elizabeth Kwong; James M Trzaskos; Jilly F Evans; Makoto M Taketo

1996-01-01

173

Cancer Chemoprevention by Cyclooxygenase 2 (COX2) Blockade  

Microsoft Academic Search

Significant use of selective cyclooxygenase-2 (COX-2) blocking agents prescribed for the treatment of arthritis during 1999\\u000a to 2005 facilitates epidemiologic investigations to illuminate their chemopreventive effects against human cancer. We therefore\\u000a conducted a set of case control studies of selective COX-2 blocking agents to determine their chemopreventive potential for\\u000a the four major cancers: breast, prostate, colon, and lung. Newly diagnosed

RANDALL E. HARRIS; Joanne Beebe-Donk; GALAL A. ALSHAFIE

174

Design, synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors  

Microsoft Academic Search

A new series of ketoprofen analogs were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.057–0.085?M range, and COX-2 selectivity indexes in the 115 to >1298.7 range. Compounds possessing azido

Afshin Zarghi; Razieh Ghodsi

2010-01-01

175

siRNA-mediated knock-down of COX-2 in melanocytes suppresses melanogenesis.  

PubMed

Cyclooxygenase-2 (COX-2) is an enzyme induced in response to multiple mitogenic and inflammatory stimuli, including UV light. UV-induced COX-2 expression induces production of prostaglandin E2 (PGE2) in keratinocytes, which mediates inflammation and cell proliferation. Until recently, studies regarding COX-2 and PGE2 in the skin have focused on keratinocytes and skin cancer and the effect of PGs produced by keratinocytes on melanocytes. However, the effects of COX-2 itself or COX-2 inhibitors on melanogenesis are not well known. Therefore, to establish the role of COX-2 in melanogenesis, we investigated the effects of knock-down of COX-2 in melanocytes on melanin production and the expression of melanogenic molecules through silencing of COX-2 expression with COX-2 short interfering RNA (siRNA). COX-2 knock-down in melanocytes decreased the expressions of tyrosinase, TRP-1, TRP-2, gp100 and MITF and also reduced tyrosinase enzyme activity. Furthermore, COX-2 siRNA-transfected melanocytes showed markedly reduced alpha-melanocyte stimulating hormone (?-MSH)-induced melanin production. In addition, ?-MSH-induced COX-2 expression in both scrambled siRNA-transfected and COX-2 siRNA-transfected melanocytes was greater than ?-MSH-untreated cells. Our results suggest that COX-2 might be a candidate target for the development of anti-melanogenic agents and ?-MSH-induced pigmentation could be closely associated with COX-2 expression. COX-2 inhibitors might therefore be of particular use in whitening cosmetics for hyperpigmentation disorders such as melasma, postinflammatory hyperpigmentation and solar lentigo. PMID:22506937

Kim, Ji Y; Shin, Jae Y; Kim, Miri R; Hann, Seung-Kyung; Oh, Sang H

2012-04-16

176

Anti-cancer effects of celecoxib on nasopharyngeal carcinoma HNE-1 cells expressing COX2 oncoprotein  

Microsoft Academic Search

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor with antitumor and antiangiogenic activities. To investigate the\\u000a effects of celecoxib on nasopharyngeal carcinoma (NPC), HNE-1 cells were treated with celecoxib at various concentrations.\\u000a MTT assay, migration assay and invasion assay were performed to observe the inhibitory activity of celecoxib on HNE-1 cells.\\u000a Additionally, VEGF-A expression and radiation survival of NPC cell were

Jiongyu Chen; Yonggang Ran; Chaoqun Hong; Zhijian Chen; Yanjie You

2010-01-01

177

Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation  

SciTech Connect

Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis. Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.

Colleselli, Daniela [Pneumology Service-Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck (Austria); Bijuklic, Klaudija [Inflammation Research, Laboratory Division of General Internal Medicine, Department of Internal Medicine, Medical University of Innsbruck (Austria); Mosheimer, Birgit A. [Inflammation Research, Laboratory Division of General Internal Medicine, Department of Internal Medicine, Medical University of Innsbruck (Austria); Kaehler, Christian M. [Pneumology Service-Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck (Austria)]. E-mail: C.M.Kaehler@uibk.ac.at

2006-09-10

178

Molecular Dynamics Simulations of Arachidonic Acid Complexes with COX-1 and COX-2  

PubMed Central

The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H2. As a result, these enzymes are pharmacologically important targets for non-steroidal anti-inflammatory drugs, such as aspirin and newer COX-2 selective inhibitors. The cyclooxygenases are functional homodimers, and each subunit contains both a cyclooxygenase and a peroxidase active site. These enzymes are quite interesting mechanistically, as the conversion of arachidonic acid to prostaglandin H2 requires two oxygenation and two cyclization reactions, resulting in the formation of five new chiral centers with nearly absolute regio- and stereochemical fidelity. We have used molecular dynamics (MD) simulations to investigate the equilibrium behavior of both COX-1 and COX-2 enzyme isoforms with bound arachidonate. These simulations were compared with reference simulations of arachidonate in solution to explore the effect of enzyme on substrate conformation and positioning in the active site. The simulations suggest that the substrate has greater conformational freedom in the COX-2 active site, consistent with the larger COX-2 active site volume observed in X-ray crystal structures. The simulations reveal different conformational behavior for arachidonate in each subunit over the course of extended equilibrium MD simulations. The simulations also provide detailed information for several protein channels that might be important for oxygen and water transport to or from active sites, or for intermediate trafficking between the cyclooxygenase and peroxidase active sites. The detailed comparisons for COX-1 versus COX-2 active site structural fluctuations may also provide useful information for design of new isozyme-selective inhibitors.

Furse, Kristina E.; Pratt, Derek A.; Porter, Ned A.; Lybrand, Terry P.

2008-01-01

179

Prevention of upper aerodigestive tract cancer in zinc-deficient rodents: Inefficacy of genetic or pharmacological disruption of COX-2  

PubMed Central

Zinc deficiency in humans is associated with an increased risk of upper aerodigestive tract (UADT) cancer. In rodents, zinc deficiency predisposes to carcinogenesis by causing proliferation and alterations in gene expression. We examined whether in zinc-deficient rodents, targeted disruption of the cyclooxygenase (COX)-2 pathway by the COX-2 selective inhibitor celecoxib or by genetic deletion prevent UADT carcinogenesis. Tongue cancer prevention studies were conducted in zinc-deficient rats previously exposed to a tongue carcinogen by celecoxib treatment with or without zinc replenishment, or by zinc replenishment alone. The ability of genetic COX-2 deletion to protect against chemically-induced for-estomach tumorigenesis was examined in mice on zinc-deficient versus zinc-sufficient diet. The expression of 3 predictive bio-markers COX-2, nuclear factor (NF)-? B p65 and leukotriene A4 hydrolase (LTA4H) was examined by immunohistochemistry. In zinc-deficient rats, celecoxib without zinc replenishment reduced lingual tumor multiplicity but not progression to malignancy. Celecoxib with zinc replenishment or zinc replenishment alone significantly lowered lingual squamous cell carcinoma incidence, as well as tumor multiplicity. Celecoxib alone reduced overexpression of the 3 biomarkers in tumors slightly, compared with intervention with zinc replenishment. Instead of being protected, zinc-deficient COX-2 null mice developed significantly greater tumor multiplicity and forestomach carcinoma incidence than wild-type controls. Additionally, zinc-deficient COX-2?/? forestomachs displayed strong LTA4H immunostaining, indicating activation of an alter-native pathway under zinc deficiency when the COX-2 pathway is blocked. Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer.

Fong, Louise Y.Y.; Jiang, Yubao; Riley, Maurisa; Liu, Xianglan; Smalley, Karl J.; Guttridge, Denis C.; Farber, John L.

2009-01-01

180

Phenotypes of the COX-deficient mice indicate physiological and pathophysiological roles for COX-1 and COX-2.  

PubMed

The development of mice deficient in either cyclooxygenase-1 (COX-1) or COX-2, as well as mice deficient in both COX isoforms, has provided models to elucidate the physiological and pathophysiological roles of these enzymes. The findings obtained with the COX-deficient mice suggest that COX-2 may be more important than COX-1 for supplying prostaglandins (PGs) to maintain tissue homeostasis. Furthermore, both isoforms may be involved in the development of diseases, such as inflammation and cancer. Therefore, the contribution of each isoform to the prevention or development of disease is more complex than originally described. Studies with the COX-deficient mice suggest that in addition to COX-2-selective inhibition, therapeutic advances may also be achieved with COX-1-selective inhibitors which lack gastrointestinal side effects. PMID:12432917

Loftin, Charles D; Tiano, Howard F; Langenbach, Robert

2002-08-01

181

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells.  

PubMed

High exposure to cadmium is a risk factor for many neuronal diseases. Overexpression of cyclooxygenase (COX)-2 is linked to many neuroinflammatory and neoplastic diseases. We, herein, investigated the effect of cadmium on the expression of COX-2 in C6 rat glioma cells. Treatment with cadmium sulfate (cadmium) increased the expression of COX-2 mRNA. Remarkably, cadmium treatment further increased expression of not only the N-glycosylated COX-2 protein of 72 kDa but also the unglycosylated COX-2 of 66 kDa, as assessed by the unglycosylated COX-2 induced by tunicamycin or glucosamine, known inhibitors of COX-2 N-glycosylation. Of note, when translation was blocked in the presence of cycloheximide (CHX), levels of both N-glycosylated and unglycosylated COX-2 proteins induced by cadmium rapidly declined but the decline was prevented by MG132, a 26S proteasomal inhibitor. However, in the absence of CHX, cadmium induced and maintained expression of the unglycosylated COX-2 proteins. Pharmacological inhibition studies importantly demonstrated that the cadmium-mediated COX-2 transcriptional upregulation in C6 cells was not shown by exogenous glutathione (GSH) supplementation or treatment with inhibitors of extracellular signal-regulated protein kinase-1/2 (ERK-1/2), p38 MAPK and c-Jun N-terminal protein kinase-1/2 (JNK-1/2), respectively. Expression of COX-2 was not noted in C6 cells exposed to other heavy metals (cobalt or manganese). These results demonstrate that cadmium specifically induces expression of COX-2 through both transcriptional and co-translational (N-glycosylation) regulation in C6 cells in which the cadmium-induced COX-2 transcriptional upregulation is closely related to oxidative stress-dependent activation of the family of MAPKs and the cadmium-induced expression of both N-glycosylated and unglycosylated COX-2 proteins is proteasome- and translation-dependent. PMID:22767315

Park, Yu-Kyoung; Hong, Hua; Jang, Byeong-Churl

2012-07-03

182

Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils  

PubMed Central

In the present study, we characterized the generation of prostaglandin (PG)E2 in human neutrophils. We found that the Ca2+-dependent type IV cytosolic phospholipase A2 (cPLA2) was pivotally involved in the COX-2-mediated generation of PGE2 in response to a calcium ionophore, as determined by the use of selected PLA2 inhibitors. PGE2 biosynthesis elicited by bacterial-derived peptides or by phagocytic stimuli acting on cell surface receptors also showed to be dependent on cPLA2 activity. We then assessed metabolism of unesterified arachidonic acid (AA), and observed that PGE2 production becomes favored over that of LTB4 with higher AA concentrations. Withdrawal of calcium prevented the generation of PGE2 in response to a calcium ionophore but did not affect the up-regulation of COX-2 or its capacity to convert AA, thus limiting its implication at the level of cPLA2 activation. Of the main eicosanoids produced by neutrophils, only LTB4 was able to up-regulate COX-2 expression. Finally, the only PGE synthase isoform found in neutrophils is microsomal PGE synthase-1; it co-localized with COX-2 and its expression appeared mainly constitutive. These results highlight key differences in regulatory processes of the 5-LO and COX pathways, and enhance our knowledge at several levels in the PGE2 biosynthesis in neutrophils.

St-Onge, Mireille; Flamand, Nicolas; Biarc, Jordane; Picard, Serge; Bouchard, Line; Dussault, Andree-Anne; Laflamme, Cynthia; James, Michael J.; Caughey, Gillian E.; Cleland, Leslie G.; Borgeat, Pierre; Pouliot, Marc

2010-01-01

183

Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2  

PubMed Central

This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. Lumiracoxib inhibited purified COX-1 and COX-2 with Ki values of 3 and 0.06??M, respectively. In cellular assays, lumiracoxib had an IC50 of 0.14??M in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30??M (HEK 293 cells transfected with human COX-1). In a human whole blood assay, IC50 values for lumiracoxib were 0.13??M for COX-2 and 67??M for COX-1 (COX-1/COX-2 selectivity ratio 515). Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1?h. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B2 (TxB2) generation with an ID50 of 33?mg?kg?1, whereas COX-2-derived production of prostaglandin E2 (PGE2) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID50 value of 0.24?mg?kg?1. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100?mg?kg?1 orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.

Esser, Ronald; Berry, Carol; Du, Zhengming; Dawson, Janet; Fox, Alyson; Fujimoto, Roger A; Haston, William; Kimble, Earl F; Koehler, Julie; Peppard, Jane; Quadros, Elizabeth; Quintavalla, Joseph; Toscano, Karen; Urban, Laszlo; van Duzer, John; Zhang, Xiaoli; Zhou, Siyuan; Marshall, Paul J

2005-01-01

184

Induction of COX-2 protein expression by vanadate in A549 human lung carcinoma cell line through EGF receptor and p38 MAPK-mediated pathway  

SciTech Connect

Vanadate is a transition metal widely distributed in the environment. It has been reported that vanadate associated with air pollution particles can modify DNA synthesis, causing cell growth arrest, and apoptosis. Moreover, vanadium exposure was also found to cause the synthesis of inflammatory cytokines, such as interleukin-1, tumor necrosis factor-{alpha}, and prostaglandin E{sub 2}. Here, we found that exposure of A549 human lung carcinoma cells to vanadate led to extracellular signal-regulated kinase, c-Jun NH{sub 2}-terminal protein kinases (JNKs), p38 mitogen-activated protein kinase (p38) activation, and COX-2 protein expression in a dose-dependent manner. SB203580, a p38 MAPK inhibitor, but not PD098059 and SP600125, specific inhibitor of MKK1 and selective inhibitor of JNK, respectively, suppressed COX-2 expression. Furthermore, the epithelial growth factor (EGF) receptor specific inhibitor (PD153035) reduced vanadate-induced COX-2 expression. However, scavenging of vanadate-induced reactive oxygen species by catalase, a specific H{sub 2}O{sub 2} inhibitor, or DPI, an NADPH oxidase inhibitor, resulted in no inhibition on COX-2 expression. Together, we suggested that EGF receptor and p38 MAPK signaling pathway may be involved in vanadate-induced COX-2 protein expression in A549 human lung carcinoma cell line.

Chien, P.-S. [Institute of Biotechnology, National Cheng Kung University, No. 1 University Rd. 701, Tainan, Taiwan (China); Mak, O.-T. [Institute of Biotechnology, National Cheng Kung University, No. 1 University Rd. 701, Tainan, Taiwan (China); Department of Life Sciences, National Cheng Kung University, No. 1 University Rd. 701, Tainan, Taiwan (China); Huang, H.-J. [Institute of Biotechnology, National Cheng Kung University, No. 1 University Rd. 701, Tainan, Taiwan (China) and Department of Life Sciences, National Cheng Kung University, No. 1 University Rd. 701, Tainan, Taiwan (China)]. E-mail: haojen@mail.ncku.edu.tw

2006-01-13

185

Notch2-induced COX-2 expression enhancing gastric cancer progression.  

PubMed

Gastric carcinoma is one of the most common and mortal types of malignancy worldwide. To date, the mechanisms controlling its aggressiveness are not yet fully understood. Notch signal pathway can function as either an oncogene or a tumor suppressor in tumorigenesis. Four members (Notch1-4) of Notch receptors were found in mammals and each exhibits distinct roles in tumor progression. Previous study showed that the activated Notch1 receptor promoted gastric cancer progression through cyclooxygenase-2 (COX-2). This study addressed whether Notch2 signal pathway is also involved in gastric cancer progression. Constitutive expression of Notch2 intracellular domain (N2IC), the activated form of Notch2 receptor, promoted both cell proliferation and xenografted tumor growth of human stomach adenocarcinoma SC-M1 cells. The colony formation, migration, invasion, and wound-healing abilities of SC-M1 cells were enhanced by N2IC expression, whereas these abilities were suppressed by Notch2 knockdown. Similarly, Notch2 knockdown inhibited cancer progressions of AGS and AZ521 gastric cancer cells. Expression of N2IC also caused epithelial-mesenchymal transition in SC-M1 cells. Furthermore, N2IC bound to COX-2 promoter and induced COX-2 expression through a CBF1-dependent manner in SC-M1 cells. The ability of N2IC to enhance tumor progression in SC-M1 cells was suppressed by knockdown of COX-2 or treatment with NS-398, a COX-2 inhibitor. Moreover, the suppression of tumor progression by Notch2 knockdown in SC-M1 cells was reversed by exogenous COX-2 or its major enzymatic product PGE(2) . Taken together, this study is the first to demonstrate that the Notch2-COX-2 signaling axis plays an important role in controlling gastric cancer progression. PMID:21976141

Tseng, Yun-Chien; Tsai, Yu-Hui; Tseng, Min-Jen; Hsu, Kai-Wen; Yang, Min-Chieh; Huang, Kuo-Hung; Li, Anna Fen-Yau; Chi, Chin-Wen; Hsieh, Rong-Hong; Ku, Hung-Hai; Yeh, Tien-Shun

2011-10-04

186

Sulfonamido, azidosulfonyl and N-acetylsulfonamido analogues of rofecoxib: 4-[4-( N-acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5 H)furanone is a potent and selective cyclooxygenase-2 inhibitor  

Microsoft Academic Search

4-[4-(N-Acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone, possessing a N-acetylsulfonamido pharmacophore, has been identified as a potent and selective COX-2 inhibitor that has the potential to acetylate the COX-2 isozyme.

Afshin Zarghi; P. N Praveen Rao; Edward E Knaus

2004-01-01

187

Sulfonamido, azidosulfonyl and N-acetylsulfonamido analogues of rofecoxib: 4-[4-(N-acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone is a potent and selective cyclooxygenase-2 inhibitor.  

PubMed

4-[4-(N-Acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone, possessing a N-acetylsulfonamido pharmacophore, has been identified as a potent and selective COX-2 inhibitor that has the potential to acetylate the COX-2 isozyme. PMID:15050636

Zarghi, Afshin; Praveen Rao, P N; Knaus, Edward E

2004-04-19

188

Vascular COX-2 modulates blood pressure and thrombosis in mice.  

PubMed

Prostacyclin (PGI(2)) is a vasodilator and platelet inhibitor, properties consistent with cardioprotection. More than a decade ago, inhibition of cyclooxygenase-2 (COX-2) by the nonsteroidal anti-inflammatory drugs (NSAIDs) rofecoxib and celecoxib was found to reduce the amount of the major metabolite of PGI(2) (PGI-M) in the urine of healthy volunteers. This suggested that NSAIDs might cause adverse cardiovascular events by reducing production of cardioprotective PGI(2). This prediction was based on the assumption that the concentration of PGI-M in urine likely reflected vascular production of PGI(2) and that other cardioprotective mediators, especially nitric oxide (NO), were not able to compensate for the loss of PGI(2). Subsequently, eight placebo-controlled clinical trials showed that NSAIDs that block COX-2 increase adverse cardiovascular events. We connect tissue-specific effects of NSAID action and functional correlates in mice with clinical outcomes in humans by showing that deletion of COX-2 in the mouse vasculature reduces excretion of PGI-M in urine and predisposes the animals to both hypertension and thrombosis. Furthermore, vascular disruption of COX-2 depressed expression of endothelial NO synthase and the consequent release and function of NO. Thus, suppression of PGI(2) formation resulting from deletion of vascular COX-2 is sufficient to explain the cardiovascular hazard from NSAIDs, which is likely to be augmented by secondary mechanisms such as suppression of NO production. PMID:22553252

Yu, Ying; Ricciotti, Emanuela; Scalia, Rosario; Tang, Soon Yew; Grant, Gregory; Yu, Zhou; Landesberg, Gavin; Crichton, Irene; Wu, Weichen; Puré, Ellen; Funk, Colin D; FitzGerald, Garret A

2012-05-01

189

Are All COX2 Inhibitors Created Equal?  

Microsoft Academic Search

rostaglandins (PGs) are biologically active lipids de- rived from the cyclooxygenase (COX)-mediated me- tabolism of arachidonic acid. They are constitutively produced in certain tissues (eg, brain, gut, and kidney), and their synthesis is increased at sites of inflammation. Prosta- noids function as important mediators of inflammation and modulate a variety of physiological processes, including maintenance of gastric mucosal integrity, renal

Ingrid J. Chang; Raymond C. Harris

2010-01-01

190

463. COX2Based Gene Therapy: Reduction of Intraocular Pressure in a Glaucoma Gene Therapy Animal Model with Lentiviral Vectors Expressing COX2, a Prostaglandin Synthase, or a Prostaglandin Receptor  

Microsoft Academic Search

BACKGROUND: Cyclooxygenase-2 (COX-2), an inducible enzyme in the prostaglandin (PG) biosynthesis cascade, is important in medically significant disease states, including glaucoma and cancer. Most recently, COX-2 inhibitors have been implicated in adverse cardiovascular outcomes. Durable COX-2 expression by exogenous genes has not been previously achieved. We hypothesized that the inducible PG biosynthetic and response pathways could be manipulated via a

Roman A. Barraza; Eric M. Poeschla

2006-01-01

191

IL-10 production in non-small cell lung carcinoma patients is regulated by ERK, P38 and COX-2.  

PubMed

Immune dysfunction is hallmark of patients with non-small cell lung carcinoma (NSCLC). The molecular mechanism involved in COX-2- and PGE2-mediated production of immunosuppressive cytokine IL-10 is not well-understood. Our study addresses the involvement of T cell downstream signalling intermediates, cytokines (IL-10 and IFN-?) and their transcription factors (T-bet and GATA-3) in COX-2-mediated regulation of lymphocyte functions in NSCLC patients. In comparison to healthy individual, a marked decrease in lymphocyte proliferation to anti-CD3 MAb was observed in NSCLC patients by thymidine incorporation assay. Using flow cytometry, decrease in intracellular calcium release with increase in reactive oxygen species was observed in lymphocytes of NSCLC patients. These patients showed increased IL-10 and PGE2 with reduced IFN-? production by ELISA. Results demonstrated defect in regulation of transcription factors T-bet and GATA-3 as analysed by Western blotting (WB), immunoprecipitation and EMSA. Overexpression of p-p38, p-ERK and COX-2 were observed with diminished p-JNK by WB. IL-10/IFN-? levels were found to be differentially regulated via p38 and ERK mitogen-activated protein kinase (MAPK) pathways in cooperation with COX-2. Inhibition of these pathways using selective inhibitors lead to increased lymphocyte proliferative response to anti-CD3 MAb and IFN-? production with decrease in IL-10 production. Studies showed involvement of ERK, p38 and COX-2 pathways in high IL-10 production, driven by lung tumour derived PGE2. The selective COX-2 inhibitor rofecoxib showed ability to alter the cytokine balance by affecting regulation of T-bet and GATA-3 transcription factors. PMID:21507199

Patel, Swati; Vetale, Shamal; Teli, Pradeep; Mistry, Rajesh; Chiplunkar, Shubhada

2012-03-01

192

Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor.  

PubMed

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

Horrillo, Raquel; Planagumà, Anna; González-Périz, Ana; Ferré, Natàlia; Titos, Esther; Miquel, Rosa; López-Parra, Marta; Masferrer, Jaime L; Arroyo, Vicente; Clària, Joan

2007-08-31

193

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) selectivity of COX inhibitors.  

PubMed

In vitro evaluations of the selectivity of COX inhibitors are based on a great variety of experimental protocols. As a result, data available on cyclooxygenase (COX)-1/COX-2/5- lipoxygenase (LOX) selectivity of COX inhibitors lack consistency. We, therefore, performed a systematic analysis of the COX-1/COX-2/5-LOX selectivity of 14 compounds with selective COX inhibitory activity (Coxibs). The compounds belonged to different structural classes and were analyzed employing the well-recognized whole-blood assay. 5-LOX activity was also tested on isolated human polymorphonuclear leukocytes. Among COX inhibitors, celecoxib and ML-3000 (licofelone) inhibited 5-LOX in human neutrophils at micromolar ranges. Surprisingly, ML-3000 had no effect on 5-LOX product synthesis in whole-blood assay. In addition, we could show that inhibition of COX pathways did not increase the transformation of arachidonic acid by the 5-LOX pathway. PMID:18280718

Sud'ina, G F; Pushkareva, M A; Shephard, P; Klein, T

2008-02-15

194

Anti-cancer effects of celecoxib on nasopharyngeal carcinoma HNE-1 cells expressing COX-2 oncoprotein  

PubMed Central

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor with antitumor and antiangiogenic activities. To investigate the effects of celecoxib on nasopharyngeal carcinoma (NPC), HNE-1 cells were treated with celecoxib at various concentrations. MTT assay, migration assay and invasion assay were performed to observe the inhibitory activity of celecoxib on HNE-1 cells. Additionally, VEGF-A expression and radiation survival of NPC cell were also examined after treatment with celecoxib. Celecoxib treatment presented an anti-proliferation function in a time and dose-dependent manner on HNE-1 cells which highly express COX-2 protein. Celecoxib also displayed an obvious inhibitory activity on invasive capacity of NPC cells. Moreover, the celecoxib’s effects to suppress VEGF-A expression and enhance radiosensitivity were detected in HNE-1 cells. These findings implicate that application of celecoxib may be an effective strategy for NPC therapy.

Chen, Jiongyu; Ran, Yonggang; Hong, Chaoqun; Chen, Zhijian

2010-01-01

195

COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells.  

PubMed

Cardiovascular safety of cyclooxygenase (COX)-2-selective inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of worldwide concern. COX-2 inhibitors and NSAIDs act by inhibiting arachidonic acid metabolism to prostaglandins. They confer a cardiovascular hazard manifested as an elevated risk of myocardial infarction. Mechanisms underlying these cardiovascular effects are uncertain. Here we determine whether interference with cytosolic phospholipase A2 (cPLA-2) or COX-2 through pharmacologic blockade or silencing RNA impacts expression of scavenger receptor CD36 and scavenger receptor A, both involved in cholesterol uptake in monocytes and macrophages. THP-1 human monocytes and human peripheral blood mononuclear cells were exposed to celecoxib, a COX-2 selective inhibitor currently in clinical use, and to arachidonyl trifluoromethyl ketone (AACOCF3), an arachidonic acid analog that selectively inhibits cPLA-2. Celecoxib and AACOCF3 each upregulated expression of CD36, but not scavenger receptor A, as determined by quantitative PCR and immunoblotting. Silencing of cPLA-2 or COX-2 had comparable effects to pharmacologic treatments. Oil red O staining revealed a profound increase in foam cell transformation of THP-1 macrophages exposed to either celecoxib or AACOCF3 (both 25 ?M), supporting a role for the COX pathway in maintaining macrophage cholesterol homeostasis. Demonstration of disrupted cholesterol balance by AACOCF3 and celecoxib provides further evidence of the possible mechanism by which COX inhibition may promote lipid overload leading to atheromatous lesion formation and increased cardiovascular events. PMID:21181286

Anwar, Kamran; Voloshyna, Iryna; Littlefield, Michael J; Carsons, Steven E; Wirkowski, Peter A; Jaber, Nadia L; Sohn, Andrew; Eapen, Sajan; Reiss, Allison B

2010-12-22

196

Defects in mouse nephrogenesis induced by selective and non-selective cyclooxygenase-2 inhibitors  

PubMed Central

BACKGROUND AND PURPOSE Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described. EXPERIMENTAL APPROACH We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21. KEY RESULTS All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE2 synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2?/? mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology. CONCLUSIONS AND IMPLICATIONS Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.

Olliges, Anke; Wimmer, Stefanie; Nusing, Rolf M

2011-01-01

197

COX-2 and c-kit expression in canine gliomas.  

PubMed

Gliomas are among the most common primary neural tumours of dogs. Cyclooxygenase-2 (COX-2) and c-kit overexpression are associated with increased aggressiveness of gliomas and decreased survival in human beings. COX-2 is the inducible form of cyclooxygenase, which catalyzes prostaglandin formation and may increase tumour proliferation and angiogenesis. C-kit is a tyrosine kinase receptor involved in normal cell physiology; c-kit is upregulated in some canine tumours. In this retrospective study, 20 canine gliomas were identified: 11 (55%) oligodendrogliomas, including 1 anaplastic variant; 1 (5%) oligoastrocytoma; and 8 (40%) astrocytomas, of which 2 were glioblastoma multiforme. None of the gliomas expressed COX-2. None of the gliomas were immunoreactive for c-kit, although all three high-grade tumours had intramural vascular expression. Consequently, COX-2 inhibitors would likely be ineffective against canine gliomas. C-kit inhibitors may have an anti-angiogenic effect in high-grade gliomas, but would likely be ineffective in low- and medium-grade tumours. PMID:22235799

Jankovsky, J M; Newkirk, K M; Ilha, M R; Newman, S J

2011-11-23

198

COX-2 structural analysis and docking studies with gallic acid structural analogues.  

PubMed

Emblica officinalis is an ayurvedic herbal plant. The compounds isolated from this plant have good inhibitory effects against cyclooxygenase-2 (COX-2), among them gallic acid (GA) has the highest inhibitory effect. COX-2 (1.14.99.1) is an oxidoreductase having a role in prostaglandin biosynthesis, inflammatory responses and in cardiovascular events. COX-2 has gained special focus on research since past few decades. The sequence and structural studies reveals Mus musculus COX-2 shares the common conserved sequence and structural pattern with human COX-2. Molecular modeling and docking analysis with gallic acid and their structural analogues showed that 2-[(2E,4E)-hexa-2,4-dienyl]-3,4,5-trihydroxybenzoic acid, (3,4,5-trihydroxybenzoyl) 3,4,5-trihydroxybenzoate and 3-hydroxy-4-sulfooxybenzoic acid are more interactive and binding strongly than gallic acid at active site. Hence these three compounds should be considered as strong inhibitors for COX-2. PMID:23483789

Amaravani, M; Prasad, Nirmal K; Ramakrishna, Vadde

2012-12-10

199

Effects of selective COX2 and 5LOX inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster  

Microsoft Academic Search

Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis, however, the effect on liver metastasis in pancreatic cancer is still unknown.Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N-nitrosobis-2-oxopropylamine (BOP) in Syrian hamster. Animals received selective inhibition of cyclooxygenase-2 (Celebrex) and 5-lipoxygenase (Zyflo). In week 33, hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver

J. I. Gregor; M. Kilian; I. Heukamp; C. Kiewert; G. Kristiansen; I. Schimke; M. K. Walz; C. A. Jacobi; F. A. Wenger

2005-01-01

200

COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction.  

PubMed

Bilateral ureteral obstruction (BUO) is associated with marked changes in the expression of renal aquaporins (AQPs) and sodium transport proteins. To examine the role of prostaglandin in this response, we investigated whether 24-h BUO changed the expression of cyclooxygenases (COX-1 and -2) in the kidney and tested the effect of the selective COX-2 inhibitor parecoxib (5 mg.kg(-1).day(-1) via osmotic minipumps) on AQPs and sodium transport. Sham and BUO kidneys were analyzed by semiquantitative immunoblotting, and a subset of kidneys was perfusion fixed for immunocytochemistry. BUO caused a significant 14-fold induction of inner medullary COX-2 (14.40 +/- 1.8 vs. 1.0 +/- 0.4, n = 6; P < 0.0001) and a reduction in medullary tissue osmolality, whereas COX-1 did not change. Immunohistochemistry confirmed increased COX-2 labeling associated with medullary interstitial cells. COX isoforms did not change in cortex/outer medulla after 24-h BUO. In BUO kidneys, inner medullary AQP2 expression was reduced, and this decrease was prevented by parecoxib. In the inner stripe of outer medulla, the type 3 Na(+)/H(+) exchanger (NHE3) and apical Na(+)-K(+)-2Cl(-) cotransporter (BSC-1) were significantly reduced by BUO, and this decrease was significantly attenuated by parecoxib. Immunohistochemistry for AQP2, NHE3, and BSC-1 confirmed the effect of parecoxib. Parecoxib had no significant effect on the Na-K-ATPase alpha(1)-subunit, type II Na-P(i) cotransporter, or AQP3. In conclusion, acute BUO leads to marked upregulation of COX-2 in inner medulla and selective COX-2 inhibition prevents dysregulation of AQP2, BSC-1, and NHE3 in response to BUO. These data indicate that COX-2 may be an important factor contributing to the impaired renal water and sodium handling in response to BUO. PMID:15840770

Nørregaard, Rikke; Jensen, Boye L; Li, Chunling; Wang, Weidong; Knepper, Mark A; Nielsen, Søren; Frøkiaer, Jørgen

2005-04-19

201

COX-2 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction.  

PubMed

Release of bilateral ureteral obstruction (BUO) is associated with reduced expression of renal aquaporins (AQPs), polyuria, and impairment of urine-concentrating capacity. Recently, we demonstrated that 24 h of BUO is associated with increased cyclooxygenase (COX)-2 expression in the inner medulla (IM) and that selective COX-2 inhibition prevents downregulation of AQP2. In the present study, we tested the hypothesis that COX-2 activity increases in the postobstructive phase and that this increase in COX-2 activity contributes to polyuria and impaired urine-concentrating capacity. We examined the effect of the selective COX-2 inhibitor parecoxib (5 mg.kg(-1).day(-1) via osmotic minipumps) on renal functions and protein abundance of AQP2, AQP3, Na-K-2Cl cotransporter type 2 (NKCC2), and Na-K-ATPase 3 days after release of BUO. At 3 days after release of BUO, rats exhibited polyuria, dehydration and urine and IM tissue osmolality were decreased. There were inverse changes of COX-1 and COX-2 in the IM: COX-2 mRNA, protein, and activity increased, while COX-1 mRNA and protein decreased. Parecoxib reduced urine output 1 day after release of BUO, but sodium excretion and glomerular filtration rate were unchanged. Parecoxib normalized urinary PGE(2) and PGI(2) excretion and attenuated downregulation of AQP2 and AQP3, while phosphorylated AQP2 and NKCC2 remained suppressed. Parecoxib did not improve urine-concentrating capacity in response to 24 h of water deprivation. We conclude that decreased NKCC2 and collapse of the IM osmotic gradient, together with suppressed phosphorylated AQP2, are likely causes for the impaired urine-concentrating capacity and that COX-2 activity is not likely to mediate these changes in the chronic postobstructive phase after ureteral obstruction. PMID:17229676

Nørregaard, Rikke; Jensen, Boye L; Topcu, Sukru Oguzkan; Diget, Maria; Schweer, Horst; Knepper, Mark A; Nielsen, Søren; Frøkiaer, Jørgen

2007-01-16

202

Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna.  

PubMed

Anti-inflammatory drugs are widely used to manage pain associated with stress fractures (SFxs), but little is known about their effects on healing of those injuries. We hypothesized that selective and non-selective anti-inflammatory treatments would retard the healing of SFx in the rat ulna. SFxs were created by cyclic loading of the ulna in Wistar rats. Ulnae were harvested 2, 4 or 6 weeks following loading. Rats were treated with non-selective NSAID, ibuprofen (30 mg/kg/day); selective COX-2 inhibition, [5,5-dimethyl-3-3 (3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone] (DFU) (2.0 mg/kg/day); or the novel c5a anatagonist PMX53 (10 mg/kg/day, 4 and 6 weeks only); with appropriate vehicle as control. Quantitative histomorphometric measurements of SFx healing were undertaken. Treatment with the selective COX-2 inhibitor, DFU, reduced the area of resorption along the fracture line at 2 weeks, without affecting bone formation at later stages. Treatment with the non-selective, NSAID, ibuprofen decreased both bone resorption and bone formation so that there was significantly reduced length and area of remodeling and lamellar bone formation within the remodeling unit at 6 weeks after fracture. The C5a receptor antagonist PMX53 had no effect on SFx healing at 4 or 6 weeks after loading, suggesting that PMX53 would not delay SFx healing. Both selective COX-2 inhibitors and non-selective NSAIDs have the potential to compromise SFx healing, and should be used with caution when SFx is diagnosed or suspected. PMID:22847634

Kidd, Lisa J; Cowling, Nick R; Wu, Andy C; Kelly, Wendy L; Forwood, Mark R

2012-07-30

203

COX1 and COX2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: An in vitro analysis  

Microsoft Academic Search

We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone

C. Beretta; G. Garavaglia; M. Cavalli

2005-01-01

204

COX-2 is not required for the development of murine chronic pancreatitis.  

PubMed

Chronic pancreatitis is a severe inflammation of the pancreas associated with destruction of the parenchyma, fibrosis, and persistent abdominal pain. Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins, key mediators of the inflammatory response, are elevated in patients with chronic pancreatitis. Previous studies investigated COX-2 as a therapeutic target. These reports showed a reduced pathology in COX-2-deficient mice with a better outcome. Here we compared the role of COX-2 in acute and chronic pancreatic inflammation using the same COX-2(-/-) mouse model of cerulein-induced pancreatitis. In a setting of acute pancreatitis, juvenile COX-2(-/-) mice exhibited a reduced histopathological score compared with wild-type littermates; on the contrary, adult mice did not show any difference in the development of the disease. Similarly, in a setting of chronic pancreatitis induced over a period of 4 wk, adult mice of the two strains showed comparable histological score and collagen deposition. However, the abundance of mRNAs coding for profibrotic genes, such as collagen, ?-smooth muscle actin, and transforming growth factor-? was consistently lower in COX-2(-/-) mice. In addition, comparable histological scores and collagen deposition were observed in wild-type mice treated with a COX-2 inhibitor. We conclude that, in contrast to what was observed in the rat pancreatitis models, COX-2 has a limited and age-dependent effect on inflammatory processes in the mouse pancreas. These results suggest that COX-2 modulates the inflammatory process during the development of pancreatitis in a species-specific manner. Thus the pathophysiological roles of COX-2 and its therapeutic implications in patients with pancreatitis should be reexamined. PMID:21372163

Silva, Alberto; Weber, Achim; Bain, Martha; Reding, Theresia; Heikenwalder, Mathias; Sonda, Sabrina; Graf, Rolf

2011-03-03

205

The use of Cox-2 and PPAR? signaling in anti-cancer therapies  

PubMed Central

Increased production of the pro-inflammatory enzyme cyclooxygenase-2 (Cox-2) and altered expression and activity of peroxisome proliferator-activated receptor ? (PPAR?) have been observed in many malignancies. Both the PPAR? ligands and the Cox-2 inhibitors possess anti-inflammatory and anti-neoplastic effects in vitro and have been assessed for their therapeutic potential in several pre-clinical and clinical studies. Recently, multiple interactions between PPAR? and Cox-2 signaling pathways have been revealed. Understanding of the cross-talk between PPAR? and Cox-2 might provide important novel strategies for the effective treatment and/or prevention of cancer. This article summarizes recent achievements involving the functional interactions between the PPAR? and Cox-2 signaling pathways and discusses the implications of such interplay for clinical use.

KNOPFOVA, LUCIA; SMARDA, JAN

2010-01-01

206

The HMGA1-COX-2 axis: A key molecular pathway and potential target in pancreatic adenocarcinoma  

PubMed Central

Context Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions. Methods Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activated K-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis. Results HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r2=0.93; p<0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels of HMGA1. Conclusions Our studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.

Hillion, Joelle; Smail, Shamayra S.; Di Cello, Francescopaolo; Belton, Amy; Shah, Sandeep; Huso, Tait; Schuldenfrei, Andrew; Nelson, Dwella Moton; Cope, Leslie; Campbell, Nathaniel; Karikari, Collins; Aderinto, Abimbola; Maitra, Anirban; Huso, David L.; Resar, Linda M. S.

2012-01-01

207

A role for COX2-derived PGE2 and PGE2-receptor subtypes in head and neck squamous carcinoma cell proliferation  

PubMed Central

The overexpression of cyclooxygenase (COX)-2 is a frequent event in squamous cell carcinomas of the head and neck (HNSCC), and non-steroidal anti-inflammatory drugs, which are potent inhibitors of COX-1 and COX-2, exert chemopreventive effects on HNSCC cancer development. COX-2 promotes the release of the pro-inflammatory mediator prostaglandin E2 (PGE2), which acts on its cell surface G protein-coupled receptors EP1, EP2, EP3, and EP4. Here, we investigated the role of PGE2 and its receptors in cellular proliferation in HNSCC. The expression of COX-2 and EP1-4 was examined in immortalized oral epithelial cells and in a representative panel of HNSCC cell lines, and based on these data EP1-EP3 and COX-2 expression were evaluated by immunohistochemistry in a large clinical sample collection using HNSCC tissue microarrays. The ability of selective COX-2 inhibition to block PGE2 secretion was measured by ELISA specific assays. The effects of PGE2 on cell proliferation were evaluated using PGE2, its stable analog, and EP2 and EP3-specific synthetic agonists. The results presented here show that HNSCC tumoral lesions and their derived cell lines constitutively express COX-2 and the EP1, EP2 and EP3 receptors for PGE2. HNSCC cells secrete PGE2, which can be suppressed by low concentrations of COX-2 selective inhibitors, without inhibiting cell proliferation. Exogenously added stable PGE2 and EP3-specific agonists induce DNA synthesis in all HNSCC cell lines tested. Overall, our study supports the emerging notion that PGE2 produced in the tumor microenvironment by the overexpression of COX-2 in tumoral and inflammatory cells may promote the growth of HNSCC cells in an autocrine and paracrine fashion by acting on PGE2 receptors that are widely expressed in most HNSCC cancer cells. In particular, our findings suggest that EP3 receptor may play a more prominent role in HNSCC cell growth promotion, thus providing a rationale for the future evaluation of this PGE2 receptor as a target for HNSCC prevention strategies.

ABRAHAO, Aline Correa; CASTILHO, Rogerio M.; SQUARIZE, Cristiane H.; MOLINOLO, Alfredo A.; dos SANTOS-PINTO, Decio; GUTKIND, J. Silvio

2010-01-01

208

Involvement of COX-2/PGE2 Pathway in the Upregulation of MMP-9 Expression in Pancreatic Cancer  

PubMed Central

COX-2 and MMP-9 have been reported to show an overexpression in pancreatic cancer, and thus an attempt to explore the correlation between them has become a target of this study. Besides, PGE2, a product of COX-2, was also under research as to whether it is involved in the upregulation of MMP-9 expression by COX-2. Expression of COX-2 and MMP-9 mRNA varied in pancreatic adenocarcinomas, and the mRNA level of COX-2 was correlated positively with MMP-9. Both BxPC-3 and Capan-1 cells had strong expression of COX-2 and MMP-9. MMP-9 expression was downregulated significantly in BxPC-3 and Capan-1 cells after treatment with COX-2 inhibitors or COX-2 siRNA plasmids, and upregulated in BxPC-3 significantly by exogenous TNF-?, LPS or PGE2. The upregulation of MMP-9 by TNF-? or LPS was inhibited by COX-2 inhibitor NS398. There was a significant increase in the migration of BxPC-3 cells with TNF-?, LPS, or PGE2 treatment; however, the increase caused by TNF-? or LPS was also inhibited remarkably by NS398. Our findings demonstrated that COX-2 upregulates MMP-9 expression in pancreatic cancer, and PGE2 may be involved in it.

Bu, Xianmin; Zhao, Chenghai; Dai, Xianwei

2011-01-01

209

Heterotypic contact reveals a COX-2-mediated suppression of osteoblast differentiation by endothelial cells: A negative modulatory role for prostanoids in VEGF-mediated cell: cell communication?  

SciTech Connect

In bone, angiogenesis must be initiated appropriately, but limited once remodelling or repair is complete. Our recent findings have supported a role for prostaglandins (PG), known modulators of osteoblast (OB) and endothelial cell (EC) behaviour, in facilitating VEGF-mediated paracrine communication from OBs to 'remotely located' ECs, but the mechanism(s) regulating OB:EC crosstalk when these cells are closely opposed are undefined. In this study we have examined: (i) the effects of exogenous PGE{sub 2} on VEGF-driven events in ECs, and (ii) the role of endogenous COX-2-derived prostanoids in mediating communication between intimately opposed OBs and ECs in direct contact. Exposure of ECs to PGE{sub 2} increased ERK1/2 phosphorylation, COX-2 induction, 6-keto-PGF{sub 1{alpha}} release and EC proliferation. In contrast, PGE{sub 2} attenuated VEGF{sub 165}-induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, suggesting that exogenous PGE{sub 2} restricts the actions of VEGF. However, the COX-2-selective inhibitor, NS398, also attenuated VEGF-induced proliferation, implying a distinct role for endogenous COX-2 activity in regulating EC behaviour. To examine the effect of OB:EC proximity and the role of COX-2 products further, we used a confrontational co-culture model. These studies showed that COX-2 blockade with NS398 enhanced EC-dependent increases in OB differentiation, that this effect was reversed by exogenous PGH{sub 2} (immediate COX-2 product), and that exogenous VEGF did not influence EC-dependent OB differentiation under these conditions. Our findings indicate that locally produced prostanoids may serve distinct roles depending on OB:EC proximity and negatively modulate VEGF-mediated changes in EC behaviour when these cells are closely opposed to control angiogenesis during bone (re)modelling.

Clarkin, Claire E. [Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU (United Kingdom)], E-mail: claire.clarkin@kcl.ac.uk; Garonna, Elena; Pitsillides, Andrew A.; Wheeler-Jones, Caroline P.D. [Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU (United Kingdom)

2008-10-15

210

Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on ovarian carcinoma in vivo.  

PubMed

The present study was designed to investigate the combined effects of cyclooxygenase (COX)-1 and COX-2 selective inhibitors on human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone, 25 mg/kg celecoxib (a COX-2 selective inhibitor) alone, or SC-560/celecoxib by gavage, twice a day for three weeks. To test the mechanism of inhibition of tumor growth by COX selective inhibitors, the index of proliferating cells in tumor tissues was determined by immunostaining and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. The inhibitory rate on tumor growth in the combination group was 35.54% which is significant statistically compared with that of the control group (P < 0.05). In the combination group, the index of cell proliferation and apoptosis were 12.40% and 51.03% respectively, which are significant statistically compared with those of the control group (22.56%, 19.07%, all P < 0.05). These studies indicate that synergism between two COX inhibitors and inhibitor combination treatment has particular potential for chemoprevention of ovarian cancer growth. PMID:21340007

Li, Wei; Wang, Jie; Jiang, Hong-Ru; Xu, Xiao-Li; Zhang, Jun; Liu, Mei-Lin; Zhai, Ling-Yun

2011-01-18

211

Modulation of COX2 expression by statins in human monocytic cells  

Microsoft Academic Search

Macrophage cyclooxygenase-2 (COX-2) plays an important role in prostaglandin E2 and throm- boxane A2 production. Statins are inhibitors of HMG CoA (3-Hydroxy-3-methylglutaryl coenzyme A) reduc- tases and cholesterol synthesis, which block the expres- sion of several inflammatory proteins independent of their capacity to lower endogenous cholesterol. In the present study, we investigated the effect of simvastatin and mevastatin on COX-2

Aida Habib; Ishraq Shamseddeen; Mona S. Nasrallah; Tania Abi Antoun; Georges Nemer; Jacques Bertoglio; Rami Badreddine; Kamal F. Badr

2007-01-01

212

The clinical pharmacology of cyclooxygenase-2-selective and dual inhibitors.  

PubMed

Over the past decade, there have been several nonsteroidal anti-inflammatory drugs (NSAIDS) introduced in veterinary medicine with an increased gastrointestinal safety profile consistent with a cyclooxygenase (COX)-1-sparing effect. More recently, an NSAID with additional 5-lipoxygenase (5-LOX) activity has also been approved for use. Although it is tempting to equate in vitro COX-2/COX-1 and 5-LOX inhibition to overall in vivo safety, the data do not support this approach. The true overall safety for any individual compound is based on its evaluation in laboratory margin-of-safety studies, reproductive safety studies, and blind multicenter field studies in client-owned animals. Therefore, when choosing a COX-2-selective or dual-inhibitor NSAID for clinical use, all in vivo data must be taken into account to understand comparative safety, and continued use must be based on the drug's performance in the individual being treated. Until head-to-head trials in multicenter blind studies are published, comments on comparative safety and effectiveness must be reserved. PMID:16984827

Clark, Terrence P

2006-09-01

213

Molecular Dynamics Simulations of Arachidonic Acid-Derived Pentadienyl Radical Intermediate Complexes with COX-1 and COX-2  

PubMed Central

The two cyclooxygenase enzymes, COX-1 and COX-2, are responsible for the committed step in prostaglandin biosynthesis, and are the targets of the non-steroidal anti-inflammatory drugs aspirin, ibuprofen and the COX-2 selective inhibitors, Celebrex™, Vioxx™ and Bextra™. The enzymes are remarkable in that they catalyze two dioxygenations and two cyclizations of the native substrate, arachidonic acid, with near absolute regio- and stereoselectivity. Several theories have been advanced to explain the nature of enzymatic control over this series of reactions, including suggestions of steric shielding and oxygen channeling. As proposed here, selective radical trapping and spin localization in the substrate-derived pentadienyl radical intermediate can also be envisioned. Herein we describe the results of explicit, 10 ns molecular dynamics simulations of both COX-1 and COX-2 with the substrate-derived pentadienyl radical intermediate bound in the active site. The enzymes’ influence on the conformation of the pentadienyl radical was investigated, along with the accessible space above and below the radical plane, and the width of several channels to the active site that could function as access routes for molecular oxygen. Additional simulations demonstrated the extent of molecular oxygen mobility within the active site. The results suggest that spin localization is unlikely to play a role in enzymatic control of this reaction. Instead, a combination of oxygen channeling, steric shielding and selective radical trapping appears to be responsible. This work adds a dynamic perspective to the strong foundation of static structural data available for these enzymes.

Furse, Kristina E.; Pratt, Derek A.; Schneider, Claus; Brash, Alan R.; Porter, Ned A.; Lybrand, Terry P.

2008-01-01

214

Novel selective COX-1 inhibitors suppress neuroinflammatory mediators in LPS-stimulated N13 microglial cells.  

PubMed

COX-1 plays a previously unrecognized part in the neuroinflammation. Genetic ablation or pharmacological inhibition of COX-1 activity attenuates the inflammatory response and neuronal loss. In this context, the effects of selective COX-1 inhibitors (P6, P10, SC-560, aspirin) and coxibs (celecoxib and etoricoxib) on LPS-stimulated microglial cell function (a worldwide accepted neuroinflammation model) were investigated, and the effects on COX-1/COX-2, cPGES mRNA and iNOS expression, PGE(2) and NO production and NF-?B activation by I?B? phosphorylation were evaluated. The total suppression of the expression of both COX-1 and COX-2 by their respective selective inhibitors occurred. NF-?B remained almost completely inactive in the presence of coxibs, as expected, and totally inactive in the presence of P6. P6 also markedly counteracted LPS enhancing cPGES mRNA expression and PGE(2) production. Since COX-1 is predominantly localized in microglia, its high selective inhibition rather than COX-2 (by coxibs) is more likely to reduce neuroinflammation and has been further investigated as a potential therapeutic approach and prevention in neurodegenerative diseases with a marked inflammatory component. PMID:22001217

Calvello, Rosa; Panaro, Maria Antonietta; Carbone, Maria Luigia; Cianciulli, Antonia; Perrone, Maria Grazia; Vitale, Paola; Malerba, Paola; Scilimati, Antonio

2011-10-01

215

COX-2 verexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy  

SciTech Connect

Purpose: To determine the utility of COX-2 expression as a response predictor for patients with rectal cancer who are undergoing neoadjuvant radiochemotherapy (RCT). Methods and Materials: Pretreatment biopsies (PTB) from 49 patients who underwent RCT were included. COX-2 and proliferation in PTB were assessed by immunohistochemistry (IHC) and apoptosis was detected by TUNEL stain. Response to treatment was assessed by a 5-point tumor-regression grade (TRG) based on the ratio of residual tumor to fibrosis. Results: Good response (TRG 1 + 2), moderate response (TRG 3), and poor response (TRG 4 + 5) were seen in 21 patients (42%), 11 patients (22%), and 17 patients (34%), respectively. Patients with COX-2 overexpression in PTB were more likely to demonstrate moderate or poor response (TRG 3 + 4) to treatment than were those with normal COX-2 expression (p = 0.026, chi-square test). Similarly, poor response was more likely if patients had low levels of spontaneous apoptosis in PTBs (p = 0.0007, chi-square test). Conclusions: COX-2 overexpression and reduced apoptosis in PTB can predict poor response of rectal cancer to RCT. As COX-2 inhibitors are commercially available, their administration to patients who overexpress COX-2 warrants assessment in clinical trials in an attempt to increase overall response rates.

Smith, Fraser M. [Departments of Surgery and Histopathology, and Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland); Reynolds, John V. [Departments of Surgery and Histopathology, and Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland)]. E-mail: reynoldsjv@stjames.ie; Kay, Elaine W. [Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin (Ireland); Crotty, Paul [Department of Histopathology, Adelaide and Meath Hospital, Tallaght, Dublin (Ireland); Murphy, James O. [Departments of Surgery and Histopathology, and Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland); Hollywood, Donal [Departments of Surgery and Histopathology, and Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland); Gaffney, Eoin F. [Departments of Surgery and Histopathology, and Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland); Stephens, Richard B. [Departments of Surgery and Histopathology, and Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland); Kennedy, M. John [Departments of Surgery and Histopathology, Academic Unit of Clinical and Molecular Oncology, St. James's Hospital, Dublin (Ireland)

2006-02-01

216

Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism  

SciTech Connect

Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by {gamma}H{sub 2}AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observed radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual {gamma}H2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2.

Dittmann, Klaus H. [Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen (Germany)], E-mail: klaus.dittmann@uni-tuebingen.de; Mayer, Claus; Ohneseit, Petra A. [Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen (Germany); Raju, Uma [Department of Experimental Radiation Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX (United States); Andratschke, Nickolaus H. [Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Klinikum Rechts Der Isar, Technische Universitaet Muenchen, Munich (Germany); Milas, Luka [Department of Experimental Radiation Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX (United States); Rodemann, H. Peter [Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen (Germany)

2008-01-01

217

Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention.  

PubMed

A recent meta-analysis examining long-term mortality in subjects who participated in controlled studies evaluating the impact of daily aspirin on vascular risk, has concluded that aspirin confers substantial protection from cancer mortality. Remarkably, low-dose aspirin was as effective as higher-dose regimens; hence this protection may be achievable with minimal risk. There is reason to believe that this protection stems primarily from inhibition of cox-2 in pre-neoplastic lesions. Since safe aspirin regimens can only achieve a partial and transitory inhibition of cox-2, it may be feasible to complement the cancer-protective benefit of aspirin with other measures which decrease cox-2 expression or which limit the bioactivity of cox-2-derived PGE2. Oxidative stress boosts cox-2 expression by up-regulating activation of NF-kappaB and MAP kinases; NADPH oxidase activation may thus promote carcinogenesis by increasing cox-2 expression while also amplifying oxidant-mediated mutagenesis. A prospective cohort study has observed that relatively elevated serum bilirubin levels are associated with a marked reduction in subsequent cancer mortality; this may reflect bilirubin's physiological role as a potent inhibitor of NADPH oxidase. It may be feasible to mimic this protective effect by supplementing with spirulina, a rich source of a phycobilin which shares bilirubin's ability to inhibit NADPH oxidase. Ancillary antioxidant measures - phase 2 inducing phytochemicals, melatonin, N-acetylcysteine, and astaxanthin - may also aid cox-2 down-regulation. The cancer protection often associated with high-normal vitamin D status may be attributable, in part, to the ability of the activated vitamin D receptor to decrease cox-2 expression while promoting PGE2 catabolism and suppressing the expression of PGE2 receptors. Diets with a relatively low ratio of omega-6 to long-chain omega-3 fats may achieve cancer protection by antagonizing the production and bioactivity of PGE2. Growth factors such as IGF-I increase cox-2 expression by several complementary mechanisms; hence, decreased cox-2 activity may play a role in the remarkably low mortality from "Western" cancers enjoyed by Third World cultures in which systemic growth factor activity was minimized by quasi-vegan diets complemented by leanness and excellent muscle insulin sensitivity. Practical strategies for achieving a modest degree of calorie restriction may also have potential for down-regulating cox-2 expression while decreasing cancer risk. Soy isoflavones, linked to reduced cancer risk in Asian epidemiology, may suppress cox-2 induction by activating ERbeta. In aggregate, these considerations suggest that a comprehensive lifestyle strategy targeting cox-2 expression and bioactivity may have tremendous potential for cancer prevention. PMID:22001128

McCarty, Mark F

2011-10-15

218

Design, synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors.  

PubMed

A new series of ketoprofen analogs were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were potent and selective inhibitors of the COX-2 isozyme with IC(50) values in the highly potent 0.057-0.085 microM range, and COX-2 selectivity indexes in the 115 to >1298.7 range. Compounds possessing azido pharmacophore group (8a and 8b) exhibited highly COX-2 inhibitory selectivity and potency even more than reference drug celecoxib. Molecular modeling studies indicated that the azido substituent can be inserted deeply into the secondary pocket of COX-2 active site for interactions with Arg(513). PMID:20650641

Zarghi, Afshin; Ghodsi, Razieh

2010-07-03

219

Selective cyclooxygenase-2 inhibitor suppresses renal thromboxane production but not proliferative lesions in the MRL/lpr murine model of lupus nephritis  

PubMed Central

Background Proliferative lupus nephritis (LN) is marked by increased renal thromboxane (TXA2) production. Targeting the TXA2 receptor or TXA2 synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: 1) TXA2 production in the MRL/MpJ-Tnfrsf6lpr/J (MRL/lpr) model of proliferative lupus nephritis is COX2-dependent, and 2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response, and glomerular pathology. Methods 20 female MRL/lpr and 20 BALB/cJ mice were divided into two equal treatment groups: 1) SC-236, a moderately selective COX2 inhibitor, or 2) vehicle. After treatment from 10 to 20 weeks of age, the effectiveness of inhibition of TXA2 was determined by measuring urine TXB2. Response endpoints measured at 20 weeks of age were renal function (GFR), proteinuria, urine nitrate + nitrite (NOX), and glomerular histopathology. Results SC236 therapy reduced surrogate markers of renal TXA2 production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NOX) during therapy were observed. However, the beneficial effect of SC236 therapy on GFR was only transient, and renal histopathology was not improved in late disease. Conclusions These data demonstrate that renal TXA2 production is COX2-dependent in murine LN and suggest that NO production is directly or indirectly COX2-dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN.

Oates, Jim C.; Halushka, Perry V.; Hutchison, Florence N.; Ruiz, Philip; Gilkeson, Gary S.

2010-01-01

220

Cross talk between PKC and CREB in the induction of COX-2 by PGF2? in human amnion fibroblasts.  

PubMed

Compelling evidence indicates a crucial role of prostaglandin F2? (PGF2?) in parturition. Both the maternal and fetal sides of the fetal membranes synthesize PGF2?, which exerts effects via the prostaglandin F2? receptor (FP) that is coupled to the activation of protein kinase C (PKC). Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step of the inducible synthesis of prostaglandin. Although activation of PKC is known to induce COX-2 expression, it is not clear whether PGF2? can induce COX-2 via FP receptor-coupled PKC activation. COX-2 promoter carries a cAMP-response element (CRE) and phosphorylation of CRE binding protein 1 (CREB1) is associated with COX-2 expression in human amnion fibroblasts. We demonstrated that human amnion fibroblasts produced PGF2? and expressed FP receptor. PGF2? increased COX-2 expression and CREB1 phosphorylation, which could be blocked by either the FP receptor antagonist AL8810 or PKC inhibitor Ro31-7549. The PKC activator, phorbol-12-myristate-13-acetate (PMA), could mimic the induction of COX-2 and CREB1 phosphorylation. The induction of COX-2 by PGF2? and PMA could be attenuated by the small interfering RNA-mediated knockdown of CREB1 expression or overexpressing dominant-negative CREB1. A chromatin immunoprecipitation assay showed that the binding of CREB1 to the COX-2 promoter was increased by PGF2? and PMA in amnion fibroblasts. In conclusion, we provide evidence that PGF2? induces COX-2 expression via the FP receptor and phosphorylates CREB1 by PKC, thus increasing CREB1 binding to the COX-2 promoter and the expression of COX-2 in human amnion fibroblasts. This feed-forward loop may be crucial for the production of prostaglandins in the fetal membranes prior to the onset of labor. PMID:22919060

Guo, C M; Kasaraneni, N; Sun, K; Myatt, L

2012-08-23

221

Cross Talk between PKC and CREB in the Induction of COX-2 by PGF2? in Human Amnion Fibroblasts  

PubMed Central

Compelling evidence indicates a crucial role of prostaglandin F2? (PGF2?) in parturition. Both the maternal and fetal sides of the fetal membranes synthesize PGF2?, which exerts effects via the prostaglandin F2? receptor (FP) that is coupled to the activation of protein kinase C (PKC). Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step of the inducible synthesis of prostaglandin. Although activation of PKC is known to induce COX-2 expression, it is not clear whether PGF2? can induce COX-2 via FP receptor-coupled PKC activation. COX-2 promoter carries a cAMP-response element (CRE) and phosphorylation of CRE binding protein 1 (CREB1) is associated with COX-2 expression in human amnion fibroblasts. We demonstrated that human amnion fibroblasts produced PGF2? and expressed FP receptor. PGF2? increased COX-2 expression and CREB1 phosphorylation, which could be blocked by either the FP receptor antagonist AL8810 or PKC inhibitor Ro31-7549. The PKC activator, phorbol-12-myristate-13-acetate (PMA), could mimic the induction of COX-2 and CREB1 phosphorylation. The induction of COX-2 by PGF2? and PMA could be attenuated by the small interfering RNA-mediated knockdown of CREB1 expression or overexpressing dominant-negative CREB1. A chromatin immunoprecipitation assay showed that the binding of CREB1 to the COX-2 promoter was increased by PGF2? and PMA in amnion fibroblasts. In conclusion, we provide evidence that PGF2? induces COX-2 expression via the FP receptor and phosphorylates CREB1 by PKC, thus increasing CREB1 binding to the COX-2 promoter and the expression of COX-2 in human amnion fibroblasts. This feed-forward loop may be crucial for the production of prostaglandins in the fetal membranes prior to the onset of labor.

Guo, C. M.; Kasaraneni, N.

2012-01-01

222

BMP9 and COX-2 form an important regulatory loop in BMP9-induced osteogenic differentiation of mesenchymal stem cells.  

PubMed

Mesenchymal stem cells (MSCs) can self-renew and differentiate into osteogenic, chondrogenic, adipogenic and myogenic lineages. It's reported that bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic BMPs to initiate the commitment of MSCs to osteoblast lineage. Cyclooxygenase-2 (COX-2) is critical for bone fracture healing and osteogenic differentiation in MSCs. However, the relationship between COX-2 and BMP9 in osteogenesis remains unknown. Herein, we investigate the role of COX-2 in BMP9-induced osteogenesis in MSCs. We demonstrate that COX-2 is up-regulated as a target of BMP9 in MSCs. Both COX-2 inhibitor (NS-398) and COX-2 knockdown siRNAs can effectively decrease alkaline phosphatase (ALP) activities induced by BMP9 in MSCs. NS-398 also down-regulates BMP9-induced expression of osteopontin and osteocalcin, so does the matrix mineralization. The in vivo studies indicate that knockdown of COX-2 attenuates BMP9-induced ectopic bone formation. In perinatal limb culture assay, NS-398 is shown to reduce the hypertropic chondrocyte zone and ossification induced by BMP9. Mechanistically, knockdown of COX-2 significantly inhibits the BMP9 up-regulated expression of Runx2 and Dlx-5 in MSCs, which can be rescued by exogenous expression of COX-2. Furthermore, knockdown of COX-2 apparently reduces BMP9 induced BMPR-Smad reporter activity, the phosphorylation of Smad1/5/8, and the expression of Smad6 and Smad7 in MSCs. NS-398 blocks the expression of BMP9 mediated by BMP9 recombinant adenovirus. Taken together, our findings suggest that COX-2 plays an important role in BMP9 induced osteogenic differentiation in MSCs; BMP9 and COX-2 may form an important regulatory loop to orchestrate the osteogenic differentiation in MSCs. PMID:23981660

Wang, Jin-Hua; Liu, Ying-Zi; Yin, Liang-Jun; Chen, Liang; Huang, Jun; Liu, Yang; Zhang, Ran-Xi; Zhou, Long-Yang; Yang, Qiu-Jun; Luo, Jin-Yong; Zuo, Guo-Wei; Deng, Zhong-Liang; He, Bai-Cheng

2013-08-24

223

Involvement of MAPK activation in chemokine or COX-2 productions by Toxoplasma gondii  

PubMed Central

This experiment focused on MAPK activation in host cell invasion and replication of T. gondii, as well as the expression of CC chemokines, MCP-1 and MIP-1?, and enzyme, COX-2/prostaglandin E2 (PGE2) in infected cells via western blot, [3H]-uracil incorporation assay, ELISA and RT-PCR. The phosphorylation of ERK1/2 and p38 in infected HeLa cells was detected at 1 hr and/or 6 hr postinfection (PI). Tachyzoite proliferation was reduced by p38 or JNK MAPK inhibitors. MCP-1 secretion was enhanced in infected peritoneal macrophages at 6 hr PI. MIP-1? mRNA was increased in macrophages at 18 hr PI. MCP-1 and MIP-1? were reduced after treatment with inhibitors of ERK1/2 and JNK MAPKs. COX-2 mRNA gradually increased in infected RAW 264.7 cells and the secretion of COX-2 peaked at 6 hr PI. The inhibitor of JNK suppressed COX-2 expression. PGE2 from infected RAW 264.7 cells was increased and synthesis was suppressed by PD98059, SB203580, and SP600125. In this study, the activation of p38, JNK and/or ERK1/2 MAPKs occurred during the invasion and proliferation of T. gondii tachyzoites in HeLa cells. Also, increased secretion and expression of MCP-1, MIP-1?, COX-2 and PGE2 were detected in infected macrophages, and appeared to occur via MAPK signaling pathways.

Kim, Ji-Young; Song, Hyun-Ouk; Choi, Jong-Hak; Ryu, Jae-Sook; Min, Duk-Young; Cho, Myung-Hwan

2006-01-01

224

Effects of selective cyclooxygenase inhibitors on ischemia/reperfusion-induced hepatic microcirculatory dysfunction in mice.  

PubMed

We examined the effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-alpha also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-alpha. Moreover, the effects of the thromboxane (TX) A(2) (TXA(2)) synthase inhibitor OKY-046 and the TXA(2) receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-alpha production, and that TXs derived from COX are partly responsible for I/R-induced liver injury. PMID:12928598

Ito, Y; Katagiri, H; Ishii, K; Kakita, A; Hayashi, I; Majima, M

225

Human fecal water inhibits COX-2 in colonic HT-29 cells: role of phenolic compounds.  

PubMed

The inducible enzyme cyclooxygenase-2 (COX-2) plays a major role in the regulation of inflammation and possibly in the development of colon cancer. The aim of the present study was to screen for COX-2 inhibitors in samples of fecal water (the aqueous phase of feces) and investigate whether phenolic compounds are responsible for any observed effects on COX-2. Volunteers (n = 20) were recruited and asked to supply a 24-h stool sample. Fecal water samples were prepared and analyzed by GC-MS for their content of phenolic compounds. These samples were also evaluated for their effects on COX-2 protein levels (Western blot) and prostaglandin (PG)E2 production in tumor necrosis-alpha-stimulated HT-29 cells and pure enzymatic activity in a COX-2-catalyzed prostaglandin biosynthesis in vitro assay. The major phenolic compounds identified were phenylpropionic acid, phenylacetic acid, cinnamic acid, and benzoic acid derivatives. Of 13 fecal water samples analyzed, 12 significantly decreased PGE2 production (range 5.4-39.7% inhibition, P-value < 0.05) compared with control cells and 13 of 14 samples analyzed decreased COX-2 protein levels in HT-29 cells (19-63% inhibition). Of the 20 fecal water samples, 2 also weakly inhibited enzymatic activity of purified COX-2 (22-24% inhibition). Three compounds identified in fecal water, 3-phenylpropionic acid, 3-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)-propionic acid, decreased the protein level at 250 micromol/L (15-62% inhibition). This study shows for the first time that human fecal water contains components that can affect both the COX-2 protein level and enzymatic activity. PMID:16177193

Karlsson, Pernilla C; Huss, Ulrika; Jenner, Andrew; Halliwell, Barry; Bohlin, Lars; Rafter, Joseph J

2005-10-01

226

Soman Increases Neuronal COX-2 Levels: Possible Link between Seizures and Protracted Neuronal Damage  

PubMed Central

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4 hr to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity.

Angoa-Perez, Mariana; Kreipke, Christian W.; Thomas, David M.; Van Shura, Kerry E.; Lyman, Megan; McDonough, John H.; Kuhn, Donald M.

2010-01-01

227

Up-regulation of p53 and mitochondrial signaling pathway in apoptosis by a combination of cox-2 inhibitor, celecoxib and dolastatin 15, a marine mollusk linear peptide in experimental colon carcinogenesis.  

PubMed

Programmed cell death, also known as apoptosis, is an active process occurring in eukaryotic cells and it depends on various sets of pro and anti-apoptotic proteins. Chemoprevention of colorectal cancer can be achieved by inducing apoptosis using synthetic compound, Celecoxib and natural peptide, Dolastatin 15 in an effective manner. But the apoptotic signaling by these two drugs remain unclear. The present study was thus focused on the role of Bcl2 family of proteins and their interplay with p53 in rats during the chemoprevention by these two drugs. After treatment for 6?wk with 1, 2-dimethylhydrazine (DMH), animals showed a marked occurrence of multiple plaque lesions. However, a simultaneous treatment with Celecoxib and Dolastatin 15 decreases such number to a significant level. DMH treatment also decreases the number of apoptotic cells in the colonic enterocytes which were corrected to the normal level by Celecoxib and Dolastatin 15. An increased expression of Bcl2 while other proteins like Bax, Apaf-1, cyt c, and caspases in the apoptotic pathway, and the tumor suppressor proteins, p53 and p21 get down-regulated after DMH treatment which were reverted back to normal with Celecoxib and Dolastatin 15. Also, cells having high mitochondrial membrane potential had been seen to increase to significant levels which were reduced after the administration of these anti-inflammatory drugs. In silico molecular docking studies also showed that Dolastatin 15 and Celecoxib may bind to the active site pocket of Bcl2 , thus revealing the direct target of Dolastatin 15 and Celecoxib apart from binding to COX-2. Copyright © 2012 Wiley Periodicals, Inc. PMID:22623379

Piplani, Honit; Vaish, Vivek; Rana, Chandan; Sanyal, Sankar N

2012-05-23

228

Paradoxical effects of a selective cyclooxygenase-2 inhibitor, etodolac, on proliferative changes of forestomach in alloxan-induced diabetic rats  

Microsoft Academic Search

A single intravenous injection of alloxan, a non-genotoxic diabetogenic chemical, induces proliferative changes in forestomach mucosa of rats, and some lesions progress to squamous cell carcinoma accompanied with inflammatory change. The present study was conducted to examine the effects of a selective cyclooxygenase-2 (COX-2) inhibitor, etodolac, on the proliferative changes of forestomach mucosa in alloxan-induced diabetic rats. Alloxan-induced diabetic rats

Tomoya Sano; Kiyokazu Ozaki; Yasushi Kodama; Tetsuro Matsuura; Isao Narama

2009-01-01

229

Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study  

PubMed Central

Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting. Methods We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls. Results Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk. Conclusions Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.

2010-01-01

230

Pharmacodynamic of cyclooxygenase inhibitors in humans.  

PubMed

We provide comprehensive knowledge on the differential regulation of expression and catalysis of cyclooxygenase (COX)-1 and COX-2 in health and disease which represents an essential requirement to read out the clinical consequences of selective and nonselective inhibition of COX-isozymes in humans. Furthermore, we describe the pharmacodynamic and pharmacokinetic characteristics of major traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and coxibs (selective COX-2 inhibitors) which play a prime role in their efficacy and toxicity. Important information derived from our pharmacological studies has clarified that nonselective COX inhibitors should be considered the tNSAIDs with a balanced inhibitory effect on both COX-isozymes (exemplified by ibuprofen and naproxen). In contrast, the tNSAIDs meloxicam, nimesulide and diclofenac (which are from 18- to 29-fold more potent towards COX-2 in vitro) and coxibs (i.e. celecoxib, valdecoxib, rofecoxib, etoricoxib and lumiracoxib, which are from 30- to 433-fold more potent towards COX-2 in vitro) should be comprised into the cluster of COX-2 inhibitors. However, the dose and frequency of administration together with individual responses will drive the degree of COX-2 inhibition and selectivity achieved in vivo. The results of clinical pharmacology of COX inhibitors support the concept that the inhibition of platelet COX-1 may translate into an increased incidence of serious upper gastrointestinal bleeding but this effect on platelet COX-1 may mitigate the cardiovascular hazard associated with the profound inhibition of COX-2-dependent prostacyclin (PGI2). PMID:17164136

Capone, Marta L; Tacconelli, Stefania; Di Francesco, Luigia; Sacchetti, Andrea; Sciulli, Maria G; Patrignani, Paola

2006-07-03

231

Essential structural profile of a dual functional inhibitor against cyclooxygenase-2 (COX2) and 5-lipoxygenase (5LOX): Molecular docking and 3D-QSAR analyses on DHDMBF analogues  

Microsoft Academic Search

It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX, both are key enzymes involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig out helpful information in designing dual functional inhibitors against the two enzymes, homology modeling, molecular dynamics (MD) simulations, automated docking, and 3D-QSAR analyses were

Mingyue Zheng; Zhenshan Zhang; Weiliang Zhu; Hong Liu; Xiaomin Luo; Kaixian Chen; Hualiang Jiang

2006-01-01

232

The effects of the short-term administration of low therapeutic doses of anti-COX-2 agents on the healing of fractures. An experimental study in rabbits.  

PubMed

We have evaluated the effect of the short-term administration of low therapeutic doses of modern COX-2 inhibitors on the healing of fractures. A total of 40 adult male New Zealand rabbits were divided into five groups. A mid-diaphyseal osteotomy of the right ulna was performed and either normal saline, prednisolone, indometacin, meloxicam or rofecoxib was administered for five days. Radiological, biomechanical and histomorphometric evaluation was performed at six weeks. In the group in which the highly selective anti-COX-2 agent, rofecoxib, was used the incidence of radiologically-incomplete union was similar to that in the control group. All the biomechanical parameters were statistically significantly lower in both the prednisolone and indometacin (p = 0.01) and in the meloxicam (p = 0.04) groups compared with the control group. Only the fracture load values were found to be statistically significantly lower (p = 0.05) in the rofecoxib group. Histomorphometric parameters were adversely affected in all groups with the specimens of the rofecoxib group showing the least negative effect. Our findings indicated that the short-term administration of low therapeutic doses of a highly selective COX-2 inhibitor had a minor negative effect on bone healing. PMID:17905969

Karachalios, T; Boursinos, L; Poultsides, L; Khaldi, L; Malizos, K N

2007-09-01

233

COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells  

PubMed Central

Epidemiological studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and reduced glioma risks in humans. Most NSAIDs function as cyclooxygenase-2 (COX-2) inhibitors that prevent production of prostaglandin E2 (PGE2). Since PGE2 induces expansion of myeloid-derived suppressor cells (MDSCs), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 in the TME along with numbers of CD11b+Ly6GhiLy6Clo granulocytic MDSCs in both the bone marrow and TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2-mediated accumulation in the TME, there were defects in these processes in glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immune suppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Lastly, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immune suppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSC and their accumulation in the TME, where they limit CTL infiltration.

Fujita, Mitsugu; Kohanbash, Gary; Fellows-Mayle, Wendy; Hamilton, Ronald L.; Komohara, Yoshihiro; Decker, Stacy A.; Ohlfest, John R.; Okada, Hideho

2011-01-01

234

Field Trial Validation of the Efficacy and Acceptability of Firocoxib, a Highly Selective Cox2 Inhibitor, in a Group of 96 Lame Horses  

Microsoft Academic Search

The objective was to generate evidence for clinical efficacy and acceptability of a second generation coxib, firocoxib, administered orally for 14 days to lame horses under field conditions compared with a classic nonsteroidal anti-inflammatory drug, vedaprofen, in a prospective, randomized, controlled, double-blinded, multicenter field trial. Ninety-six client-owned horses with American Association of Equine Practitioners score of at least grade 3

Marc Koene; Xavier Goupil; Clemens Kampmann; Peter D. Hanson; Davida Denton; Matthias G. Pollmeier

2010-01-01

235

Anti-inflammatory, cyclooxygenase (COX)-2, COX-1 inhibitory, and free radical scavenging effects of Rumex nepalensis.  

PubMed

Evaluation of the topical anti-inflammatory activity of chloroform and ethyl acetate extracts of RUMEX NEPALENSIS roots in a TPA-induced acute inflammation mouse model demonstrated a significant reduction in ear edema. The extracts were further tested on purified enzymes for COX-1 and COX-2 inhibition to elucidate their mechanism of action, and a strong inhibition was observed. Six anthraquinones and two naphthalene derivatives were isolated from the ethyl acetate extract. Among the isolated compounds, emodin was found to be a potent inhibitor with slight selectivity towards COX-2, and nepodin exhibited selectivity towards COX-1. Emodin, endocrocin, and nepodin also exhibited significant topical anti-inflammatory activity in mice. Interestingly, nepodin showed better radical scavenging activity than trolox and ascorbic acid against DPPH and ABTS radicals. The strong radical scavenging activity of chloroform and ethyl acetate extracts could be explained by the presence of nepodin as well as by the high phenolic content of the ethyl acetate extract. Thus, the anti-inflammatory effect of R. NEPALENSIS roots was assumed to be mediated through COX inhibition by anthraquinones and naphthalene derivatives and through the radical scavenging activities of naphthalene derivatives. PMID:20379952

Gautam, Raju; Karkhile, Kailas V; Bhutani, Kamlesh K; Jachak, Sanjay M

2010-04-08

236

The selective cyclooxygenase-2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation.  

PubMed

The importance of inflammation in initiating the sequence of events that lead to liver fibrosis is increasingly recognized. In this study, we tested the effects of SC-236, a selective cyclooxygenase (COX)-2 inhibitor, in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. Livers from CCl4-treated rats showed increased COX-2 expression and 15-deoxy-prostaglandin (PG)J2 (15d-PGJ2) formation, as well as decreased peroxisome proliferator-activated receptor (PPAR)gamma expression. In these animals, SC-236 reduced liver fibrosis as revealed by histological analysis and by a reduction in hepatic hydroxyproline levels, metalloproteinase-2 activity, and alpha-smooth muscle actin expression. Interestingly, SC-236 normalized 15d-PGJ2 levels and restored PPARgamma expression in the liver of CCl4-treated rats. In isolated hepatic stellate cells (HSCs)--the major player in liver fibrogenesis--and Kupffer cells--the cell type primarily responsible for increased hepatic COX-2-SC-236 exhibited remarkable pro-apoptotic and growth inhibitory properties. Of interest, SC-236 decreased HSC viability to a similar extent than the PPARgamma ligand rosiglitazone. Moreover, SC-236 significantly induced PPARgamma expression in HSCs and acted as a potent PPARgamma agonist in a luciferase-reporter trans-activation assay. These data indicate that, by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation, the selective COX-2 inhibitor SC-236 might have therapeutic potential for prevention of liver fibrosis. PMID:15876570

Planagumà, Anna; Clària, Joan; Miquel, Rosa; López-Parra, Marta; Titos, Esther; Masferrer, Jaime L; Arroyo, Vicente; Rodés, Joan

2005-05-04

237

COX-2 regulates E-cadherin expression through the NF-?B/Snail signaling pathway in gastric cancer.  

PubMed

Cyclooxygenase-2 (COX-2) participates in cancer invasion and metastasis by decreasing the expression of E-cadherin. However, the molecular mechanisms through which COX-2 regulates E-cadherin expression and function have not yet been fully elucidated. The aim of this study was to investigate the possible molecular mechanisms through which COX-2 regulates E-cadherin expression in gastric cancer. The mRNA and protein expression of COX-2, nuclear factor-?B (NF-?B), Snail and E-cadherin was detected in gastric cancer cells by quantitative PCR and western blot analysis, respectively. The expression of these genes was also detected in healthy gastric mucosa and gastric cancer tissues by immunohistochemistry. We detected various levels of COX-2, nuclear factor-?B (NF-?B), Snail and E-cadherin expression in the normal gastric mucosa and cancer tissues; however, the expression patterns differed: the increased expression of COX-2, NF-?B and Snail was observed in the gastric cancer tissues, whereas there was a considerable reduction in E-cadherin expression in the cancer tissues compared to the normal gastric mucosa. The expression patterns of COX-2, NF-?B and Snail were similar. The increased expression of COX-2 in the gastric cancer tissues closely correlated with the increased expression of NF-?B and Snail, but inversely correlated with the expression of E-cadherin. Treatment of the SGC7901 cells (which express high levels of COX-2) with celecoxib, a COX-2 inhibitor, not only led to a marked dose- and time-dependent decrease in the expression of COX-2, NF-?B and Snail, but also led to a significant increase in the expression of E-cadherin, and this was associated with a reduction in cell invasion. By contrast, the same treatment did not alter the expression of these genes in another gastric cancer cell line, MGC803 (which barely expresses COX-2). These data suggest that COX-2 regulates the expression of E-cadherin through the NF-?B and Snail signaling pathway in gastric cancer. PMID:23670240

Chen, Zhaofeng; Liu, Min; Liu, Xiaojun; Huang, Shanshan; Li, Linlin; Song, Bo; Li, Hailong; Ren, Qian; Hu, Zenan; Zhou, Yongning; Qiao, Liang

2013-05-10

238

Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.  

PubMed

Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents. PMID:22263894

Liedtke, Andy J; Crews, Brenda C; Daniel, Cristina M; Blobaum, Anna L; Kingsley, Philip J; Ghebreselasie, Kebreab; Marnett, Lawrence J

2012-02-14

239

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2?-Des-methyl-sulindac Sulfide Scaffold  

PubMed Central

Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2?-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

2012-01-01

240

Synthesis and biological evaluation of new 4-carboxyl quinoline derivatives as cyclooxygenase-2 inhibitors.  

PubMed

A group of 4-carboxyl quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-7 and C-8 quinoline ring. Among the 4-carboxyl quinolines, 7,8,9,10-tetrahydro-2-(4-(methyl sulfonyl)phenyl)benzo[h]quinoline-4-carboxylic acid (9e) was identified as potent and high selective COX-2 inhibitor (COX-2 IC(50)=0.043microM; selectivity index>513) that was more potent than the reference drug celecoxib (COX-2 IC(50)=0.060microM; SI=405). A molecular modeling study where 9e was docked in the binding site of COX-2 showed that the p-MeSO(2) substituent on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carboxyl group can interact with Arg120. The structure activity data acquired indicate that the presence of lipophilic substituents on the C-7 and C-8 quinoline ring is important for COX-2 inhibitory activity. PMID:19560931

Zarghi, Afshin; Ghodsi, Razieh; Azizi, Ebrahim; Daraie, Bahram; Hedayati, Mehdi; Dadrass, Orkideh G

2009-06-12

241

Design, synthesis, and biological evaluation of 1,3-diarylprop-2-en-1-ones : a novel class of cyclooxygenase-2 inhibitors.  

PubMed

A group of regioisomeric (E)-1,3-diarylprop-2-en-1-one derivatives possessing a COX-2 SO2Me pharmacophore at the para position of the C-1 or C-3 phenyl ring, in conjunction with a C-3 or C-1 phenyl (4-H) or substituted-phenyl ring (4-F, 4-OMe and 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target (E)-1,3-diarylprop-2-en-1-ones were synthesized via a Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified (E)-1-(4-methanesulfonylphenyl)-3-(4-methylphenyl)prop-2-en-1-one (9f) as a potent COX-2 inhibitor (IC50=0.3 microM) with a high COX-2 selectivity index (SI=106) comparable to that of the reference drug rofecoxib (COX-2 IC50=0.5 microM; COX-2 SI>200). A molecular modeling study where 9f was docked in the binding site of COX-2 showed that the para-SO2Me substituent on the C-1 phenyl ring is oriented in the vicinity of the secondary COX-2 binding site near Val523. The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design novel acyclic 1,3-diarylprop-2-en-1-ones with selective COX-2 inhibitory activity. PMID:16356730

Zarghi, Afshin; Arfaee, Sara; Rao, P N Praveen; Knaus, Edward E

2005-12-13

242

Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model  

PubMed Central

Background COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. Methods LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 ?M diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT). Results LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05). Conclusions These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.

2013-01-01

243

Cyclooxygenase-2 (COX-2) Inhibition Constrains Indoleamine 2,3-Dioxygenase 1 (IDO1) Activity in Acute Myeloid Leukaemia Cells.  

PubMed

Indoleamine 2,3-dioxygenase 1 (IDO1) metabolizes L-tryptophan to kynurenines (KYN), inducing T-cell suppression either directly or by altering antigen-presenting-cell function. Cyclooxygenase (COX)-2, the rate-limiting enzyme in the synthesis of prostaglandins, is over-expressed by several tumours. We aimed at determining whether COX-2 inhibitors down-regulate the IFN-g-induced expression of IDO1 in acute myeloid leukaemia (AML) cells. IFN-? at 100 ng/mL up-regulated COX-2 and IDO1 in HL-60 AML cells, both at mRNA and protein level. The increased COX-2 and IDO1 expression correlated with heightened production of prostaglandin (PG)E2 and kynurenines, respectively. Nimesulide, a preferential COX-2 inhibitor, down-regulated IDO1 mRNA/protein and attenuated kynurenine synthesis, suggesting that overall IDO inhibition resulted both from reduced IDO1 gene transcription and from inhibited IDO1 catalytic activity. From a functional standpoint, IFN-g-challenged HL-60 cells promoted the in vitro conversion of allogeneic CD4+CD25- T cells into bona fide CD4+CD25+FoxP3+ regulatory T cells, an effect that was significantly reduced by treatment of IFN-?-activated HL-60 cells with nimesulide. Overall, these data point to COX-2 inhibition as a potential strategy to be pursued with the aim at circumventing leukaemia-induced, IDO-mediated immune dysfunction. PMID:23973990

Iachininoto, Maria Grazia; Nuzzolo, Eugenia Rosa; Bonanno, Giuseppina; Mariotti, Andrea; Procoli, Annabella; Locatelli, Franco; De Cristofaro, Raimondo; Rutella, Sergio

2013-08-22

244

Pharmacologic Inhibition of COX-1 and COX-2 in Influenza A Viral Infection in Mice  

PubMed Central

Background We previously demonstrated that cyclooxygenase (COX)-1 deficiency results in greater morbidity and inflammation, whereas COX-2 deficiency leads to reduced morbidity, inflammation and mortality in influenza infected mice. Methodology/Principal Findings We investigated the effects of COX-1 and COX-2 inhibitors in influenza A viral infection. Mice were given a COX-1 inhibitor (SC-560), a COX-2 inhibitor (celecoxib) or no inhibitor beginning 2 weeks prior to influenza A viral infection (200 PFU) and throughout the course of the experiment. Body weight and temperature were measured daily as indicators of morbidity. Animals were sacrificed on days 1 and 4 post-infection and bronchoalveolar lavage (BAL) fluid was collected or daily mortality was recorded up to 2 weeks post-infection. Treatment with SC-560 significantly increased mortality and was associated with profound hypothermia and greater weight loss compared to celecoxib or control groups. On day 4 of infection, BAL fluid cells were modestly elevated in celecoxib treated mice compared to SC-560 or control groups. Viral titres were similar between treatment groups. Levels of TNF-? and G-CSF were significantly attenuated in the SC-560 and celecoxib groups versus control and IL-6 levels were significantly lower in BAL fluid of celecoxib treated mice versus control and versus the SC-560 group. The chemokine KC was significantly lower in SC-560 group versus control. Conclusions/Significance Treatment with a COX-1 inhibitor during influenza A viral infection is detrimental to the host whereas inhibition of COX-2 does not significantly modulate disease severity. COX-1 plays a critical role in controlling the thermoregulatory response to influenza A viral infection in mice.

Carey, Michelle A.; Bradbury, J. Alyce; Rebolloso, Yvette D.; Graves, Joan P.; Zeldin, Darryl C.; Germolec, Dori R.

2010-01-01

245

Selective Inhibition of Cyclooxygenase2 by C-Phycocyanin, a Biliprotein from Spirulina platensis  

Microsoft Academic Search

We report data from two related assay systems (isolated enzyme assays and whole blood assays) that C-phycocyanin a biliprotein from Spirulina platensis is a selective inhibitor of cyclooxygenase-2 (COX-2) with a very low IC50 COX-2\\/IC50 COX-1 ratio (0.04). The extent of inhibition depends on the period of preincubation of phycocyanin with COX-2, but without any effect on the period of

C. Madhava Reddy; Vadiraja B. Bhat; G. Kiranmai; M. Narsa Reddy; P. Reddanna; K. M. Madyastha

2000-01-01

246

Indomethacin but not a selective cyclooxygenase-2 inhibitor inhibits esophageal adenocarcinogenesis in rats  

PubMed Central

AIM: To evaluate the effects of indomethacin [dual cyclooxygenase (COX)-1/COX-2 inhibitor] and 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone (MF-tricyclic) (COX-2 selective inhibitor) in a rat experimental model of Barrett’s esophagus and esophageal adenocarcinoma. METHODS: A total of 112 surviving post-surgery rats were randomly divided into three groups: the control group (n = 48), which did not receive any treatment; the indomethacin group (n = 32), which were given 2 mg/kg per day of the COX-1/COX-2 inhibitor; and the MF-tricyclic group (n = 32), which received 10 mg/kg per day of the selective COX-2 inhibitor. Randomly selected rats were killed either 8 wk or 16 wk after surgery. The timing of the deaths was in accordance with a previous study performed in our group. Only rats that were killed at the times designated by the protocol were included in the study. We then assessed the histology and prostaglandin E2 (PGE2) expression levels in the rat esophagi. An additional group of eight animals that did not undergo esophagojejunostomy were included in order to obtain normal esophageal tissue as a control. RESULTS: Compared to a control group with no treatment (vehicle-treated rats), indomethacin treatment was associated with decreases in ulcerated esophageal mucosa (16% vs 35% and 14% vs 17%, 2 mo and 4 mo after surgery, respectively; P = 0.021), length of intestinal metaplasia in continuity with anastomosis (2 ± 1.17 mm vs 2.29 ± 0.75 mm and 1.25 ± 0.42 mm vs 3.5 ± 1.54 mm, 2 mo and 4 mo after surgery, respectively; P = 0.007), presence of intestinal metaplasia beyond anastomosis (20% vs 71.4% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P = 0.009), severity of dysplasia (0% vs 71.4% and 20% vs 85.7% high-grade dysplasia, 2 mo and 4 mo after surgery, respectively; P = 0.002), and adenocarcinoma incidence (0% vs 57.1% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P < 0.0001). Treatment with the selective COX-2 inhibitor, MF-tricyclic, did not prevent development of intestinal metaplasia or adenocarcinoma. In parallel, we observed a significant decrease in PGE2 levels in indomethacin-treated rats, but not in those treated with MF-tricyclic, at both 2 mo and 4 mo. Compared to control rats that did not undergo surgery (68 ± 8 ng/g, P = 0.0022 Kruskal-Wallis test) there was a significant increase in PGE2 levels in the esophageal tissue of the rats that underwent surgery either 2 mo (1332 ± 656 ng/g) or 4 mo (1121 ± 1015 ng/g) after esophagojejunostomy. However, no differences were found when esophageal PGE2 levels were compared 2 mo vs 4 mo post-esophagojejunostomy. At both the 2- and 4-mo timepoints, we observed a significant decrease in PGE2 levels in indomethacin-treated rat esophagi compared to those in either the control or MF-tricyclic groups (P = 0.049 and P = 0.017, respectively). No differences in PGE2 levels were found when we compared levels in rats treated with MF-tricyclic to not-treated rats. CONCLUSION: In this rat model of gastrointestinal reflux, indomethacin was associated with a decrease in the severity of esophagitis and reduced development of esophageal intestinal metaplasia and adenocarcinoma.

Esquivias, Paula; Morandeira, Antonio; Escartin, Alfredo; Cebrian, Carmelo; Santander, Sonia; Esteva, Francisco; Garcia-Gonzalez, Maria Asuncion; Ortego, Javier; Lanas, Angel; Piazuelo, Elena

2012-01-01

247

Isoform-selective histone deacetylase inhibitors  

PubMed Central

Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical trials as anti-cancer drugs. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. This tutorial review focuses on the recent progress toward the identification of class-selective and isoform-selective HDAC inhibitors. The emerging trends suggest that subtle differences in the active sites of the HDAC isoforms can be exploited to dictate selectivity.

Bieliauskas, Anton V.

2008-01-01

248

Overexpression of Cox2 in Human Osteosarcoma Cells Decreases Proliferation and Increases Apoptosis  

Microsoft Academic Search

Overexpression of cyclooxygenase-2 (COX-2) is generally considered to promote tumorigenesis. To investigate a potential role of COX-2 in osteosarcoma, we overexpressed COX-2 in human osteosarcoma cells. Saos-2 cells deficient in COX-2 expression were retrovirally transduced or stably transfected with murine COX-2 cDNA. Functional expression of COX-2 was confirmed by Northern and Western analyses and prostaglandin production. Overexpression of COX-2 reduced

Zheng Xu; Shilpa Choudhary; Olga Voznesensky; Meenal Mehrotra; Monica Woodard; Marc Hansen; Harvey Herschman; Carol Pilbeam

2006-01-01

249

Seizure susceptibility in immature brain due to lack of COX-2-induced PGF2?.  

PubMed

The immature brain is prone to seizure; however, the mechanism underlying this vulnerability has not been clarified. Febrile seizure is common in young children, and the use of non-steroidal anti-inflammatory drugs for febrile seizure is not recommended. In previous studies, we established that prostaglandin (PG) F2?, a product of cyclooxygenase (COX), acts as an endogenous anticonvulsant in the adult mouse. Therefore, we assumed that COX-2 activity was involved with seizure susceptibility in early life. In the present study, immature mice (postnatal day 9) were far more prone to kainic acid (KA)-induced seizures than mature mice (after postnatal day 35). Seizure activity began later in immature mice, but was more severe and was unaffected by a potent COX inhibitor, indomethacin; in contrast, indomethacin aggravated seizure activity in mature mice. Immature mouse brains exhibited little basal COX-2 expression and little KA-induced COX-2 induction, while KA-induced COX-2 expression and PGF2? release were prominent in mature brains. During brain development, COX expression was increased and glycosylated in an age-dependent manner, which was necessary for COX enzyme activity. Intracisternal PGF2? administration also reduced KA-induced seizure activity and mortality. Taken together, low COX activity and the resulting deficiency of PGF2? may be an essential cause of increased seizure susceptibility in the immature brain. PMID:24005111

Chung, Jee-In; Kim, A Young; Lee, Soo Hwan; Baik, Eun Joo

2013-09-01

250

OMEGA-3 POLYUNSATURATED FATTY ACIDS INHIBIT HEPATOCELLULAR CARCINOMA CELL GROWTH THROUGH BLOCKING ?-CATENIN AND COX-2  

PubMed Central

Hepatocellular carcinoma (HCC) is a common human cancer with high mortality and currently there is no effective chemoprevention or systematic treatment. Recent evidence suggests that COX-2-derived PGE2 and Wnt/?-catenin signaling pathways are implicated in hepatocarcinogenesis. Here we report that ?-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), inhibit HCC growth through simultaneously inhibition of COX-2 and ?-catenin. DHA and EPA treatment resulted in a dose-dependent reduction of cell viability with cleavage of PARP, caspase-3 and caspase-9 in three human HCC cell lines (Hep3B, Huh-7, HepG2). In contrast, arachidonic acid (AA), a ?-6 PUFA, exhibited no significant effect. DHA and EPA treatment caused dephosphorylation and thus activation of GSK-3?, leading to ?-catenin degradation in Hep3B cells. The GSK3-? inhibitor, LiCl, partially prevented DHA-induced ?-catenin protein degradation and apoptosis. Additionally, DHA induced the formation of ?-catenin/Axin/GSK-3? binding complex, which serves as a parallel mechanism for ?-catenin degradation. Furthermore, DHA inhibited PGE2 signaling through downregulation of COX-2 and upregulation of the COX-2 antagonist, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Finally, the growth of HCC in vivo was significantly reduced when mouse HCCs (Hepa1–6) were inoculated into the Fat-1 transgenic mice which express a Caenorhabditis elegans desaturase converting ?-6 to ?-3 PUFAs endogenously. These findings provide important preclinical evidence and molecular insight for utilization of ?-3 PUFAs for the chemoprevention and treatment of human HCC.

Lim, Kyu; Han, Chang; Dai, Yifan; Shen, Miaoda; Wu, Tong

2009-01-01

251

c-Src-dependent EGF receptor transactivation contributes to ET-1-induced COX-2 expression in brain microvascular endothelial cells  

PubMed Central

Background Endothelin-1 (ET-1) is elevated and participates in the regulation of several brain inflammatory disorders. The deleterious effects of ET-1 on endothelial cells may aggravate brain inflammation mediated through the upregulation of cyclooxygenase-2 (COX-2) gene expression. However, the signaling mechanisms underlying ET-1-induced COX-2 expression in brain microvascular endothelial cells remain unclear. Objective The goal of this study was to examine whether ET-1-induced COX-2 expression and prostaglandin E2 (PGE2) release were mediated through a c-Src-dependent transactivation of epidermal growth factor receptor (EGFR) pathway in brain microvascular endothelial cells (bEnd.3 cells). Methods The expression of COX-2 induced by ET-1 was evaluated by Western blotting and RT-PCR analysis. The COX-2 regulatory signaling pathways were investigated by pretreatment with pharmacological inhibitors, short hairpin RNA (shRNA) or small interfering RNA (siRNA) transfection, chromatin immunoprecipitation (ChIP), and promoter activity reporter assays. Finally, we determined the PGE2 level as a marker of functional activity of COX-2 expression. Results First, the data showed that ET-1-induced COX-2 expression was mediated through a c-Src-dependent transactivation of EGFR/PI3K/Akt cascade. Next, we demonstrated that ET-1 stimulated activation (phosphorylation) of c-Src/EGFR/Akt/MAPKs (ERK1/2, p38 MAPK, and JNK1/2) and then activated the c-Jun/activator protein 1 (AP-1) via Gq/i protein-coupled ETB receptors. The activated c-Jun/AP-1 bound to its corresponding binding sites within COX-2 promoter, thereby turning on COX-2 gene transcription. Ultimately, upregulation of COX-2 by ET-1 promoted PGE2 biosynthesis and release in bEnd.3 cells. Conclusions These results demonstrate that in bEnd.3 cells, c-Src-dependent transactivation of EGFR/PI3K/Akt and MAPKs linking to c-Jun/AP-1 cascade is essential for ET-1-induced COX-2 upregulation. Understanding the mechanisms of COX-2 expression and PGE2 release regulated by ET-1/ETB system on brain microvascular endothelial cells may provide rational therapeutic interventions for brain injury and inflammatory diseases.

2012-01-01

252

TCDD Induced Pericardial Edema and Relative COX-2 Expression in Medaka (Oryzias Latipes) Embryos  

PubMed Central

Exposure to dioxin and other aryl hydrocarbon receptor (AhR) ligands results in multiple, specific developmental cardiovascular phenotypes including pericardial edema and circulatory failure in small aquarium fish models. Although phenotypes are well described, mechanistic underpinnings for such toxicities remain elusive. Here we suggest that AhR activation results in stimulation of inflammation and “eicosanoid” pathways, which contribute to the observed developmental, cardiovascular phenotypes. We demonstrate that medaka embryos exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.05–1 ppb) during early development result in a dose-related increase in the prevalence of pericardial edema and that this phenotype correlates with an increase in cyclooxygenase-2 (COX-2) gene expression. Those individuals exhibiting the edema phenotype had significantly greater COX-2 mRNA than their nonedematous cohort. Selective pharmacological inhibition of COX-2, with NS-398, and genetic knock down of COX-2 with a translation initiation morpholino significantly attenuated prevalence and severity of edema phenotype. Subsequently, exposures of medaka embryos to arachidonic acid (AA) resulted in recapitulation of the pericardial edema phenotype and significantly increased COX-2 expression only in those individuals exhibiting the edema phenotype compared with their nonedematous cohort. AA exposure does not result in significant induction of cytochrome P450 1A expression, suggesting that pericardial edema can be induced independent of AhR/aryl hydrocarbon receptor nuclear translocator/dioxin response element interactions. Results from this study demonstrate that developmental exposure to TCDD results in an induction of inflammatory mediators including COX-2, which contribute to the onset, and progression of heart dysmorphogenesis in the medaka model.

Dong, Wu; Matsumura, Fumio; Kullman, Seth W.

2010-01-01

253

Disseminating drug prescribing information: the cox-2 inhibitors withdrawals.  

PubMed

This case study examined the recent withdrawal of valdecoxib to determine the timeliness of updates in commonly used information sources used by healthcare professionals. The method included assembling a purposive sample of 15 drug reference and warning systems that were then systematically monitored for several months after the withdrawal of valdecoxib to determine the time to update this information. These information sources were classified and described qualitatively. A time to diffusion curve was plotted and the average number of days to report the drug withdrawal or update reference databases was calculated. Only 2 of 15 information systems reported the drug withdrawal on the actual date of the FDA announcement. Institutional electronic textbooks took an average of 109.8 days (+/-14 days) to report the withdrawal. In addition, one pharma-sponsored dissemination source (Peerview Press) had not updated their information as of this publication. PMID:16622163

Strayer, Scott M; Slawson, David C; Shaughnessy, Allen F

2006-04-18

254

COX2 inhibition does not reverse the increased sympathetic modulation in MSG obese rats  

Microsoft Academic Search

We evaluate the effects of chronic treatment with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, on blood pressure (BP) and heart rate variability (HRV) in obese rats induced by neonatal monosodium glutamate (MSG). The animals were treated with celecoxib or saline for 30days (from the 60th to the 90th day of age). On the 90th day, the MSG obesity induced an increase

Natália Veronez da Cunha; Phileno Pinge-Filho; Octávio Barbosa Neto; Sabrina Grassiolli; Marli Cardoso Martins-Pinge

2011-01-01

255

Kaposi's Sarcoma Associated Herpes Virus (KSHV) Induced COX-2: A Key Factor in Latency, Inflammation, Angiogenesis, Cell Survival and Invasion  

PubMed Central

Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. Primary infection of human micro vascular endothelial cells (HMVEC-d) results in the establishment of latent infection and reprogramming of host genes, and cyclooxygenase-2 (COX-2) is one of the highly up-regulated genes. Our previous study suggested a role for COX-2 in the establishment and maintenance of KSHV latency. Here, we examined the role of COX-2 in the induction of ICs, GFs, angiogenesis and invasive events occurring during KSHV de novo infection of endothelial cells. A significant amount of COX-2 was detected in KS tissue sections. Telomerase-immortalized human umbilical vein endothelial cells supporting KSHV stable latency (TIVE-LTC) expressed elevated levels of functional COX-2 and microsomal PGE2 synthase (m-PGES), and secreted the predominant eicosanoid inflammatory metabolite PGE2. Infected HMVEC-d and TIVE-LTC cells secreted a variety of ICs, GFs, angiogenic factors and matrix metalloproteinases (MMPs), which were significantly abrogated by COX-2 inhibition either by chemical inhibitors or by siRNA. The ability of these factors to induce tube formation of uninfected endothelial cells was also inhibited. PGE2, secreted early during KSHV infection, profoundly increased the adhesion of uninfected endothelial cells to fibronectin by activating the small G protein Rac1. COX-2 inhibition considerably reduced KSHV latent ORF73 gene expression and survival of TIVE-LTC cells. Collectively, these studies underscore the pivotal role of KSHV induced COX-2/PGE2 in creating KS lesion like microenvironment during de novo infection. Since COX-2 plays multiple roles in KSHV latent gene expression, which themselves are powerful mediators of cytokine induction, anti-apoptosis, cell survival and viral genome maintainence, effective inhibition of COX-2 via well-characterized clinically approved COX-2 inhibitors could potentially be used in treatment to control latent KSHV infection and ameliorate KS.

Sharma-Walia, Neelam; Sadagopan, Sathish; Veettil, Mohanan Valiya; Kerur, Nagaraj; Chandran, Bala

2010-01-01

256

Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials  

Microsoft Academic Search

Objective To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events. Design Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs. Data sources Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data

Patricia M Kearney; Colin Baigent; Jon Godwin; Heather Halls; Jonathan R Emberson; Carlo Patrono

2006-01-01

257

Epidermal growth factor receptor transactivation is required for proteinase-activated receptor-2-induced COX-2 expression in intestinal epithelial cells.  

PubMed

Proteinase-activated receptor (PAR)(2), a G protein-coupled receptor activated by serine proteinases, has been implicated in both intestinal inflammation and epithelial proliferation. Cyclooxygenase (COX)-2 is overexpressed in the gut during inflammation as well as in colon cancer. We hypothesized that PAR(2) drives COX-2 expression in intestinal epithelial cells. Treatment of Caco-2 colon cancer cells with the PAR(2)-activating peptide 2-furoyl-LIGRLO-NH(2) (2fLI), but not by its reverse-sequence PAR(2)-inactive peptide, for 3 h led to an increase in intracellular COX-2 protein expression accompanied by a COX-2-dependent increase in prostaglandin E(2) production. 2fLI treatment for 30 min significantly increased metalloproteinase activity in the culture supernatant. Increased epidermal growth factor receptor (EGFR) phosphorylation was observed in cell lysates following 40 min of treatment with 2fLI. The broad-spectrum metalloproteinase inhibitor marimastat inhibited both COX-2 expression and EGFR phosphorylation. The EGFR tyrosine kinase inhibitor PD153035 also abolished 2fLI-induced COX-2 expression. Although PAR(2) activation increased ERK MAPK phosphorylation, neither ERK pathway inhibitors nor a p38 MAPK inhibitor affected 2fLI-induced COX-2 expression. However, inhibition of either Src tyrosine kinase signaling by PP2, Rho kinase signaling by Y27632, or phosphatidylinositol 3 (PI3) kinase signaling by LY294002 prevented 2fLI-induced COX-2 expression. Trypsin increased COX-2 expression through PAR(2) in Caco-2 cells and in an EGFR-dependent manner in the noncancerous intestinal epithelial cell-6 cell line. In conclusion, PAR(2) activation drives COX-2 expression in Caco-2 cells via metalloproteinase-dependent EGFR transactivation and activation of Src, Rho, and PI3 kinase signaling. Our findings provide a mechanism whereby PAR(2) can participate in the progression from chronic inflammation to cancer in the intestine. PMID:22517768

Hirota, Christina L; Moreau, France; Iablokov, Vadim; Dicay, Michael; Renaux, Bernard; Hollenberg, Morley D; MacNaughton, Wallace K

2012-04-19

258

MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1? induced in human endometriosis stromal cells in vitro  

PubMed Central

Objective: Now there are more and more evidences that Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis of endometriosis (EMs). Vascular endothelial growth factor (VEGF) has a potent angiogenic activity. However, it is worth studying about the regulating mechanism of COX-2/COX-1 and VEGF in the development of human endometriosis in vitro. The current study was designed to investigate the effect of 4 cytokines on COX-2/COX-1 expression and the effect of IL-1? on VEGF release in human endometriosis stromal cells (ESC), and to explore the related signaling pathways involved in vitro. Methods: Isolation, culture and identification of ESC. Cells were treated with 4 cytokines, and the inhibitor mitogen-activated protein-Erk (MEK) and the inhibitor p38 mitogen-activated protein kinase (MAPK) prior to adding cytokine IL-1?. COX-2 protein expression was measured by western blot and VEGF secretion was determined by ELISA. Results: Among four kinds of cytokines, IL-1? treatment increased COX-2 protein expression and VEGF release in three ESC, and TNF-? had the same effect on COX-2 protein level as IL-1? only in ectopic and eutopic ESC, and MCSF had only slight effect on ectopic ESC. In contrast, cytokines had no effect on COX-1 expression. We also demonstrated that MAPK reduced the synthesis of COX-2 by IL-1? induced. COX-2 inhibitor reduced VEGF release by IL-1? induced. Conclusions: i) In human ESC in vitro, IL-1? up-regulated the COX-2 expression through the activation of p38 MAPK pathway, and not to COX-1. ii) Up-regulation of VEGF level by IL-1? treatment was found in human endometriosis stromal cell and COX-2 inhibitor was involved in this process.

Huang, Fengying; Cao, Jing; Liu, Qiuhong; Zou, Ying; Li, Hongyun; Yin, Tuanfang

2013-01-01

259

COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP  

PubMed Central

Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-?B, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-?B-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-?B induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating ‘extrinsic' as well as ‘intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v-FLIP/K13-HMVEC cells expressed lower levels of endothelial–mesenchymal transition genes such as slug, snail and twist, and higher expression of the tumor-suppressor gene, E-cadherin. Taken together, our study provides strong evidences that FDA-approved COX-2 inhibitors have great potential in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13.

Sharma-Walia, N; Patel, K; Chandran, K; Marginean, A; Bottero, V; Kerur, N; Paul, A G

2012-01-01

260

Up-regulation of Rac1 by Epidermal Growth Factor Mediates COX-2 Expression in Recurrent Respiratory Papillomas  

PubMed Central

Recurrent respiratory papillomas are epithelial tumors of the airway caused by human papillomaviruses. We previously reported that the epidermal growth factor receptor (EGFR) is overexpressed in papilloma cells, that cyclooxygenase-2 (COX-2) is induced, and that COX-2 expression in primary papilloma cells requires activation of the EGFR but not Erk. Rac1, a member of the Rho family of GTPases, is a key signaling element that is known to control multiple pathways downstream of the EGFR. Here we report that Rac1 is overexpressed in papilloma cells compared with normal laryngeal epithelial cells and that the increased levels of Rac1 are mediated by EGFR activation. Transfecting cells with Rac1-specific siRNA suppressed COX-2 expression. Surprisingly, Rac1 mediated phosphorylation of p38 mitogen-activated kinase in papilloma cells but not normal cells, and inhibition of p38 with the specific inhibitor SB202190 suppressed COX-2 expression in papilloma cells but had no effect on low-level COX-2 expression in normal cells. Thus, the signaling cascades that regulate COX-2 expression are different in HPV-infected papilloma cells, with a significant contribution by the EGFR ? Rac1 ? p38 pathway.

Wu, Rong; Coniglio, Salvatore J; Chan, Amanda; Symons, Marc H; Steinberg, Bettie M

2007-01-01

261

Cyclooxygenase-2 inhibitors modulate skin aging in a catalytic activity-independent manner  

PubMed Central

It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1.

Lee, Mi Eun; Kim, So Ra; Lee, Seungkoo; Jung, Yu-Jin; Choi, Sun Shim; Kim, Woo Jin

2012-01-01

262

Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor.  

PubMed

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis. PMID:21745460

Imanishi, Junko; Morita, Yoshiaki; Yoshimi, Eiji; Kuroda, Kanae; Masunaga, Tomoko; Yamagami, Kaoru; Kuno, Masako; Hamachi, Emi; Aoki, Satoshi; Takahashi, Fumie; Nakamura, Katsuya; Miyata, Susumu; Ohkubo, Yoshitaka; Mutoh, Seitaro

2011-07-02

263

Inhibitory effect of etodolac, a selective cyclooxygenase-2 inhibitor, on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils  

SciTech Connect

The effect of the selective COX-2 inhibitor, etodolac, on Helicobacter pylori (Hp)-associated stomach carcinogenesis was investigated in Mongolian gerbils (MGs). Hp-infected MGs were fed for 23 weeks with drinking water containing 10 ppm N-methyl-N-nitrosourea. They were then switched to distilled water and placed on a diet containing 5-30 mg/kg/day etodolac for 30 weeks. We found that etodolac dose-dependently inhibited the development of gastric cancer, and no cancer was detected at a dose of 30 mg/kg/day. Etodolac did not affect the extent of inflammatory cell infiltration or oxidative DNA damage, but it significantly inhibited mucosal cell proliferation and dose-dependently repressed the development of intestinal metaplasia in the stomachs of Hp-infected MGs. These results suggest that COX-2 is a key molecule in inflammation-mediated stomach carcinogenesis and that chemoprevention of stomach cancer should be possible by controlling COX-2 expression or activity.

Magari, Hirohito [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Shimizu, Yasuhito [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Inada, Ken-ichi [First Dept. of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192 (Japan); Enomoto, Shotaro [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Tomeki, Tatsuji [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Yanaoka, Kimihiko [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Tamai, Hideyuki [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Arii, Kenji [Second Dept. of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Nakata, Hiroya [Second Dept. of Internal Medicine, Wakayama Medical Univ., 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Oka, Masashi [Second Dept. of Internal Medicine, Wakayama Medical Univ., 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Utsunomiya, Hirotoshi [Dept. of Pathology, Wakayama Medical Univ., 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan); Tsutsumi, Yutaka [First Dept. of Pathology, Fujita Health Univ. School of Medicine, Toyoake, Aichi 470-1192 (Japan); Tsukamoto, Tetsuya [Lab. of Pathology, Aichi Cancer Center Research Inst., Aichi 464-8681 (Japan); Tatematsu, Masae [Lab. of Pathology, Aichi Cancer Center Research Inst., Aichi 464-8681 (Japan); Ichinose, Masao [Second Dept. of Internal Medicine, Wakayama Medical Univ., 811-1 Kimiidera, Wakayama-City, Wakayama 641-0012 (Japan)] E-mail: ichinose@wakayama-med.ac.jp

2005-08-26

264

Involvement of ERK AND p38 MAP kinase in AAPH-induced COX-2 expression in HaCaT cells.  

PubMed

Cyclooxygenase-2 (COX-2) appears to play an important role in inflammation and carcinogenesis, and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is a hydrophilic azo compound known to generate free radicals. Because reactive oxygen species (ROS) are known to elevate COX-2 expression, we evaluated the effect of AAPH on the expression of COX-2 in a human keratinocyte cell line, HaCaT. When cells were exposed to AAPH, marked COX-2 induction was observed. To clarify the signaling mechanism involved, we next investigated the effects of AAPH upon three major subfamilies of the mitogen-activated protein kinases (MAPKs). AAPH caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase (JNK). Furthermore, we found that PD98059, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished AAPH-induced COX-2 expression and PGE(2) production, whereas JNK inhibitor did not suppress COX-2 expression or PGE(2) production by AAPH. These findings suggest that the ERK and p38 MAPK pathways, but not the JNK pathway, are involved in AAPH-induced inflammatory progression. In addition, we found that both the water-soluble Vitamin E derivative, Trolox, and the green tea constituent, (-)-epigallocatechin gallate (EGCG), diminished AAPH-induced COX-2 expression and p38 activation. PMID:14998726

Cui, Yong; Kim, Dong-Seok; Park, Seo-Hyoung; Yoon, Jin-A; Kim, Soon-Kyum; Kwon, Sun-Bang; Park, Kyoung-Chan

2004-04-01

265

COX2 silencing inhibits cell proliferation in A549 cell  

Microsoft Academic Search

Objective  The aim of this study was to explore the effects on malignant proliferation of A549 cell by silencing cyclooxygenase (COX)-2.\\u000a \\u000a \\u000a \\u000a Methods  In the present study, we constructed three siRNA vectors producing small interference RNA. The siRNA vectors and the vacant\\u000a vectors were transfected into A549 cell with lipofectamine respectively and the transfected cell strains were constructed.\\u000a The change of COX-2 expression

Weiying Li; Wentao Yue; Lina Zhang; Xiaoting Zhao; Li Ma; Xuehui Yang; Chunyan Zhang; Yue Wang; Meng Gu

2011-01-01

266

UVB-induced COX-2 expression requires histone H3 phosphorylation at Ser10 and Ser28  

PubMed Central

Cyclooxygenase-2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation in response to chemical carcinogens and environmental stresses, including ultraviolet B (UVB) irradiation. Although post-translational histone modifications are believed to play an important role in modulating transcriptional regulation of UVB-induced COX-2, the underlying biochemical mechanisms are completely unknown. Here, we show that UVB activates the p38 MAPK/MSK1 kinase cascade to phosphorylate histone H3 at Ser10 and Ser28, contributing to UVB-induced COX-2 expression. UVB has no effect on the global trimethylation level of histone H3 (H3K4me3, H3K9me3, and H3K27me3). We observed that selected mammalian 14-3-3 proteins bind to UVB-induced phosphorylated histone H3 (Ser10 and Ser28). In particular, 14-3-3? is critical for recruiting MSK1 and Cdk9 to the chromatin and subsequently phosphorylating the C-terminal domain (CTD) of RNA polymerase II in the cox-2 promoter. We propose that histone H3 phosphorylation at Ser10 and Ser28 serve as critical switches to promote cox-2 gene expression by facilitating the recruitment of MSK1 and Cdk9 to the cox-2 promoter, thereby promoting RNA polymerase II phosphorylation.

Keum, Young-Sam; Kim, Hong-Gyum; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

2012-01-01

267

In vitro effects of VA441, a new selective cyclooxygenase-2 inhibitor, on human osteoarthritic chondrocytes exposed to IL-1?.  

PubMed

The aim of this in vitro study was to examine the possible effect of [2-methyl-5-(4-methylsulphonyl)phenyl-1-phenyl-3-(2-n-propyloxyethyl)]-1H-pyrrole (VA441), a new selective cyclooxygenase (COX)-2 inhibitor, on human osteoarthritic (OA) chondrocyte cultivated in the presence or absence of interleukin-1? (IL-1?). In particular, we assessed the effects of 1 and 10 ?M of VA441, celecoxib, and indomethacin on cell viability, COX-2 and inducible nitric oxide synthase (iNOS) gene expression, prostaglandin E(2) (PGE(2)) production, and nitric oxide (NO) and metalloproteinase-3 (MMP-3) release. Furthermore, we carried out morphological assessment by transmission electron microscopy (TEM). The presence of IL-1? led to a significant increase in PGE(2), MMP-3, and NO production, as well as a significant increase in gene expression of COX-2 and iNOS. All the drugs tested had a statistically significant inhibitory effect on PGE(2) production and gene expression of COX-2 stimulated by IL-1?. VA441 and celecoxib significantly suppressed IL-1?-stimulated MMP-3 and NO and iNOS gene expression in a dose-dependent manner, while indomethacin did not show any significant effect on MMP-3 and NO production or on iNOS gene expression. TEM demonstrated that IL-1? severely alters the structure of chondrocytes; after co-incubation with VA441 or celecoxib, the cells recovered their ultrastructure. Our data suggest that VA441 and celecoxib may have a beneficial effect on chondrocyte metabolism. PMID:22878602

Fioravanti, Antonella; Tinti, Laura; Pascarelli, Nicola Antonio; Di Capua, Angela; Lamboglia, Antonello; Cappelli, Andrea; Biava, Mariangela; Giordani, Antonio; Niccolini, Silvia; Galeazzi, Mauro; Anzini, Maurizio

2012-08-08

268

Suppressive effect of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) activity in mouse macrophage cells.  

PubMed

Prostaglandins and nitric oxide produced by inducible cyclooygenase (COX-2) and nitric oxide synthase (iNOS), respectively, have been implicated as important mediators in the processes of inflammation and carcinogenesis. These potential COX-2 and iNOS inhibitors have been considered as antiinflammatory and cancer chemopreventive agents. In this study, we investigated the effect of natural sesquiterpenoids isolated from plants of the Zingiberaceae family on the activities of COX-2 and iNOS in cultured lipopolysaccharide (LPS)-activated mouse macrophage cell RAW 264.7 to discover new lead compounds as COX-2 or iNOS inhibitors. Xanthorrhizol, a sesquiterpenoid, isolated from the rhizome of Curcuma xanthorrhiza Roxb. (Zingiberaceae), exhibited a potent inhibition of COX-2 (IC50 = 0.2 microg/mL) and iNOS activity (IC50 = 1.0 microg/mL) in the assay system of prostaglandin E2 (PGE2) accumulation and nitric oxide production, respectively. Western blot analyses revealed that the inhibitory potential of xanthorrhizol on the COX-2 activity coincided well with the suppression of COX-2 protein expression in LPS-induced macrophages. In addition, sesquiterpenoids beta-turmerone and ar-turmerone isolated from the rhizome of Curcuma zedoaria Roscoe (Zingiberaceae) also showed a potent inhibitory activity of COX-2 (beta-turmerone, IC50 = 1.6 microg/mL; ar-turmerone, IC50 = 5.2 microg/mL) and iNOS (beta-turmerone, IC50 = 4.6 microg/mL; ar-turmerone, IC50 = 3.2 microg/mL). These results suggest that natural sesquiterpenoids from C. xanthorrhiza and C. zedoaria might be lead candidates for further developing COX-2 or iNOS inhibitors possessing cancer chemopreventive or anti-inflammatory properties. PMID:12086400

Lee, Sang Kook; Hong, Chai-Hee; Huh, Sun-Kyung; Kim, Sun-Sook; Oh, O-Jin; Min, Hye-Young; Park, Kwang-Kyun; Chung, Won-Yoon; Hwang, Jae-Kwan

2002-01-01

269

Nickel alterations of TLR2-dependent chemokine profiles in lung fibroblasts are mediated by COX-2.  

PubMed

Particulate matter air pollution (PM) has been linked with chronic respiratory diseases. Real-life exposures are likely to involve a mixture of chemical and microbial stimuli, yet little attention has been paid to the potential interactions between PM components (e.g., Ni) and microbial agents on the development of inflammatory-like conditions in the lung. Using the Toll-like receptor (TLR)-2 agonist MALP-2 as a lipopeptide relevant to microbial colonization, we hypothesized that nickel sensitizes human lung fibroblasts (HLF) for microbial-driven chemokine release through modulation of TLR signaling pathways. NiSO(4) (200 muM) synergistically enhanced CXCL8, yet antagonized CXCL10 mRNA expression and protein release from HLF in response to MALP-2. RT(2)-PCR pathway-focused array results indicated that NiSO(4) exposure did not alter the expression of TLRs or their downstream signaling mediators, yet significantly increased the expression of cyclooxygenase 2 (COX-2). Moreover, when NiSO(4) was given in combination with MALP-2, there was an amplified induction of COX-2 mRNA and protein along with its metabolic product, PGE2, in HLF. The COX-2 inhibitor, NS-398, attenuated NiSO(4) and MALP-2-induced PGE2 and CXCL8 release and partially reversed the NiSO(4)-dependent inhibition of MALP-2-induced CXCL10 release from HLF. These data indicate that NiSO(4) alters the pattern of TLR-2-dependent chemokine release from HLF via a COX-2-mediated pathway. The quantitative and qualitative effects of NiSO(4) on microbial-driven chemokine release from HLF shed new light on how PM-derived metals can exacerbate respiratory diseases. PMID:18096868

Brant, Kelly A; Fabisiak, James P

2007-12-20

270

Counteracting effect of TRPC1-associated Ca2+ influx on TNF-?-induced COX-2-dependent prostaglandin E2 production in human colonic myofibroblasts.  

PubMed

TNF-?-NF-?B signaling plays a central role in inflammation, apoptosis, and neoplasia. One major consequence of this signaling in the gut is increased production of prostaglandin E(2) (PGE(2)) via cyclooxygenase-2 (COX-2) induction in myofibroblasts, which has been reported to be dependent on Ca(2+). In this study, we explored a potential role of canonical transient receptor potential (TRPC) proteins in this Ca(2+)-mediated signaling using a human colonic myofibroblast cell line CCD-18Co. In CCD-18Co cell, treatment with TNF-? greatly enhanced Ca(2+) influx induced by store depletion along with increased cell-surface expression of TRPC1 protein (but not of the other TRPC isoforms) and induction of a Gd(3+)-sensitive nonselective cationic conductance. Selective inhibition of TRPC1 expression by small interfering RNA (siRNA) or functionally effective TRPC1 antibody targeting the near-pore region of TRPC1 (T1E3) antagonized the enhancement of store-dependent Ca(2+) influx by TNF-?, whereas potentiated TNF-? induced PGE(2) production. Overexpression of TRPC1 in CCD-18Co produced opposite consequences. Inhibitors of NF-?B (curcumin, SN-50) attenuated TNF-?-induced enhancement of TRPC1 expression, store-dependent Ca(2+) influx, and COX-2-dependent PGE(2) production. In contrast, inhibition of calcineurin-nuclear factor of activated T-cell proteins (NFAT) signaling by FK506 or NFAT Activation Inhibitor III enhanced the PGE(2) production without affecting TRPC1 expression and the Ca(2+) influx. Finally, the suppression of store-dependent Ca(2+) influx by T1E3 antibody or siRNA knockdown significantly facilitated TNF-?-induced NF-?B nuclear translocation. In aggregate, these results strongly suggest that, in colonic myofibroblasts, NF-?B and NFAT serve as important positive and negative transcriptional regulators of TNF-?-induced COX-2-dependent PGE(2) production, respectively, at the downstream of TRPC1-associated Ca(2+) influx. PMID:21546578

Hai, Lin; Kawarabayashi, Yasuhiro; Imai, Yuko; Honda, Akira; Inoue, Ryuji

2011-05-05

271

COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and ...  

Center for Drug Evaluation (CDER)

... [4/7/2005] The Food and Drug Administration (FDA) has issued supplemental request letters to sponsors of all non-steroidal anti-inflammatory ... More results from www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders

272

Selective inhibitors of biosynthesis of aminergic neurotransmitters  

Microsoft Academic Search

ALTHOUGH the enzymatic decarboxylation of amino acids is of substantial importance to biochemistry1, there are few inhibitors of the decarboxylase enzymes which combine activity with selectivity. Several of the amines formed by in vivo decarboxylation of amino acids (biogenic amines) have key roles in physiology. The neurotransmitters dopamine, 5-hydroxytryptamine, histamine and gamma-aminobutyric acid result from such enzymatic decarboxylation; dopamine in

J. Kollonitsch; A. A. Patchett; S. Marburg; A. L. Maycock; L. M. Perkins; G. A. Doldouras; D. E. Duggan; S. D. Aster

1978-01-01

273

Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.  

PubMed

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series. PMID:23350847

Padilla, Fernando; Bhagirath, Niala; Chen, Shaoqing; Chiao, Eric; Goldstein, David M; Hermann, Johannes C; Hsu, Jonathan; Kennedy-Smith, Joshua J; Kuglstatter, Andreas; Liao, Cheng; Liu, Wenjian; Lowrie, Lee E; Luk, Kin Chun; Lynch, Stephen M; Menke, John; Niu, Linghao; Owens, Timothy D; O-Yang, Counde; Railkar, Aruna; Schoenfeld, Ryan C; Slade, Michelle; Steiner, Sandra; Tan, Yun-Chou; Villaseñor, Armando G; Wang, Ce; Wanner, Jutta; Xie, Wenwei; Xu, Daigen; Zhang, Xiaohu; Zhou, Mingyan; Lucas, Matthew C

2013-02-12

274

Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells  

Microsoft Academic Search

INTRODUCTION: Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. METHODS: MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and

Gargi D Basu; Latha B Pathangey; Teresa L Tinder; Sandra J Gendler; Pinku Mukherjee

2005-01-01

275

(MIS)COMMUNICATING COX2 CLINICAL TRIAL RISKS  

Microsoft Academic Search

Would you take a drug that saved 1,000 lives last year but killed 1% of the patients? Summary The FDA has approved Cox-2 NSAID drugs to treat short-term acute pain and for long-term treatment of rheumatoid arthritis and osteoarthritis. These benefits, however, appear to come at the price of higher risks for heart attacks (cardiovascular events) and strokes (cerebrovascular events).

Mark Hochhauser; Norman M. Goldfarb

276

Cyclooxygenase2 (COX2) in Inflammatory and Degenerative Brain Diseases  

Microsoft Academic Search

Cyclooxygenase (COX) catalyses the first committed step in the synthesis of prostanoids, a large family of arachidonic acid metabolites comprising prostaglandins, prostacyclin, and thromboxanes, and is a major target of non-steroidal anti-inflammatory drugs (NSAIDs). COX exists as constitutive and inducible isoforms. COX-2 is the inducible isoform, rapidly expressed in several cell types in response to growth factors, cytokines, and pro-inflammatory

LUISA MINGHETTI

2004-01-01

277

New insights into the role of COX 2 in inflammation  

Microsoft Academic Search

Cyclo-oxygenase (COX) is responsible for the synthesis of bioactive prostanoids, the inhibition of which serves as the basis for the mode of action of clinically used nonsteroidal anti-inflammatory drugs. While there were suggestions as early as the 1970s that an inducible isoform of COX exists, it was only in the early 1990s that COX 2 was identified, cloned and sequenced.

Derek W. Gilroy; Paul R. Colville-Nash

2000-01-01

278

COX-2 in cancer: Gordian knot or Achilles heel?  

PubMed Central

The networks of blood and lymphatic vessels and of the extracellular matrix and their cellular and structural components, that are collectively termed the tumor microenvironment, are frequently co-opted and shaped by cancer cells to survive, invade, and form distant metastasis. With an enviable capacity to adapt to continually changing environments, cancer represents the epitome of functional chaos, a stark contrast to the hierarchical and organized differentiation processes that dictate the development and life of biological organisms. The consequences of changing landscapes such as hypoxia and acidic extracellular pH in and around tumors create a cascade of changes in multiple pathways and networks that become apparent only several years later as recurrence and metastasis. These molecular and phenotypic changes, several of which are mediated by COX-2, approach the complexities of a “Gordian Knot.” We review evidence from our studies and from literature suggesting that cyclooxygenase-2 (COX-2) biology presents a nodal point in cancer biology and an “Achilles heel” of COX-2-dependent tumors.

Stasinopoulos, Ioannis; Shah, Tariq; Penet, Marie-France; Krishnamachary, Balaji; Bhujwalla, Zaver M.

2013-01-01

279

Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a methanesulfonamido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors.  

PubMed

A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO(2)NH, or N(3), COX-2 pharmacophore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 phenyl ring (4-H, 4-Me, 4-F, and 4-OMe). Among the 1,3-diphenylprop-2-en-1-ones possessing a C-1 para-MeSO(2)NH COX-2 pharmacophore, (E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) was identified as a selective COX-2 inhibitor (COX-2 IC(50)=1.0 microM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC(50)=0.50 microM; SI>200). The corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N(3) COX-2 pharmacophore, (E)-1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7f), exhibited potent and selective COX-2 inhibition (COX-1 IC(50)=22.2 microM; COX-2 IC(50)=0.3 microM; SI=60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that the p-MeSO(2)NH and N(3) substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90, Arg513, Phe518, and Val523). The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity. PMID:16798002

Zarghi, Afshin; Zebardast, Tannaz; Hakimion, Farinaz; Shirazi, Farshad H; Rao, P N Praveen; Knaus, Edward E

2006-06-22

280

Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids  

PubMed Central

Background and purpose: Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB1) receptors was determined. Experimental approach: Effects of spinal and peripheral administration of nimesulide (1–100 µg per 50 µL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB1 receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry. Key results: Spinal, but not peripheral, injection of nimesulide (1–100 µg per 50 µL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB1 receptor antagonist AM251 (1 µg per 50 µL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide. Conclusions and implications: Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB1 receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x

Staniaszek, LE; Norris, LM; Kendall, DA; Barrett, DA; Chapman, V

2010-01-01

281

Arachidonic acid supplementation enhances in vitro skeletal muscle cell growth via a COX-2-dependent pathway.  

PubMed

Arachidonic acid (AA) is the metabolic precursor to a diverse range of downstream bioactive lipid mediators. A positive or negative influence of individual eicosanoid species [e.g., prostaglandins (PGs), leukotrienes, and hydroxyeicosatetraenoic acids] has been implicated in skeletal muscle cell growth and development. The collective role of AA-derived metabolites in physiological states of skeletal muscle growth/atrophy remains unclear. The present study aimed to determine the direct effect of free AA supplementation and subsequent eicosanoid biosynthesis on skeletal myocyte growth in vitro. C2C12 (mouse) skeletal myocytes induced to differentiate with supplemental AA exhibited dose-dependent increases in the size, myonuclear content, and protein accretion of developing myotubes, independent of changes in cell density or the rate/extent of myogenic differentiation. Nonselective (indomethacin) or cyclooxygenase 2 (COX-2)-selective (NS-398) nonsteroidal anti-inflammatory drugs blunted basal myogenesis, an effect that was amplified in the presence of supplemental free AA substrate. The stimulatory effects of AA persisted in preexisting myotubes via a COX-2-dependent (NS-389-sensitive) pathway, specifically implying dependency on downstream PG biosynthesis. AA-stimulated growth was associated with markedly increased secretion of PGF(2?) and PGE(2); however, incubation of myocytes with PG-rich conditioned medium failed to mimic the effects of direct AA supplementation. In vitro AA supplementation stimulates PG release and skeletal muscle cell hypertrophy via a COX-2-dependent pathway. PMID:23076795

Markworth, James F; Cameron-Smith, David

2012-10-17

282

Selective serotonin reuptake inhibitors and myocardial infarction  

Microsoft Academic Search

Background—Depression is an independent risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors (SSRIs) may reduce this risk through attenuation of serotonin-mediated platelet activation in addition to treatment of depression itself. Methods and Results—A case-control study of first MI in smokers 30 to 65 years of age was conducted among all 68 hospitals in an 8-county area during a

William H. Sauer; Jesse A. Berlin; Stephen E. Kimmel

2002-01-01

283

Honokiol inhibits gastric tumourigenesis by activation of 15-lipoxygenase-1 and consequent inhibition of peroxisome proliferator-activated receptor-? and COX-2-dependent signals  

PubMed Central

Background and purpose: Peroxisome proliferator-activated receptor-? (PPAR-?), COX-2 and 15-lipoxygenase (LOX)-1 have been shown to be involved in tumour growth. However, the roles of PPAR-?, COX-2 or 15-LOX-1 in gastric tumourigenesis remain unclear. Here, we investigate the role of 15-LOX-1 induction by honokiol, a small-molecular weight natural product, in PPAR-? and COX-2 signalling during gastric tumourigenesis. Experimental approach: Human gastric cancer cell lines (AGS, MKN45, N87 and SCM-1) were cultured with or without honokiol. Gene and protein expressions were analysed by RT–PCR and Western blotting respectively. Small interfering RNAs (siRNAs) for COX-2, PPAR-? and 15-LOX-1 were used to interfere with the expressions of these genes. A xenograft gastric tumour model in mouse was used for in vivo study. Key results: PPAR-? and COX-2 proteins were highly expressed in gastric cancer cells. Inhibitors, or siRNA for COX-2 or PPAR-?, significantly decreased cell viability. Honokiol markedly inhibited PPAR-? and COX-2 expressions in gastric cancer cells and tumours of xenograft mice, and induced apoptosis and cell death. Honokiol markedly activated cellular 15-LOX-1 expression and 13-S-hydroxyoctadecadienoic acid (a primary product of 15-LOX-1 metabolism of linoleic acid) production. 15-LOX-1 siRNA could reverse the honokiol-induced down-regulation of PPAR-? and COX-2, and cell apoptosis. 15-LOX-1 was markedly induced in tumours of xenograft mice treated with honokiol. Conclusions and implications: These findings suggest that induction of 15-LOX-1-mediated down-regulation of a PPAR-? and COX-2 pathway by honokiol may be a promising therapeutic strategy for gastric cancer.

Liu, Shing Hwa; Shen, Chin Chang; Yi, Yu Chiao; Tsai, Jaw Ji; Wang, Chih Chien; Chueh, Ju Ting; Lin, Keh Liang; Lee, Tso Ching; Pan, Hung Chuan; Sheu, Meei Ling

2010-01-01

284

Effects of Cyclooxygenase Inhibitors on Apoptotic Neuroretinal Cells  

PubMed Central

Glaucoma is characterized by a loss of retinal ganglion cells (RGC) which is associated with a decrease of visual function. Neuroprotective agents as a new therapeutic strategy could prevent the remaining neurons from apoptotic cell death. Previous studies have shown the involvement of the Cyclooxygenase (COX)-2 signalling in the apoptotic death of neurons. Herein we investigated the neuroprotective effect of COX-1/COX-2- and selective COX-2- inhibitors on apoptotic. R28, a neuroretinal cell line and determined the PGE2 levels by ELISA. Furthermore we investigated differences in protein expression in the cells after exposure to elevated pressure compared to untreated cells by ProteinChip analysis. In addition, a protein profiling study of the cells after exposure to elevated pressure was performed. The protein expression profiles were measured by SELDI-TOF (Surface Enhanced Laser Desorption/Ionization-time of flight) Protein Chips. The protein identification was performed by mass spectrometry (MS). It could be shown that COX-2 inhibition significantly prevented the cells from apoptosis and reduced the PGE2 concentrations. Selective COX-2 inhibitors were significant more potent than non-selective inhibitors or COX-1 inhibitors. We found differently expressed protein patterns in neuroretinal cells cultured at atmospheric pressure compared to those cells exposed to elevated pressure with or without celecoxib respectively. We identified three biomarkers, ubiquitin, HSP10 and NDKB, which were differently expressed in the groups. However, our data indicates a distinct neuroprotective effect of COX-2 inhibition. The local treatment with selective COX-2 inhibitors might provide an innovative strategy of therapeutic intervention for glaucoma.

Brust, Anja-Kristina; Ulbrich, Holger K.; Seigel, Gail M.; Pfeiffer, Norbert; Grus, Franz H.

2008-01-01

285

Effect of a cyclooxygenase-2 inhibitor on postexercise muscle protein synthesis in humans  

PubMed Central

Nonselective blockade of the cyclooxygenase (COX) enzymes in skeletal muscle eliminates the normal increase in muscle protein synthesis following resistance exercise. The current study tested the hypothesis that this COX-mediated increase in postexercise muscle protein synthesis is regulated specifically by the COX-2 isoform. Sixteen males (23 ± 1 yr) were randomly assigned to one of two groups that received three doses of either a selective COX-2 inhibitor (celecoxib; 200 mg/dose, 600 mg total) or a placebo in double-blind fashion during the 24 h following a single bout of knee extensor resistance exercise. At rest and 24 h postexercise, skeletal muscle protein fractional synthesis rate (FSR) was measured using a primed constant infusion of [2H5]phenylalanine coupled with muscle biopsies of the vastus lateralis, and measurements were made of mRNA and protein expression of COX-1 and COX-2. Mixed muscle protein FSR in response to exercise (P < 0.05) was not suppressed by the COX-2 inhibitor (0.056 ± 0.004 to 0.108 ± 0.014%/h) compared with placebo (0.074 ± 0.004 to 0.091 ± 0.005%/h), nor was there any difference (P > 0.05) between the placebo and COX-2 inhibitor postexercise when controlling for resting FSR. The COX-2 inhibitor did not influence COX-1 mRNA, COX-1 protein, or COX-2 protein levels, whereas it did increase (P < 0.05) COX-2 mRNA (3.0 ± 0.9-fold) compared with placebo (1.3 ± 0.3-fold). It appears that the elimination of the postexercise muscle protein synthesis response by nonselective COX inhibitors is not solely due to COX-2 isoform blockade. Furthermore, the current data suggest that the COX-1 enzyme is likely the main isoform responsible for the COX-mediated increase in muscle protein synthesis following resistance exercise in humans.

Burd, Nicholas A.; Dickinson, Jared M.; LeMoine, Jennifer K.; Carroll, Chad C.; Sullivan, Bridget E.; Haus, Jacob M.; Jemiolo, Bozena; Trappe, Scott W.; Hughes, Gordon M.; Sanders, Charles E.

2010-01-01

286

Contribution of Vasoactive Eicosanoids and Nitric Oxide Production to the Effect of Selective Cyclooxygenase-2 Inhibitor, NS-398, on Endotoxin-Induced Hypotension in Rats  

PubMed Central

Our previous studies with the use of non-selective cyclooxygenase (COX) inhibitor, indomethacin, demonstrated that prostanoids produced during endotoxaemia increase inducible nitric oxide (NO) synthase (iNOS) protein expression and NO synthesis, and decrease cyctochrome P450 (CYP) 4A1 protein expression and CYP 4A activity. The results suggest that dual inhibition of iNOS and COX by indomethacin restores blood pressure presumably due to increased production of 20-hydroxyeicosatetraenoic acid (20-HETE) derived from CYP 4A in endotoxaemic rats. The present study examined whether increased levels of vasoconstrictor eicosanoids, 20-HETE, PGF2? and thromboxane A2 (TxA2), would contribute to the effect of selective COX-2 inhibition to prevent endotoxin-induced fall in blood pressure associated with an increase in the production of vasodilator prostanoids, PGI2 and PGE2 and NO synthesis. Mean arterial blood pressure fell by 31 mmHg and heart rate rose by 90 beats per min. in male Wistar rats treated with endotoxin (10 mg/kg, i.p.). The fall in mean arterial pressure and increase in heart rate were associated with increased levels of 6-keto-PGF1?, PGE2, TxB2, and nitrite in the serum, kidney, heart, thoracic aorta and/or superior mesenteric artery. Systemic and renal 20-HETE and PGF2? levels were also decreased in endotoxaemic rats. These effects of endotoxin were prevented by a selective COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)-methansulphonamide (10 mg/kg, i.p.), given 1 hr after injection of endotoxin. These data suggest that an increase in 20-HETE and PGF2? levels associated with decreased production of PGI2, PGE2, and TxA2, and NO synthesis contributes to the effect of selective COX-2 inhibitor to prevent the hypotension during rat endotoxaemia.

Tunctan, Bahar; Korkmaz, Belma; Cuez, Tuba; Buharalioglu, C. Kemal; Sahan-Firat, Seyhan; Falck, John; Malik, Kafait U.

2010-01-01

287

HB-EGF induces cardiomyocyte hypertrophy via an ERK5-MEF2A-COX2 signaling pathway.  

PubMed

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family that binds to and activates the EGF receptor. Transactivated by angiotensin II, ET-1, and various growth factors in cardiomyocytes, HB-EGF is known to induce cardiac hypertrophy via the PI3K-Akt, MAP kinase, and JAK-STAT pathways. However, little is known about the potential involvement of the ERK5 pathway in HB-EGF-induced cardiac hypertrophy. In the present report, we identify and characterize a novel MEK5-ERK5 pathway that is involved in HB-EGF-induced cardiomyocyte hypertrophy. HB-EGF (10ng/ml) significantly increased [(3)H]-leucine incorporation and atrial natriuretic factor (ANF) mRNA expression in H9c2 cells. In addition, HB-EGF activated a MEK5-ERK5 pathway. Pretreatment with the EGFR inhibitor AG1478 attenuated the activation of ERK5. Blockade of MEK5-ERK5 signaling using MEK5 siRNA reduced the ability of HB-EGF to increase cell size and the expression of ANF mRNA, suggesting the involvement of an EGFR-ERK5 pathway in HB-EGF-induced cardiomyocyte hypertrophy. We further analyzed cyclooxygenase-2 (COX-2). HB-EGF enhanced the expression of COX-2, a response mediated by MEK5-ERK5 signaling, while the COX-2 inhibitor rofecoxib attenuated HB-EGF-induced ANF mRNA expression, suggesting that COX-2 is also associated with HB-EGF-induced cardiomyocyte hypertrophy. It has been known that ERK5 activates the myocyte enhancer factor (MEF) 2 family of transcription factor, we next tested whether activation of MEF2A contributes to HB-EGF-induced COX-2 expression. Inhibition of MEF2A using siRNA attenuated HB-EGF-induced COX-2, ANF expression and cell size. In conclusion, HB-EGF induces cardiomyocyte hypertrophy through an EGFR-ERK5-MEF2A-COX-2 pathway. Our findings will help us to better understand the molecular mechanisms behind HB-EGF-induced cardiomyocyte hypertrophy. PMID:21244855

Lee, Kuy-Sook; Park, Jin-Hee; Lim, Hyun-Joung; Park, Hyun-Young

2011-01-16

288

Selection of small peptides, inhibitors of translation  

PubMed Central

Identification of small molecular weight compounds targeting specific sites in the ribosome can accelerate development of new antibiotics and provide new tools for ribosomal research. We demonstrate here that antibiotic-size short peptides capable of inhibiting protein synthesis can be selected by using specific elements of ribosomal RNA as a target. The ‘h18’ pseudoknot encompassing residues 500-545 of the small ribosomal subunit RNA was used as a target in screening a heptapeptide phage display library. Two of the selected peptides could efficiently interfere with both bacterial and eukaryotic translation. One of these inhibitory peptides exhibited a high-affinity binding to the isolated small ribosomal subunit (Kd of 1.1 ?M). Identification of inhibitory peptides which likely target a specific rRNA structure may pave new ways for validating new antibiotic sites in the ribosome. The selected peptides can be used as a tool in search of novel site-specific inhibitors of translation.

Llano-Sotelo, Beatriz; Klepacki, Dorota; Mankin, Alexander S.

2009-01-01

289

Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX2 dependent manner  

Microsoft Academic Search

Objective  Naturally occurring regulatory T (TR) cells suppress autoreactive T cells whereas adaptive TR cells, induced in the periphery, play an important role in chronic viral diseases and cancer. Several studies indicate that\\u000a cyclooxygenase (COX) inhibitors prevent cancer development of colon adenomas and delay disease progression in patients with\\u000a colorectal cancer (CRC). We have shown that adaptive TR cells express COX-2

Sheraz Yaqub; Karen Henjum; Milada Mahic; Frode L. Jahnsen; Einar M. Aandahl; Bjørn A. Bjørnbeth; Kjetil Taskén

2008-01-01

290

Angiostatic role of the selective cyclooxygenase-2 inhibitor etoricoxib (MK0663) in experimental lung cancer.  

PubMed

Lung cancer was induced in Sprague-Dawley rats by a single intra-tracheal instillation of 9,10-dimethybenz(a)anthracene (DMBA) and evaluated the anti-angiogenic action of etoricoxib, which is a selective cyclooxygenase-2 (COX-2) inhibitor. The animals were divided into four groups. Group 1 (Control) received 0.9% (w/v) normal saline intra-tracheal and 0.5% (w/v) carboxymethyl cellulose per oral daily as the vehicle of the drug, Group 2 received DMBA (20 mg/kg) intra-tracheal once, Group 3 received a daily oral dose of etoricoxib (0.6 mg/kg bw) in addition to the DMBA while Group 4 received etoricoxib alone. Morphological and histological analysis confirmed the presence of lung tumors 20 weeks after the administration of DMBA. Expressions of COX-2, MMP-2, MMP-9, MCP-1, MIP-1? and VEGF were studied by immunofluorescence, Western immunoblot and mRNA studies, which showed a higher expression of these proteins in the DMBA-treated animals but much lower in DMBA+etoricoxib. Gelatin zymography as applied for the detection of the extracellular protein degrading enzymes, matrix metalloproteinases showed more intense activity in DMBA-treated rats as compared to the other groups. Also, the isolated alveolar macrophages were stained with Merocyanine540 (MC540) to study the membrane fluidity and lipid packing effect. DMBA treatment resulted in a significant increase in the number of lung cells exhibiting a high intensity of MC540 staining, which was reduced by the co-administration of etoricoxib. Thus the effects of etoricoxib on the expression of the angiogenic proteins have been observed, which clearly shows an anti-angiogenic mechanism of action of etoricoxib in lung cancer chemoprevention. PMID:22681911

Nadda, N; Vaish, V; Setia, S; Sanyal, S N

2012-05-10

291

Celecoxib prevents tumor growth in an animal model by a COX2 independent mechanism  

Microsoft Academic Search

Purpose  Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to reduce cell growth in several tumors. Among these possible\\u000a antineoplastic drugs are cyclooxygenase-2 (COX-2)-selective drugs, such as celecoxib, in which antitumoral mechanisms were\\u000a evaluated in rats bearing Walker-256 (W256) tumor.\\u000a \\u000a \\u000a \\u000a Methods  W256 carcinosarcoma cells were inoculated subcutaneously (107 cells\\/rat) in rats submitted to treatment with celecoxib (25 mg kg?1) or vehicle for 14 days. Tumor growth,

Amanda Leite Bastos-Pereira; Daiana Lugarini; Adriana de Oliveira-Christoff; Thiago Vinicius Ávila; Simone Teixeira; Amanda do Rocio Andrade Pires; Sílvia Maria Suter Correia Cadena; Lucélia Donatti; Helena Cristina da Silva de Assis; Alexandra Acco

2010-01-01

292

Cyclooxygenase2 (COX2) expression at the site of recent myocardial infarction: friend or foe?  

Microsoft Academic Search

Background: Cyclo-oxygenase-2 (COX-2) is induced in cardiomyocytes only in response to stress, such as ischaemia.Objective: To assess COX-2 expression at the site of recent myocardial infarction.Methods: COX-2 expression was evaluated by specific immunostaining in cardiomyocytes from 23 subjects who died 10–60 days after acute myocardial infarction. The relation between COX-2 myocardial expression and apoptotic rate was investigated. Cardiomyocyte apoptotic rate

A Abbate; D Santini; G G L Biondi-Zoccai; S Scarpa; F Vasaturo; G Liuzzo; R Bussani; F Silvestri; F Baldi; F Crea; L M Biasucci; A Baldi

2004-01-01

293

Synthesis and biological evaluation of new 4-carboxyl quinoline derivatives as cyclooxygenase-2 inhibitors  

Microsoft Academic Search

A group of 4-carboxyl quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1\\/COX-2 structure–activity relationships were determined by varying the substituents on the C-7 and C-8 quinoline ring. Among the 4-carboxyl quinolines, 7,8,9,10-tetrahydro-2-(4-(methyl sulfonyl)phenyl)benzo[h]quinoline-4-carboxylic acid (9e) was identified as potent and high

Afshin Zarghi; Razieh Ghodsi; Ebrahim Azizi; Bahram Daraie; Mehdi Hedayati; Orkideh G. Dadrass

2009-01-01

294

Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib.  

PubMed

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 µM and remained sufficient to completely inhibit prostaglandin E(2) production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity. PMID:22678114

Kirane, Amanda; Toombs, Jason E; Larsen, Jill E; Ostapoff, Katherine T; Meshaw, Kathryn R; Zaknoen, Sara; Brekken, Rolf A; Burrows, Francis J

2012-06-07

295

Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression  

PubMed Central

Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E2 (PGE2), an autocrine inhibitor of fibrogenesis. Exogenous PGE2 or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE2, in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis.

Liu, Fei; Mih, Justin D.; Shea, Barry S.; Kho, Alvin T.; Sharif, Asma S.; Tager, Andrew M.

2010-01-01

296

Post-exposure therapeutic efficacy of COX-2 inhibition against Burkholderia pseudomallei.  

PubMed

Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus and the etiologic agent of melioidosis, a severe disease in Southeast Asia and Northern Australia. Like other multidrug-resistant pathogens, the inherent antibiotic resistance of B. pseudomallei impedes treatment and highlights the need for alternative therapeutic strategies that can circumvent antimicrobial resistance mechanisms. In this work, we demonstrate that host prostaglandin E2 (PGE2) production plays a regulatory role in the pathogenesis of B. pseudomallei. PGE2 promotes B. pseudomallei intracellular survival within macrophages and bacterial virulence in a mouse model of pneumonic melioidosis. PGE2-mediated immunosuppression of macrophage bactericidal effector functions is associated with increased arginase 2 (Arg2) expression and decreased nitric oxide (NO) production. Treatment with a commercially-available COX-2 inhibitor suppresses the growth of B. pseudomallei in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to B. pseudomallei-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with B. pseudomallei and other intracellular pathogens. PMID:23675544

Asakrah, Saja; Nieves, Wildaliz; Mahdi, Zaid; Agard, Mallory; Zea, Arnold H; Roy, Chad J; Morici, Lisa A

2013-05-09

297

Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib  

PubMed Central

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2–4 µM and remained sufficient to completely inhibit prostaglandin E2 production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial–mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.

Burrows, Francis J

2012-01-01

298

TLR4-mediated Cox-2 expression increases intestinal ischemia/reperfusion-induced damage  

PubMed Central

Mesenteric IR induces significant inflammation and immune-mediated mucosal damage. TLR4 is a critical receptor in the induction of the inflammatory response and plays a role in intestinal homeostasis. To determine the role of TLR4 in IR-induced epithelial damage, we performed IR studies using TLR4lps-def and TLR4lps-n mice and analyzed mucosal damage and inflammation. We found that the absence of TLR4 or TLR4-induced signaling attenuated local mucosal damage with significantly decreased cytokine and eicosanoid secretion including PGE2 production. Similar results were seen in MyD88?/? mice. Wild-type mice treated with NS-398 (a Cox-2 inhibitor) not only decreased PGE2 production but also attenuated tissue damage. In contrast, PGE2 was not sufficient to induce damage in the TLR4lps-def mice. Together, these data indicate that TLR4 stimulation of Cox-2 activation of PGE2 production is necessary but not sufficient for intestinal IR-induced damage and inflammation.

Moses, Tiffany; Wagner, Lynn; Fleming, Sherry D.

2009-01-01

299

The role of osmotic polysorbitol-based transporter in RNAi silencing via caveolae-mediated endocytosis and COX-2 expression.  

PubMed

Polymeric diversity allows us to design gene carriers as an alternative to viral vectors, control cellular uptake, target intracellular molecules, and improve transfection and silencing capacity. Recently, we developed a polysorbitol-based osmotically active transporter (PSOAT), which exhibits several interesting mechanisms to accelerate gene delivery into cells. Herein, we report the efficacy of using the PSOAT system for small interfering RNA (siRNA) delivery and its specific mechanism for cellular uptake to accelerate targeted gene silencing. We found that PSOAT functioned via a caveolae-mediated uptake mechanism due to hyperosmotic activity of the transporter. Moreover, this selective caveolae-mediated endocytosis of the polyplexes (PSOAT/siRNA) was regulated coincidently with the expression of caveolin (Cav)-1 and cyclooxygenase (COX)-2. Interestingly, COX-2 expression decreased dramatically over time due to degradation by the constant expression of Cav-1, as confirmed by high COX-2 expression after the inhibition of Cav-1, suggesting that PSOAT-mediated induction of Cav-1 directly influenced the selective caveolae-mediated endocytosis of the polyplexes. Furthermore, COX-2 expression was involved in the initial phase for rapid caveolae endocytic uptake of the particles synergistically with Cav-1, resulting in accelerated PSOAT-mediated target gene silencing. PMID:22975426

Islam, Mohammad Ariful; Shin, Ji-Young; Firdous, Jannatul; Park, Tae-Eun; Choi, Yun-Jaie; Cho, Myung-Haing; Yun, Cheol-Heui; Cho, Chong-Su

2012-09-11

300

Revaprazan, a novel acid pump antagonist, exerts anti-inflammatory action against Helicobacter pylori-induced COX-2 expression by inactivating Akt signaling  

PubMed Central

Chronic gastric inflammation developing after Helicobacter pylori (H. pylori) infection is responsible for either dyspeptic symptom relevant to gastritis/peptic ulcer or gastric tumorigenesis, in which acid suppressants, especially proton pump inhibitors (PPIs), play role in relieving dyspepsia as well as the eradication regimen. Among several mediators engaged in propagating gastric inflammation after H. pylori infection, cyclooxygenase-2 (COX-2) might be the principal one, and several prescriptions have been made for decreasing the COX-2 levels. Multiple line of evidence are available for anti-inflammatory action of PPIs beyond acid suppression, but revaprazan, a novel acid pump antagonist launched in clinic, has also been suggested to exert significant anti-inflammatory actions as much as PPI. In the current study, we hypothesized that revaprazan could regulate H. pylori-driven COX-2 expression as one of its anti-inflammatory pharmacological actions. The changes of gastric COX-2 expression as well as responsible transcription factors were measured after H. pylori infection in the presence or absence of revaprazan. Infection of AGS cells with H. pylori induced significant up-regulation of COX-2 in time- and concentration-dependent manners, which was mediated by Akt phosphorylation. Revaprazan treatment significantly inhibited IkappaB-alpha degradation as well as Akt inactivation, resulting in attenuation of H. pylori-induced COX-2 expression. Additional rescuing action of revaprazan against H. pylori-induced cytotoxicity was noted. In conclusion, revaprazan imposed significant anti-inflammatory actions on H. pylori infection beyond acid suppression.

Lee, Jeong-Sang; Cho, Ji-Yoon; Song, Heup; Kim, Eun-Hee; Hahm, Ki-Baik

2012-01-01

301

Inhibition of COX-2 in Colon Cancer Modulates Tumor Growth and MDR-1 Expression to Enhance Tumor Regression in Therapy-Refractory Cancers In Vivo12  

PubMed Central

Higher cyclooxygenase 2 (COX-2) expression is often observed in aggressive colorectal cancers (CRCs). Here, we attempt to examine the association between COX-2 expression in therapy-refractory CRC, how it affects chemosensitivity, and whether, in primary tumors, it is predictive of clinical outcomes. Our results revealed higher COX-2 expression in chemoresistant CRC cells and tumor xenografts. In vitro, the combination of either aspirin or celecoxib with 5-fluorouracil (5-FU) was capable of improving chemosensitivity in chemorefractory CRC cells, but a synergistic effect with 5-FU could only be demonstrated with celecoxib. To examine the potential clinical significance of these observations, in vivo studies were undertaken, which also showed that the greatest tumor regression was achieved in chemoresistant xenografts after chemotherapy in combination with celecoxib, but not aspirin. We also noted that these chemoresistant tumors with higher COX-2 expression had a more aggressive growth rate. Given the dramatic response to a combination of celecoxib + 5-FU, the possibility that celecoxib may modulate chemosensitivity as a result of its ability to inhibit MDR-1 was examined. In addition, assessment of a tissue microarray consisting of 130 cases of CRCs revealed that, in humans, higher COX-2 expression was associated with poorer survival with a 68% increased risk of mortality, indicating that COX-2 expression is a marker of poor clinical outcome. The findings of this study point to a potential benefit of combining COX-2 inhibitors with current regimens to achieve better response in the treatment of therapy-refractory CRC and in using COX-2 expression as a prognostic marker to help identify individuals who would benefit the greatest from closer follow-up and more aggressive therapy.

Rahman, Mahbuba; Selvarajan, Krithika; Hasan, Mohammad R; Chan, Annie P; Jin, Chaoyang; Kim, Jieun; Chan, Simon K; Le, Nhu D; Kim, Young-Bae; Tai, Isabella T

2012-01-01

302

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes*  

PubMed Central

Pathological conditions and pro-inflammatory stimuli in the brain induce cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism mediating the production of prostanoids that, among other actions, have strong vasoactive properties. Although low basal cerebral COX-2 expression has been reported, COX-2 is strongly induced by pro-inflammatory challenges, whereas COX-1 is constitutively expressed. However, the contribution of these enzymes in prostanoid formation varies depending on the stimuli and cell type. Astrocyte feet surround cerebral microvessels and release molecules that can trigger vascular responses. Here, we investigate the regulation of COX-2 induction and its role in prostanoid generation after a pro-inflammatory challenge with the bacterial lipopolysaccharide (LPS) in astroglia. Intracerebral administration of LPS in rodents induced strong COX-2 expression mainly in astroglia and microglia, whereas COX-1 expression was predominant in microglia and did not increase. In cultured astrocytes, LPS strongly induced COX-2 and microsomal prostaglandin-E2 (PGE2) synthase-1, mediated by the MyD88-dependent NF?B pathway and influenced by mitogen-activated protein kinase pathways. Studies in COX-deficient cells and using COX inhibitors demonstrated that COX-2 mediated the high production of PGE2 and, to a lesser extent, other prostanoids after LPS. In contrast, LPS down-regulated COX-1 in an MyD88-dependent fashion, and COX-1 deficiency increased PGE2 production after LPS. The results show that astrocytes respond to LPS by a COX-2-dependent production of prostanoids, mainly vasoactive PGE2, and suggest that the coordinated down-regulation of COX-1 facilitates PGE2 production after TLR-4 activation. These effects might induce cerebral blood flow responses to brain inflammation.

Font-Nieves, Miriam; Sans-Fons, M. Gloria; Gorina, Roser; Bonfill-Teixidor, Ester; Salas-Perdomo, Angelica; Marquez-Kisinousky, Leonardo; Santalucia, Tomas; Planas, Anna M.

2012-01-01

303

A Cross-Talk Between NFAT and NF-?B Pathways is Crucial for Nickel-Induced COX-2 Expression in Beas-2B Cells  

PubMed Central

Cyclooxygenase-2 (COX-2) is a critical enzyme implicated in chronic inflammation-associated cancer development. Our studies have shown that the exposure of Beas-2B cells, a human bronchial epithelial cell line, to lung carcinogenic nickel compounds results in increased COX-2 expression. However, the signaling pathways leading to nickel-induced COX-2 expression are not well understood. In the current study, we found that the exposure of Beas-2B cells to nickel compounds resulted in the activation of both nuclear factor of activated T cell (NFAT) and nuclear factor-?B (NF-?B). The expression of COX-2 induced upon nickel exposure was inhibited by either a NFAT pharmacological inhibitor or the knockdown of NFAT3 by specific siRNA. We further found that the activation of NFAT and NF-?B was dependent on each other. Since our previous studies have shown that NF-?B activation is critical for nickel-induced COX-2 expression in Beas-2B cells exposed to nickel compounds under same experimental condition, we anticipate that there might be a cross-talk between the activation of NFAT and NF-?B for the COX-2 induction due to nickel exposure in Beas-2B cells. Furthermore, we showed that the scavenging of reactive oxygen species (ROS) by introduction of mitochondrial catalase inhibited the activation of both NFAT and NF-?B, and the induction of COX-2 due to nickel exposure. Taken together, our results defining the evidence showing a key role of the cross-talk between NFAT and NF-?B pathways in regulating nickel-induced COX-2 expression, further provide insight into the understanding of the molecular mechanisms linking nickel exposure to its lung carcinogenic effects.

Cai, T.; Li, X.; Ding, J.; Luo, W.; Li, J.; Huang, C.

2013-01-01

304

Prolonged opportunity for neuroprotection in experimental stroke with selective blockade of cyclooxygenase-2 activity  

Microsoft Academic Search

The post-treatment effects of the selective cyclooxygenase (COX)-2 inhibitor, valdecoxib, were investigated in a rat model of temporary focal ischemia. Valdecoxib reduced basal brain prostaglandin E2 concentrations at dosages that did not affect serum thromboxane B2, consistent with a selective COX-2 effect. Temporary focal cerebral ischemia was produced in rats by middle cerebral artery occlusion for 90 min. There was increased

Muzamil Ahmad; Yuquin Zhang; Hao Liu; Marie E. Rose; Steven H. Graham

2009-01-01

305

Paradoxical effects of a selective cyclooxygenase-2 inhibitor, etodolac, on proliferative changes of forestomach in alloxan-induced diabetic rats.  

PubMed

A single intravenous injection of alloxan, a non-genotoxic diabetogenic chemical, induces proliferative changes in forestomach mucosa of rats, and some lesions progress to squamous cell carcinoma accompanied with inflammatory change. The present study was conducted to examine the effects of a selective cyclooxygenase-2 (COX-2) inhibitor, etodolac, on the proliferative changes of forestomach mucosa in alloxan-induced diabetic rats. Alloxan-induced diabetic rats were fed a diet containing 0.01% etodolac (AL+Et group) and standard diet (AL group). They were sacrificed after 25 and 50 weeks of feeding, respectively. Squamous cell hyperplasia of forestomach was completely suppressed by etodolac after 25 weeks. After 50 weeks of treatment, the proliferative changes in forestomach developed in all rats of the AL+Et group, but in only 55.6% of the rats in the AL group. The severity of proliferative lesions was much enhanced in the AL+Et group compared to the AL group, and was parallel to the inflammatory changes in individual cases. Ulceration and erosion were more severe in the AL+Et group. These findings demonstrate that etodolac suppresses proliferative and inflammatory changes with COX-2 expression of forestomach in the early stage, but enhances them after 50 weeks. PMID:19081232

Sano, Tomoya; Ozaki, Kiyokazu; Kodama, Yasushi; Matsuura, Tetsuro; Narama, Isao

2008-12-09

306

Endothelium-mediated control of vascular tone: COX-1 and COX-2 products  

PubMed Central

Endothelium-dependent contractions contribute to endothelial dysfunction in various animal models of aging, diabetes and cardiovascular diseases. In the spontaneously hypertensive rat, the archetypal model for endothelium-dependent contractions, the production of the endothelium-derived contractile factors (EDCF) involves an increase in endothelial intracellular calcium concentration, the production of reactive oxygen species, the predominant activation of cyclooxygenase-1 (COX-1) and to a lesser extent that of COX-2, the diffusion of EDCF towards the smooth muscle cells and the subsequent stimulation of their thromboxane A2-endoperoxide TP receptors. Endothelium-dependent contractions are also observed in various models of hypertension, aging and diabetes. They generally also involve the generation of COX-1- and/or COX-2-derived products and the activation of smooth muscle TP receptors. Depending on the model, thromboxane A2, PGH2, PGF2?, PGE2 and paradoxically PGI2 can all act as EDCFs. In human, the production of COX-derived EDCF is a characteristic of the aging and diseased blood vessels, with essential hypertension causing an earlier onset and an acceleration of this endothelial dysfunction. As it has been observed in animal models, COX-1, COX-2 or both isoforms can contribute to these endothelial dysfunctions. Since in most cases, the activation of TP receptors is the common downstream effector, selective antagonists of this receptor should curtail endothelial dysfunction and be of therapeutic interest in the treatment of cardiovascular disorders. LINKED ARTICLES This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-3

Feletou, Michel; Huang, Yu; Vanhoutte, Paul M

2011-01-01

307

Conditional knockout mouse for tissue-specific disruption of the cyclooxygenase-2 (Cox-2) gene.  

PubMed

Cyclooxygenase-2 (Cox-2) modulates many normal functions, and appears to play a role in a wide variety of pathophysiologic conditions. Cox-2 gene expression is induced in many different cell types, in response to many distinct stimuli. We generated a conditional knockout mouse in which critical exons of the Cox-2 gene are flanked with loxP sites. Cox-2(flox/flox) mice appear normal and are fertile. Recombination at the loxP sites, loss of Cox-2 protein expression, and prevention of induced PGE2 accumulation are observed in Cox-2(flox/flox) mouse embryo fibroblasts following infection with an adenovirus expressing CRE recombinase. In vivo recombination at the Cox-2(flox) allele was demonstrated in the liver of Cox-2(flox/flox) mice following intravenous injection of adenovirus expressing CRE recombinase. Spatially and temporally restricted elimination of the Cox-2 gene in Cox-2(flox/flox) conditional knockout mice should provide a valuable tool to analyze the cell type-specific role of Cox-2 in many disease models. PMID:16496341

Ishikawa, Tomo-O; Herschman, Harvey R

2006-03-01

308

Dynamic compression inhibits fibronectin fragment induced iNOS and COX-2 expression in chondrocyte/agarose constructs.  

PubMed

Mechanical loading and the fibronectin fragments (FN-fs) are known to stimulate the anabolic and catabolic processes in articular cartilage, possible through pathways mediated by *NO. This study examined the combined effects of dynamic compression and the NH(2)-hep I or COOH-hep II FN-fs on the expression levels of iNOS and COX-2 and production of *NO and PGE(2) release. Both types of fragments induced iNOS and COX-2 expression and stimulated the production of *NO release. This response was inhibited by dynamic compression. Inhibitor experiments indicated that both dynamic compression and the iNOS inhibitor were important in restoring cell proliferation and proteoglycan synthesis in the presence of the FN-fs. This is the first study which demonstrates a downregulation of the FN-f-induced iNOS and COX-2 expression by dynamic compression. The combination of mechanical and pharmacological interventions makes this study a powerful tool to examine further the interactions of biomechanics and cell signalling in osteoarthritis. PMID:18677626

Raveenthiran, S P; Chowdhury, T T

2008-08-03

309

COX-2 and p53 in human sinonasal cancer: COX-2 expression is associated with adenocarcinoma histology and wood-dust exposure  

PubMed Central

The causal role of wood-dust exposure in sinonasal cancer (SNC) has been established in epidemiological studies, but the mechanisms of SNC carcinogenesis are still largely unknown. Increased amounts of COX-2 are found in both premalignant and malignant tissues, and experimental evidence link COX-2 to development of cancer. Many signals that activate COX-2 also induce tumour suppressor p53, a transcription factor central in cellular stress response. We investigated COX-2 and p53 expressions by immunohistochemistry in 50 SNCs (23 adenocarcinomas, and 27 squamous cell carcinomas (SCC); 48 analysed for COX-2; 41 for p53). Occupational histories and smoking habits were available for majority of the cases. Most of the adenocarcinoma cases with exposure history data had been exposed to wood-dust at work in the past (88 %, 14/16). For smokers, 63 % (12/19) presented with SSC, whereas 64 % (7/11) of non-smokers displayed adenocarcinoma. COX-2 was expressed at high levels in adenocarcinoma as compared to SSC (p < 0,001). COX-2 expression showed significant association with occupational exposure to wood dust (p = 0.024), and with non-smoking status (p = 0.001). No statistically significant associations between the exposures and p53 accumulation were found; however, the p53 accumulation pattern (p = 0.062 for wood dust exposure) resembled that of COX-2 expression. In summary, our findings show increased COX-2 expression in SNC adenocarcinoma with wood dust exposure, suggesting a role for inflammatory components in the carcinogenesis process. In contrast, SCCs predominated among smokers and expressed COX-2 rarely; this may suggest at least partially different molecular mechanisms.

Holmila, Reetta; Cyr, Diane; Luce, Daniele; Heikkila, Pirjo; Dictor, Michael; Steiniche, Torben; Stjernvall, Tuula; Bornholdt, Jette; Wallin, Hakan; Wolff, Henrik; Husgafvel-Pursiainen, Kirsti

2008-01-01

310

Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-?B pathway  

PubMed Central

In prosthetic loosening, bone resorption is induced by wear debris particles generated from the artificial joint articulation. Our prior work showed that synovial-like fibroblasts respond to titanium particles by producing receptor activator of NF-?B ligand (RANKL), a critical activator of osteoclastogenesis. While this effect occurs through a cyclooxygenase-2 (COX-2)-dependent pathway, the mechanism of COX-2 stimulation by titanium particles is not clear. Here we show that titanium particles induce COX-2 gene expression by activating NF-?B signaling. Inhibitor of NF-?B (I?B?) is degraded following particle treatment, permitting active NF-?B to translocate to the nucleus where it interacts with the COX-2 promoter and drives transcription. NF-?B activation is dependent on reactive oxygen species since antioxidants block the NF-?B signaling induced by particles. Surprisingly, I?B? degradation is independent of IKK (I?B kinase) and the 26S proteasome. Instead, calpain inhibitor can block the I?B? degradation induced by particles. Furthermore, the calpain-targeted COOH-terminal PEST sequence of I?B? is necessary for phosphorylation and degradation, consistent with a proteasome-independent mechanism of catabolism. Altogether, the data demonstrate a signaling pathway by which titanium particles induce oxidative stress, stimulate calpain-mediated NF-?B activation, and activate target gene expression, including COX-2. These findings define important targets for osteolysis but may also have importance in other diseases where fibroblasts respond to environmental particles, including pulmonary diseases.

Wei, Xiaochao; Zhang, Xinping; Flick, Lisa M.; Drissi, Hicham; Schwarz, Edward M.; O'Keefe, Regis J.

2009-01-01

311

Inhibitory effect of cyclo-oxygenase-2 inhibitor on the production of matrix metalloproteinases in rheumatoid fibroblast-like synoviocytes  

Microsoft Academic Search

Cyclo-oxygenase (COX)-2 has been associated with inflammation in rheumatoid arthritis (RA), but its role in joint destruction\\u000a remains unclear. In this study, we investigated the effect on cultured rheumatoid fibroblast-like synoviocytes (FLS) of the\\u000a selective COX-2 inhibitor celecoxib on the expression of matrix metalloproteinases (MMPs), which play an important role in\\u000a tissue degradation and angiogenesis in rheumatoid synovium. Treatment with

H. S. Cha; K. S. Ahn; C. H. Jeon; J. Kim; E. M. Koh

2004-01-01

312

Structural selectivity of human SGLT inhibitors.  

PubMed

Human Na(+)-D-glucose cotransporter (hSGLT) inhibitors constitute the newest class of diabetes drugs, blocking up to 50% of renal glucose reabsorption in vivo. These drugs have potential for widespread use in the diabetes epidemic, but how they work at a molecular level is poorly understood. Here, we use electrophysiological methods to assess how they block Na(+)-D-glucose cotransporter SGLT1 and SGLT2 expressed in human embryonic kidney 293T (HEK-293T) cells and compared them to the classic SGLT inhibitor phlorizin. Dapagliflozin [(1S)-1,5,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol], two structural analogs, and the aglycones of phlorizin and dapagliflozin were investigated in detail. Dapagliflozin and fluoro-dapagliflozin [(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-4-F-4-deoxy-D-glucitol] blocked glucose transport and glucose-coupled currents with ?100-fold specificity for hSGLT2 (K(i) = 6 nM) over hSGLT1 (K(i) = 400 nM). As galactose is a poor substrate for SGLT2, it was surprising that galacto-dapagliflozin [(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-galactitol] was a selective inhibitor of hSGLT2, but was less potent than dapagliflozin for both transporters (hSGLT2 K(i) = 25 nM, hSGLT1 K(i) = 25,000 nM). Phlorizin and galacto-dapagliflozin rapidly dissociated from SGLT2 [half-time off rate (t(1/2,Off)) ? 20-30 s], while dapagliflozin and fluoro-dapagliflozin dissociated from hSGLT2 at a rate 10-fold slower (t(1/2,Off) ? 180 s). Phlorizin was unable to exchange with dapagliflozin bound to hSGLT2. In contrast, dapagliflozin, fluoro-dapagliflozin, and galacto-dapagliflozin dissociated quickly from hSGLT1 (t(1/2,Off) = 1-2 s), and phlorizin readily exchanged with dapagliflozin bound to hSGLT1. The aglycones of phlorizin and dapagliflozin were poor inhibitors of both hSGLT2 and hSGLT1 with K(i) values > 100 ?M. These results show that inhibitor binding to SGLTs is composed of two synergistic forces: sugar binding to the glucose site, which is not rigid, and so different sugars will change the orientation of the aglycone in the access vestibule; and the binding of the aglycone affects the binding affinity of the entire inhibitor. Therefore, the pharmacophore must include variations in both the structure of the sugar and the aglycone. PMID:21940664

Hummel, Charles S; Lu, Chuan; Liu, Jie; Ghezzi, Chiari; Hirayama, Bruce A; Loo, Donald D F; Kepe, Vladimir; Barrio, Jorge R; Wright, Ernest M

2011-09-21

313

Cox-2 gene expression in chemically induced skin papillomas cannot predict subsequent tumor fate  

PubMed Central

Elevated cyclooxygenase-2 (COX-2) expression is observed in a variety of premalignant neoplastic tissues, suggesting COX-2 expression might serve as a potential indicator of subsequent tumor development. However, it has not been possible to compare the relationship between Cox-2 gene expression in premalignant lesions and their subsequent fate, because conventional studies require tissue destruction for analysis of gene expression. To monitor COX-2 expression non-invasively during tumor development, we created a Cox-2 luciferase knock-in mouse, Cox-2luc, in which the firefly luciferase coding region replaces the Cox-2 coding region. Luciferase activity was non-invasively, quantitatively and repeatedly monitored in Cox-2luc/+ mice subjected to DMBA/TPA multistage skin tumor induction. Luciferase activity is significantly higher in all papillomas than in surrounding skin. However, the magnitude of Cox-2 promoter-driven luciferase activity in small papillomas cannot predict subsequent papilloma regression or growth. Elevated Cox-2 promoter-driven luciferase signal can be detected when papillomas first become visible, but not before this time.

Ishikawa, Tomo-o; Jain, Naveen K.; Herschman, Harvey R.

2010-01-01

314

TNFalpha regulates renal COX-2 in the rat thick ascending limb (TAL).  

PubMed

We have examined cyclooxygenase (COX)-2-dependent mechanisms in preglomerular microvessels and the thick ascending limb (TAL). These renal structures are linchpins in the regulation of the renal circulation and extracellular fluid volume. Cytochrome P450 monooxygenases are the principal oxygenases in the TAL segment; however, COX-2 can be expressed in the TAL, as when challenged by angiotensin II. Glucocorticoids also affect the expression and activity of oxygenases in the TAL. Before adrenalectomy, <2% TAL cells expressed COX-2; after, >30% of TAL cells expressed COX-2. Recruitment of COX-2 is initiated in the renal cortex and proceeds to the medulla associated with: (1) COX-2 mRNA accumulation; (2) increased COX-2 expression; and (3) a two-fold increase in PGE2 production by cortical microsomes. These changes were nullified by dexamethasone. COX-2 mRNA, protein expression and PGE2 synthesis in the TAL are also increased in response to increased extracellular Ca2+. The Ca2+ sensing receptor is G-protein coupled and responds to changes in extracellular Ca2+ concentration by increasing protein kinase C activity to produce expression of COX-2. Thus, multiple signaling pathways contribute to COX-2 expression in TAL cells. PMID:14592548

Ferreri, Nicholas R; McGiff, John C; Vio, Carlos P; Carroll, Mairead A

2003-06-15

315

Treatment of selective mutism: focus on selective serotonin reuptake inhibitors.  

PubMed

Abstract Selective mutism is a pediatric psychiatric disorder that occurs when a child consistently fails to speak in specific situations in which speaking is expected, such as at school and social gatherings, but speaks appropriately in other settings. Selective mutism often is diagnosed when a child starts school and does not talk to teachers or peers, but talks to family members at home; the condition is frequently accompanied by anxiety and shyness. Although the underlying etiology of the condition remains unclear, psychotherapy is the preferred initial treatment, with the support of parents and teachers. If the child does not respond to psychotherapy, addition of pharmacologic treatment should be considered, depending on the severity of symptoms and presence of other illnesses. Although data are limited to case reports and trials with small patient populations and short follow-up periods, some patients with selective mutism respond to therapy with selective serotonin reuptake inhibitors (SSRIs). Fluoxetine is the most studied SSRI as treatment for the condition, although further investigation is required to determine the optimal dosage and duration of therapy. PMID:18225967

Kaakeh, Yaman; Stumpf, Janice L

2008-02-01

316

Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells  

PubMed Central

Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2), the key regulator of PGE2 synthesis, represents the determining factor in redirecting the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs. Exogenous PGE2 and such diverse COX2 activators as lipopolysaccharide, IL-1?, and IFN? all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs and inducing endogenous PGE2, IDO1, IL-4R?, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE2 to GM-CSF/IL-4–supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)–suppressive function. In accordance with the key role of PGE2 in the physiologic induction of human MDSCs, the frequencies of CD11b+CD33+ MDSCs in ovarian cancer are closely correlated with local PGE2 production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE2 feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation.

Obermajer, Natasa; Muthuswamy, Ravikumar; Lesnock, Jamie; Edwards, Robert P.

2011-01-01

317

Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2  

PubMed Central

Biosynthesis of the prostaglandin endoperoxide by the cyclooxygenase (COX) enzymes is accompanied by formation of a small amount of 11R-hydroxyeicosatetraenoic acid (HETE), 15R-HETE, and 15S-HETE as by-products. Acetylation of COX-2 by aspirin abrogates prostaglandin synthesis and triggers formation of 15R-HETE as the sole product of oxygenation of arachidonic acid. Here, we investigated the formation of by-products of the transformation of 5S-HETE by native COX-2 and by aspirin-acetylated COX-2 using HPLC-ultraviolet, GC-MS, and LC-MS analysis. 5S,15S- dihydroxy (di)HETE, 5S,15R-diHETE, and 5S,11R-diHETE were identified as by-products of native COX-2, in addition to the previously described di-endoperoxide (5S,15S-dihydroxy-9S,11R,8S,12S-diperoxy-6E,13E-eicosadienoic acid) as the major oxygenation product. 5S,15R-diHETE was the only product formed by aspirin-acetylated COX-2. Both 5,15-diHETE and 5,11-diHETE were detected in CT26 mouse colon carcinoma cells as well as in lipopolysaccharide-activated RAW264.7 cells incubated with 5S-HETE, and their formation was attenuated in the presence of the COX-2 specific inhibitor, NS-398. Aspirin-treated CT26 cells gave 5,15-diHETE as the most prominent product formed from 5S-HETE. 5S,15S-diHETE has been described as a product of the cross-over of 5-lipoxygenase (5-LOX) and 15-LOX activities in elicited rat mononuclear cells and human leukocytes, and our studies implicate cross-over of the 5-LOX and COX-2 pathways as an additional biosynthetic route.

Mulugeta, Surafel; Suzuki, Takashi; Hernandez, Noemi Tejera; Griesser, Markus; Boeglin, William E.; Schneider, Claus

2010-01-01

318

Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy  

SciTech Connect

Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p {<=} 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.

Pachkoria, Ketevan [Department of Oncology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden); Zhang Hong [Department of Dermatology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden); Adell, Gunnar [Department of Oncology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden); Jarlsfelt, Ingvar [Department of Pathology and Cytology, Joenkoeping Hospital, Joenkoeping (Sweden); Sun Xiaofeng [Department of Oncology, Institute of Biomedicine and Surgery, University of Linkoeping, Linkoeping (Sweden)]. E-mail: xiao-feng.sun@ibk.liu.se

2005-11-01

319

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells  

PubMed Central

TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2?/? mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1?/? cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR?/? and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2 and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

Hobbs, Stuart S.; Goettel, Jeremy A.; Liang, Dongchun; Yan, Fang; Edelblum, Karen L.; Frey, Mark R.; Mullane, Matthew T.

2011-01-01

320

Design, synthesis, and biological evaluation of 1,3-diarylprop-2-en-1-ones : A novel class of cyclooxygenase-2 inhibitors  

Microsoft Academic Search

A group of regioisomeric (E)-1,3-diarylprop-2-en-1-one derivatives possessing a COX-2 SO2Me pharmacophore at the para position of the C-1 or C-3 phenyl ring, in conjunction with a C-3 or C-1 phenyl (4-H) or substituted-phenyl ring (4-F, 4-OMe and 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target (E)-1,3-diarylprop-2-en-1-ones were synthesized via a Claisen–Schmidt condensation reaction. In vitro COX-1\\/COX-2

Afshin Zarghi; Sara Arfaee; P. N. Praveen Rao; Edward E. Knaus

2006-01-01

321

Cyclooxygenase2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells  

Microsoft Academic Search

We recently reported that inhibition of Cyclooxygenase-2 (Cox-2) reduced human B-CLL proliferation and survival. Herein, we\\u000a investigated the mechanisms whereby small molecule Cox-2 selective inhibitors, SC-58125 (a Celebrex analog) and CAY10404 blunt\\u000a survival of human B-cell lymphomas and chronic lymphocytic leukemia B-cells. SC-58125 and OSU03012 (a Celebrex analog that\\u000a lacks Cox-2 inhibitory activity) both decreased intracellular glutathione (GSH) content in

Elizabeth P. Ryan; Timothy P. Bushnell; Alan E. Friedman; Irfan Rahman; Richard P. Phipps

2008-01-01

322

Identification of a selective ERK inhibitor and structural determination of the inhibitor–ERK2 complex  

Microsoft Academic Search

Selective inhibition of extracellular signal-regulated kinase (ERK) represents a potential approach for the treatment of cancer and other diseases; however, no selective inhibitors are currently available. Here, we describe an ERK-selective inhibitor, FR180204, and determine the structural basis of its selectivity. FR180204 inhibited the kinase activity of ERK1 and ERK2, with Ki values 0.31 and 0.14?M, respectively. Lineweaver–Burk analysis of

Makoto Ohori; Takayoshi Kinoshita; Mitsuru Okubo; Kentaro Sato; Akiko Yamazaki; Hiroyuki Arakawa; Shintaro Nishimura; Noriaki Inamura; Hidenori Nakajima; Masahiro Neya; Hiroshi Miyake; Takashi Fujii

2005-01-01

323

Rational design of highly selective spleen tyrosine kinase inhibitors.  

PubMed

A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field. PMID:23151054

Lucas, Matthew C; Goldstein, David M; Hermann, Johannes C; Kuglstatter, Andreas; Liu, Wenjian; Luk, Kin Chun; Padilla, Fernando; Slade, Michelle; Villaseñor, Armando G; Wanner, Jutta; Xie, Wenwei; Zhang, Xiaohu; Liao, Cheng

2012-11-27

324

Inflammatory response and meningioma tumorigenesis and the effect of cyclooxygenase-2 inhibitors.  

PubMed

In this article the authors discuss the rationale and research supporting the hypothesis that meningioma tumorigenesis may, in part, be driven by overexpression of cyclooxygenase-2 (Cox-2) and that treatment with celecoxib, a selective Cox-2 inhibitor, may hold therapeutic promise. Because therapies for recurrent or aggressive meningiomas (atypical or malignant subtypes) such as chemotherapy and radiotherapy generally offer little therapeutic benefit, interest in targeting Cox-2 has grown. This rate-limiting enzyme of prostaglandin synthesis can be inhibited with nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and celecoxib. Treatment with NSAIDs has been shown to curb the tumorigenic properties of prostaglandins in several cancer models via both Cox-2-dependent and -independent mechanisms. In addition, celecoxib is well tolerated in humans, making its use as a chronic therapy for meningiomas attractive. PMID:17961044

Ragel, Brian T; Jensen, Randy L; Couldwell, William T

2007-01-01

325

Gastroprotective Agent Rebamipide Induces Cyclooxygenase2 (COX2) in Gastric Epithelial Cells  

Microsoft Academic Search

Cyclooxyngease-2 (COX-2) is a key enzyme in prostaglandin (PG) synthesis, and COX-2 induction plays an important role in the healing of gastric ulceration. Rebamipide is a gastroprotective agent and attenuates the activity of neutrophils. A number of reports have shown that rebamipide treatment increases PG production in the gastric mucosa {in vivo}. Although its clinical significance in ulcer healing has

Hiroaki Murata; Yuki Yabe; Shingo Tsuji; Masahiko Tsujii; Hai Ying Fu; Kayoko Asahi; Hiroshi Eguchi; Sunao Kawano; Norio Hayashi

2005-01-01

326

Dietary Zinc Modulation of COX2 Expression and Lingual and Esophageal Carcinogenesis in Rats  

Microsoft Academic Search

Background: Cancer of the upper aerodigestive tract, includ- ing esophageal and tongue carcinomas, is a major cause of cancer deaths worldwide. Esophageal and tongue cancers have both been associated with dietary zinc deficiency (ZD), and cyclooxygenase (COX-2) is often overexpressed in these cancers. Using rat models, we examined whether zinc regu- lates COX-2 expression in these cancers. Method: Expression of

Louise Y. Y. Fong; Liang Zhang; Yubao Jiang; John L. Farber

2005-01-01

327

Effect of COX-2 (PGE2) and IL-6 on Prostate Cancer Bone Metastases.  

National Technical Information Service (NTIS)

We hypothesized that (1) prostate cancer cells that express high levels of cyclooxygenase-2 (COX-2) and prostaglandin E2(PGE2) display enhanced bone targeting and (2) the level of expression of COX-2 and PGE2 in established bone metastases determines the ...

A. C. Levine

2008-01-01

328

Role of PPAR? in COX-2 activation in mycobacterial pulmonary inflammation  

PubMed Central

Preliminary studies show that intranasal (i.n.) administration of BCG in mice induces M1 activation of alveolar macrophages (MØ) that increase TNF-? production and cyclooxygenase-2 (COX-2) expression but reduce constitutive peroxisome proliferator-activated receptor gamma (PPAR?) expression. However, COX-2 is catalytically inactive for prostaglandin E2 release, unlike COX-2 active in M1 activation in vitro by BCG. In this study, we determined the role of PPAR? for BCG-induced M1 activation in vivo and in vitro. We found that treatment of mice with GW9662, a PPAR? antagonist, prior to i.n. BCG, partially restored PPAR? expression, and decreased TNF-? production and COX-2 expression. But COX-2 was still inactive. The decreased effects on TNF-? and COX-2 were also observed when alveolar MØ were treated in vitro with GW9662/BCG, but COX-2 was still active. Our results indicate that PPAR? up-regulates M1 activation of alveolar MØ, but inactive COX-2 formation is independent of PPAR? in mycobacterial pulmonary inflammation.

Kogiso, Mari; Shinohara, Tsutomu; Dorey, C. Kathleen; Shibata, Yoshimi

2012-01-01

329

Aromatase inhibitors and cyclooxygenase-2 (COX2) inhibitors in endometriosis: New questions—old answers?  

Microsoft Academic Search

The medical treatment of endometriosis needs to be optimized. Therapeutic management strategies for endometriosis-associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants. In this context, basic research is providing important results for the development of new, specific treatment modalities. Aromatase overexpression has recently been detected in endometriotic

Andreas D. Ebert; Julia Bartley; Matthias David

2005-01-01

330

Role of COX-2 in tumor progression and survival of head and neck squamous cell carcinoma  

PubMed Central

Inhibition of cyclooxygenase-2 (COX-2) pathways may have significant implications for the prevention and treatment of head and neck squamous cell carcinoma (HNSCC). COX-2 is overexpressed in both premalignant lesions and invasive HNSCC. We examined COX-2 expression by immunohistochemistry in normal tissues, different stages of premalignant lesions, and carcinoma in-situ (CIS). We also evaluated the correlation between COX-2 expression and clinical characteristics of HNSCC patients. Tissue specimens were obtained from: premalignant lesions from 25 subjects enrolled in a biochemoprevention trial; tumor samples collected at diagnosis from 38 HNSCC patients enrolled in an induction chemotherapy trial; and normal control tissues from 10 non-cancer, non-smoking subjects. COX-2 was expressed in early and intermediate stages of premalignant lesions, increasing first in the basal and parabasal layers, then lower spinous, and upper spinous layers. This correlation was noted in normal epithelium (p<0.0001), histologically normal in-field samples (p<0.0001), low-grade dysplasia (p=0.024), and moderate-grade dysplasia (p=0.009), but was lost in the majority of high-grade dysplasia/CIS (p=0.896). COX-2 expression was also noted to increase progressively through the early stages of premalignancy, and to decrease in severe/CIS stage and invasive carcinoma. COX-2 expression in tumors from patients treated with induction chemotherapy was correlated with overall survival after controlling for clinical variables. These findings elucidate the differential expression pattern of COX-2 in stages of head and neck premalignant lesions and invasive carcinoma, supporting the rationale for COX-2 inhibition as an important strategy for cancer chemoprevention. Further validation of COX-2 expression is needed in prospective ongoing chemoprevention trials.

Saba, Nabil F.; Choi, Misun; Muller, Susan; Shin, Hyung Ju C.; Tighiouart, Mourad; Papadimitrakopoulou, Vassiliki A; El-Naggar, Adel K; Khuri, Fadlo R.; Chen, Zhuo (Georgia); Shin, Dong M.

2010-01-01

331

Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury.  

PubMed

Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2)(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O(2)(-). PMID:12225656

Kulkarni, Miriam; Armstead, William M

2002-08-01

332

Severe hyponatraemia associated with selective serotonin reuptake inhibitors.  

PubMed

Depression in the elderly is a common problem, cited as occurring in up to 10% of elderly people living at home, half of whom may need specialist referral. The introduction of selective serotonin reuptake inhibitors has been reported as a major advance in the treatment of depression in that they are less sedating, have fewer anticholinergic effects and are less toxic in overdose. We report three cases of severe hyponatraemia, seen in the past 12 months, associated with the selective serotonin reuptake inhibitors fluoxetine and sertraline. Hyponatraemia has been reported as a rare adverse effect of selective serotonin reuptake inhibitors. PMID:8578303

Taylor, I C; McConnell, J G

1995-10-01

333

Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX 1- and COX 2-inhibitors in nerve-injured rats 1 An abstract of this study was presented at the 1997 APS Meeting (New Orleans). 1  

Microsoft Academic Search

The possible role of spinal prostanoids in the tactile allodynia and thermal hyperalgesia associated with an experimental model of neuropathic pain was investigated. Neuropathic pain was induced by tight ligation of the L5 and L6 spinal nerves. Tactile allodynia was assessed 7 days after the surgery by measuring hindpaw withdrawal threshold to probing with von Frey filaments. Thermal hyperalgesia and

Jason M Lashbrook; Michael H Ossipov; John C Hunter; Robert B Raffa; Ronald J Tallarida; Frank Porreca

1999-01-01

334

Enhancement of PLGF production by 15-(S)-HETE via PI3K-Akt, NF-?B and COX-2 pathways in rheumatoid arthritis synovial fibroblast.  

PubMed

Metabolites from arachidonic acids play the pivotal roles in inflammatory arthritis. Arachidonic acid could be metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) to produce the bioactive eicosanoids. Although the down-stream products of COX including prostaglandin E2 are well-known inflammatory stimulators, the role of LOX products in inflammatory arthritis is still unclear. Here we found that the downstream product of 15-LOX, 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), can enhance the expression of placenta growth factor (PLGF), which is recently considered to play an important role in rheumatoid arthritis. 15-(S)-HETE increased the expression of PLGF in human rheumatoid arthritis synovial fibroblasts in a time-dependent and concentration-dependent manner. PI3K-Akt, NF-?B signaling pathways were involved in the potentiation effects of 15-(S)-HETE. In addition, COX-2 was up-regulated by the treatment of 15-(S)-HETE and the increase of COX-2 expression participated in 15-(S)-HETE-induced PLGF expression, which was confirmed by COX-2 shRNA or pharmacological COX-2 inhibitor. Moreover, it was found that treatment of prostaglandin E2 (PGE2), which was the main down-stream metabolite of COX-2, increased the expression of PLGF. EP1, EP2, EP3 and EP4 agonists could up-regulate PLGF as well. In animal studies, we found that the adjuvant-induced expression of PLGF and COX-2 was inhibited in 15-LOX knockout mice. These results indicated that PLGF up-regulation by 15-LOX downstream product may be involved in inflammatory arthritis. PMID:23872401

Wu, Ming-Yueh; Yang, Rong-Sen; Lin, Tzu-Hung; Tang, Chih-Hsin; Chiu, Yung-Cheng; Liou, Houng-Chi; Fu, Wen-Mei

2013-07-17

335

Cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) expression in human pituitary macroadenomas.  

PubMed

Macroadenomas are tumors of the pituitary gland and are considered almost to be always benign and curable. The clinical manifestations of a pituitary tumor depend on the hormone secreted by the tumor as well as on the pattern of tumor growth within the sella turcica. Current trends attempt to target new molecular markers that also may serve as potential therapeutic targets. Cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are upregulated in a number of epithelial tumors. No published reports exist about expression of COX-2 in pituitary macroadenomas, and only a few reports with differing results exist concerning EGFR expression in pituitary macroadenomas. This study sought to determine whether a relationship exists between COX-2 and EGFR expression and pituitary macroadenomas. Thirty specimens of pituitary macroadenomas were evaluated after being identified in the surgical pathology database of Thomas Jefferson University Hospital. The hematoxylin and eosin-stained slides were reviewed, and the representative paraffin blocks containing the index case were chosen and immunohistochemically stained for COX-2 and EGFR expression. The COX-2 and EGFR-stained slides were reviewed and an immunohistochemical score was calculated and analyzed. The pituitary macroadenomas were classified on the basis of hormone expression: none (nonsecreting), minor (nondominant, plurihormonal), single (dominant nonplurihormonal), or plurihormonal (dominant plurihormonal). The hormonal classification was then analyzed for association with COX-2 expression. COX-2 expression was significantly associated with plurihormonal pituitary macroadenomas (p value 0.03). COX-2 expression was significantly associated with expression of luteinizing hormone (p value 0.007) and with expression of thyroid-stimulating hormone (TSH) (p value 0.04). Additionally, COX-2 expression was significantly associated with single-hormone of pituitary adenoma (p value 0.049). The expression of COX-2 in 100% of the normal autopsy pituitary glands establishes an additional central nervous system location of COX-2 expression. EGFR was not expressed in any of the pituitary macroadenomas. The expression of COX-2 in plurihormonal pituitary macroadenomas, particularly those secreting TSH, may be a potential target for treatment in addition to surgical and/or radiotherapy treatment in these benign but clinically significant tumors. COX-2 is expressed in normal autopsy pituitary tissue. PMID:12902861

Bloomer, Courtnay W; Kenyon, Lawrence; Hammond, Elizabeth; Hyslop, Terry; Andrews, David W; Curran, Walter J; Dicker, Adam P

2003-08-01

336

Synthesis of selective inhibitors of sphingosine kinase 1.  

PubMed

Sphingosine kinase isoform 1 (SK1) inhibitors may serve as therapeutic agents for proliferative diseases, including hypertension. We synthesized a series of sphingosine-based SK1-selective inhibitors, the most potent of which is RB-005 (IC(50) = 3.6 ?M), which also induced proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells. PMID:23388656

Baek, Dong Jae; MacRitchie, Neil; Pyne, Nigel J; Pyne, Susan; Bittman, Robert

2013-02-07

337

Preventive effects of etodolac, a selective cyclooxygenase-2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori-negative precancerous lesion.  

PubMed

The present study investigated the preventive effects of etodolac, a selective cyclo-oxygenase (COX)-2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test-positive and Helicobacter pylori antibody-negative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6-12 months for up to 5 years. Mean (standard deviation) follow-up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate = 6,266/100,000 person-years), significantly more than the 1 cancer in Group A (incidence rate = 898/100,000 person-years; p < 0.05). Long-term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX-2 expression. PMID:19711347

Yanaoka, Kimihiko; Oka, Masashi; Yoshimura, Noriko; Deguchi, Hisanobu; Mukoubayashi, Chizu; Enomoto, Shotaro; Maekita, Takao; Inoue, Izumi; Ueda, Kazuki; Utsunomiya, Hirotoshi; Iguchi, Mikitaka; Tamai, Hideyuki; Fujishiro, Mitsuhiro; Nakamura, Yasushi; Tsukamoto, Tetsuya; Inada, Kenichi; Takeshita, Tatsuya; Ichinose, Masao

2010-03-15

338

Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids  

Microsoft Academic Search

Potent and selective dipeptidyl boronic acid proteasome inhibitors are described. As compared to peptidyl aldehyde compounds, boronic acids in this series display dramatically enhanced potency. Compounds such as 15 are promising new therapeutics for treatment of cancer and inflammatory diseases.

Julian Adams; Mark Behnke; Shaowu Chen; Amy A. Cruickshank; Lawrence R. Dick; Louis Grenier; Janice M. Klunder; Yu-Ting Ma; Louis Plamondon; Ross L. Stein

1998-01-01

339

Development of a highly selective c-Src kinase inhibitor  

PubMed Central

Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge and new strategies are required. Herein, we describe the development of the first highly selective and cell permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extension of traditional inhibitor design by appending functionality proposed to interact with the phosphate-binding loop of c-Src. Using our selective inhibitor, we demonstrate that selective inhibition is significantly more efficacious than pan-kinase inhibition in slowing the growth of cancer cells. We also show that inhibition of c-Abl kinase, an off-target of most c-Src inhibitors, promotes oncogenic cell growth.

Brandvold, Kristoffer R.; Steffey, Michael E.; Fox, Christel C.; Soellner, Matthew B.

2012-01-01

340

Antitumor enhancement of celecoxib, a selective Cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing Cyclooxygenase-2  

PubMed Central

Background The goal of this study was to determine the effects of a selective Cyclooxygenase (COX)-2 inhibitor on the inhibition of tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model. Methods For immunoblot analysis of COX-2 and PGE2, cells were treated with irradiation in the presence or absence of celecoxib. The right thighs of male, 6-week old C57/BL mice were subcutaneously injected with 1 × 106 LLC cells. The animals were randomized into one of six groups: (1) no treatment, (2) 25 mg/kg celecoxib daily, (3) 75 mg/kg celecoxib daily, (4) 10 Gy irradiation, (5) 10 Gy irradiation plus 25 mg/kg celecoxib daily, and (6) 10 Gy irradiation plus 75 mg/kg celecoxib daily. Mice were irradiated only once, and celecoxib was administered orally. Mice were irradiated with 4-MV photons once the tumor volume of the control group reached 500 mm3. All mice were sacrificed when the mean tumor volume of control animals grew to 4000 mm3. The left lobes of the lungs were extracted for the measurement of metastatic nodules. Results Irradiation resulted in a dose-dependent increase in PGE2 production. PGE2 synthesis decreased markedly after treatment with celecoxib alone or in combination with irradiation. Compared to mice treated with low dose celecoxib, mean tumor volume decreased significantly in mice treated with a high dose of celecoxib with or without irradiation. Mice treated with a high dose celecoxib alone, with irradiation alone, or with irradiation plus celecoxib had markedly fewer metastatic lung nodules than controls. The mean metastatic area was the smallest for mice treated with irradiation plus a high dose celecoxib. Conclusion Oral administration of high dose celecoxib significantly inhibited tumor growth, as compared to a low dose treatment. Radiotherapy in combination with high dose celecoxib delayed tumor growth and reduced the number of pulmonary metastases to a greater extent than celecoxib or radiotherapy alone.

Park, Won; Oh, Young Taek; Han, Jae Ho; Pyo, Hongryull

2008-01-01

341

A single mutation in the first transmembrane domain of yeast COX2 enables its allotopic expression.  

PubMed

During the course of evolution, a massive reduction of the mitochondrial genome content occurred that was associated with transfer of a large number of genes to the nucleus. To further characterize factors that control the mitochondrial gene transfer/retention process, we have investigated the barriers to transfer of yeast COX2, a mitochondrial gene coding for a subunit of cytochrome c oxidase complex. Nuclear-recoded Saccharomyces cerevisiae COX2 fused at the amino terminus to various alternative mitochondrial targeting sequences (MTS) fails to complement the growth defect of a yeast strain with an inactivated mitochondrial COX2 gene, even though it is expressed in cells. Through random mutagenesis of one such hybrid MTS-COX2, we identified a single mutation in the first Cox2 transmembrane domain (W56 --> R) that (i) results in the cellular expression of a Cox2 variant with a molecular mass indicative of MTS cleavage, which (ii) supports growth of a cox2 mutant on a nonfermentable carbon source, and that (iii) partially restores cytochrome c oxidase-specific respiration by the mutant mitochondria. COX2(W56R) can be allotopically expressed with an MTS derived from S. cerevisiae OXA1 or Neurospora crassa SU9, both coding for hydrophobic mitochondrial proteins, but not with an MTS derived from the hydrophilic protein Cox4. In contrast to some other previously transferred genes, allotopic COX2 expression is not enabled or enhanced by a 3'-UTR that localizes mRNA translation to the mitochondria, such as yeast ATP2(3)('-UTR). Application of in vitro evolution strategies to other mitochondrial genes might ultimately lead to yeast entirely lacking the mitochondrial genome, but still possessing functional respiratory capacity. PMID:20194738

Supekova, Lubica; Supek, Frantisek; Greer, John E; Schultz, Peter G

2010-03-01

342

Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells.  

PubMed

The inhibitors of prostaglandin biosynthesis and nitric oxide production have been considered as potential anti-inflammatory and cancer chemopreventive agents. In this study, we evaluated approximately 170 methanol extracts of natural products including Korean herbal medicines for the inhibition of prostaglandin E(2) production (for COX-2 inhibitors) and nitric oxide formation (for iNOS inhibitors) in lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7 cells. As a result, several extracts such as Aristolochia debilis, Cinnamomum cassia, Cinnamomum loureirii, Curcuma zedoaria, Eugenia caryophyllata, Pterocarpus santalius, Rehmania glutinosa and Tribulus terrestris showed potent inhibition of COX-2 activity (>80% inhibition at the test concentration of 10 micro g/ml). In addition, the extracts of A. debilis, Caesalpinia sappan, Curcuma longa, C. zedoaria, Daphne genkwa and Morus alba were also considered as potential inhibitors of iNOS activity (>70% inhibition at the test concentration of 10 micro g/ml). These active extracts mediating COX-2 and iNOS inhibitory activities are warranted for further elucidation of active principles for development of new cancer chemopreventive and/or anti-inflammatory agents. PMID:12413723

Hong, Chae Hee; Hur, Sun Kyung; Oh, O-Jin; Kim, Sun Sook; Nam, Kyung Ae; Lee, Sang Kook

2002-11-01

343

Development of selective, potent RabGGTase inhibitors.  

PubMed

Members of the Ras superfamily of small GTPases are frequently mutated in cancer. Therefore, inhibitors have been developed to address the acitivity of these GTPases by inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase. In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have been developed. The most active RabGGTase inhibitor known until recently was an FTase inhibitor which hit RabGGTase as an off-target. We recently reported our efforts to tune the selectivity of these inhibitors toward RabGGTase. Here we describe an extended set of selective inhibitors. The requirements for selective RabGGTase inhibitors are described in detail, guided by multiple crystal structures. In order to relate in vitro and cellular activity, a high-throughput assay system to detect the attachment of [(3)H]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics. PMID:22963166

Stigter, E Anouk; Guo, Zhong; Bon, Robin S; Wu, Yao-Wen; Choidas, Axel; Wolf, Alexander; Menninger, Sascha; Waldmann, Herbert; Blankenfeldt, Wulf; Goody, Roger S

2012-10-03

344

Selected furanochalcones as inhibitors of monoamine oxidase.  

PubMed

The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase has previously been illustrated. In a systematic attempt to investigate the effect of heterocyclic substitution on the monoamine oxidase inhibitory properties of this versatile scaffold, a series of furanochalcones were synthesized. The results demonstrate that these furan substituted phenylpropenones exhibited moderate to good inhibitory activities towards MAO-B, but showed weak or no inhibition of the MAO-A enzyme. The most active compound, 2E-3-(5-chlorofuran-2-yl)-1-(3-chlorophenyl)prop-2-en-1-one, exhibited an IC50 value of 0.174 ?M for the inhibition of MAO-B and 28.6 ?M for the inhibition of MAO-A. Interestingly, contrary to data previously reported for chalcones, these furan substituted derivatives acted as reversible inhibitors, while kinetic analysis revealed a competitive mode of binding. PMID:23860591

Robinson, Sarel J; Petzer, Jacobus P; Petzer, Anél; Bergh, Jacobus J; Lourens, Anna C U

2013-06-28

345

Discovery of cyclooxygenase inhibitors from medicinal plants used to treat inflammation  

PubMed Central

Eleven authenticated botanicals used in the traditional Chinese medicine Huo-Luo-Xiao-Ling Dan were screened for ligands to cyclooxygenase (COX) using pulsed ultrafiltration liquid chromatography-mass spectrometry, and a mass spectrometry-based enzyme assay was used to determine the concentration of each of 17 ligands that inhibited COX-1 or COX-2 by 50% (IC50). Acetyl-11-keto-?-boswellic -boswellic acid, acid, acetyl-?-boswellic acid, acetyl-?-boswellic acid, and betulinic acid were COX-1 selective inhibitors with IC50 values of approximately 10 ?M. Senkyunolide O and cryptotanshinone were COX-2 selective inhibitors with IC50 values of 5 and 22 ?M, respectively. Roburic acid and phenethyl-trans-ferulate inhibited COX-1 and COX-2 equally. COX inhibition and the IC50 values of most of these natural product ligands have not been reported previously.

Cao, Hongmei; Yu, Rui; Choi, Yongsoo; Ma, Zhong-Ze; Zhang, Hongjie; Xiang, Wei; Lee, David Yue-Wei; Berman, Brian M.; Moudgil, Kamal D; Fong, Harry H.S.; van Breemen, Richard B.

2010-01-01

346

Ligand-protein interactions of selective casein kinase 1? inhibitors.  

PubMed

Casein kinase 1? (CK1?) and 1? (CK1?) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1?-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1? isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1? and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1? at sufficient central exposure levels is capable of modulating circadian rhythms. PMID:23919824

Mente, Scot; Arnold, Eric; Butler, Todd; Chakrapani, Subramanyam; Chandrasekaran, Ramalakshmi; Cherry, Kevin; Dirico, Ken; Doran, Angela; Fisher, Katherine; Galatsis, Paul; Green, Michael; Hayward, Matthew; Humphrey, John; Knafels, John; Li, Jianke; Liu, Shenping; Marconi, Michael; McDonald, Scott; Ohren, Jeff; Paradis, Vanessa; Sneed, Blossom; Walton, Kevin; Wager, Travis

2013-08-28

347

Synthesis and biological evaluation of methanesulfonamide analogues of rofecoxib: Replacement of methanesulfonyl by methanesulfonamido decreases cyclooxygenase-2 selectivity.  

PubMed

A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5H)furanones in which the methylsulfonyl (MeSO(2)) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO(2)NH) moiety, and where the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. Structure-activity relationship (SAR) studies showed that compounds having a neutral (H), or electronegative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2 selectivity indexes in the 3.1-39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective inhibitors of COX-2 (COX-1 IC(50)>100 microM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5H)furanone scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes. PMID:17067801

Zarghi, Afshin; Praveen Rao, P N; Knaus, Edward E

2006-10-25

348

Cox2 inhibition attenuates cardiovascular and inflammatory aspects in monosodium glutamate-induced obese rats  

Microsoft Academic Search

AimsThe purpose of the present work was to investigate the effect of cyclooxygenase-2 (COX-2) inhibition on the cardiovascular and inflammatory aspects promoted by monosodium glutamate (MSG)-induced obesity in rats.

N. V. Cunha; S. B. de Abreu; C. Panis; S. Grassiolli; F. A. Guarnier; R. Cecchini; T. L. Mazzuco; P. Pinge-Filho; M. C. Martins-Pinge

2010-01-01

349

The role of selective cyclooxygenase isoforms in human intestinal smooth muscle cell stimulated prostanoid formation and proliferation.  

PubMed Central

Intestinal smooth muscle plays a major role in the repair of injured intestine and contributes to the prostanoid pool during intestinal inflammatory states. Cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostanoids exists in two isoforms, COX-1 and COX-2. The purpose of this study was to determine the relative contributions of COX-1 and COX-2 in the production of prostanoids by human intestinal smooth muscle (HISM) cells when stimulated by interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS). Furthermore the effects of specific COX-1 and COX-2 inhibitors on the proliferation of smooth muscle cells was also evaluated. Confluent monolayer cultures of HISM cells were incubated with IL-1beta or LPS for 0-24h while control cells received medium alone. PGE2 and PGI2 as 6-keto-PGF1alpha and LTB4 were measured by a specific radioimmunoassay. COX enzymes were evaluated by Western immunoblotting. Unstimulated and stimulated cells were exposed to the specific COX-1 inhibitor valerylsalicylic acid (VSA) and the COX-2 inhibitors NS-398 and SC-58125. The effects of serum on proliferation were then evaluated in the presence of each of the specific COX inhibitors by incorporation of 3H-thymidine into DNA. IL-1beta and LPS increased both PGE2 and 6-keto-PGF1alpha in a dose dependent fashion with enhanced production detected two hours following exposure. Neither stimulus stimulated LTB4 release. Immunoblot analysis using isoform-specific antibodies showed that both COX-1 and COX-2 were present constitutively. Furthermore, COX-1 was upregulated by each inflammatory stimulus. In a separate set of experiments cells were pretreated with either the selective COX-1 inhibitor VSA or the selective COX-2 inhibitors NS-398 or SC-58125 prior to treatment with IL-1beta or LPS. The COX-1 and COX-2 inhibitors decreased both basal and IL-1beta and LPS stimulated prostanoid release. Spontaneous DNA synthesis was present and serum consistently increased proliferation. 3H-thymidine incorporation, stimulated by serum, was inhibited by both COX-1 and COX-2 inhibitors. This study suggests that the prostanoid response stimulated by proinflammatory agents of gut-derived smooth muscle cells appears to be mediated by both COX-1 and COX-2 enzymes. Proliferation of smooth muscles cells also appears to be influenced by both COX-1 and COX-2.

Longo, W E; Erickson, B; Panesar, N; Mazuski, J E; Robinson, S; Kaminski, D L

1998-01-01

350

PGE2 Production in Oral Cancer Cell Lines is COX2-dependent  

Microsoft Academic Search

It has been suggested that epithelial cyclooxygenase-2 (COX-2) promotes oral carcinogenesis and carcinoma malignancy through increased prostaglandin E2 (PGE2) production. Although oral squamous cell carcinomas (OSCC) often express COX-2, they may also produce PGE2 in a COX-1-dependent manner. We used 6 isolated cell lines to investigate which COX isoforms OSCC may use for PGE2 production. COX-1 and -2 expression patterns

C. Husvik; C. Khuu; M. Bryne; T. S. Halstensen

2009-01-01

351

Gene transfer from mitochondrion to nucleus: novel mechanisms for gene activation from Cox2  

Microsoft Academic Search

Summary The evolutionarily recent transfer of the gene for cytochrome c oxidase subunit 2 (cox2) from the mitochondrion to the nucleus in legumes is shown to have involved novel gene-activation steps. The acquired mitochondrial targeting presequence is bordered by two introns. Characterization of the import of soybean Cox2 indicates that the presequence is cleaved in a three-step process which is

Daniel O. Daley; Keith L. Adams; Rachel Clifton; Svenja Qualmann; A. Harvey Millar; Jeffrey D. Palmer; Elke Pratje; James Whelan

2002-01-01

352

Oesophageal squamous cell neoplasia in head and neck cancer patients: upregulation of COX2 during carcinogenesis  

Microsoft Academic Search

Patients with (previous) head and neck cancer (HNC) are at high risk for developing second squamous cell cancer of the oesophagus. The role of cyclooxygenase-2 (COX-2) in oesophageal squamous carcinogenesis has not yet been investigated in this high-risk group. Therefore, this study examined COX-2 mRNA and protein expression in oesophageal biopsies and resected tissues of 44 HNC patients. The evaluation

K Maaser; P Däubler; B Barthel; B Heine; B von Lampe; H Stein; B Hoffmeister; H Scherer; H Scherübl

2003-01-01

353

COX2 polymorphisms and the risk for head and neck cancer in white patients  

Microsoft Academic Search

BACKGROUND: Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether functional genetic polymorphisms in COX-2 may have a risk-modifying effect on head and neck carcinogenesis. METHODS: Blood from 431 white patients with oral, pharyngeal, or laryngeal

Wilbert H. M. Peters; Martin Lacko; Rene H. M. te Morsche; Adri C. Voogd; Michael B. Oude Ophuis; Johannes J. Manni

2009-01-01

354

Wnt\\/beta-Catenin Signaling Enhances Cyclooxygenase2 (COX2) Transcriptional Activity in Gastric Cancer Cells  

Microsoft Academic Search

BackgroundIncreased expression of the cyclooxygenase-2 enzyme (COX2) is one of the main characteristics of gastric cancer (GC), which is a leading cause of death in the world, particularly in Asia and South America. Although the Wnt\\/?-catenin signaling pathway has been involved in the transcriptional activation of the COX2 gene, the precise mechanism modulating this response is still unknown.Methodology\\/Principal FindingsHere we

Felipe Nuñez; Soraya Bravo; Fernando Cruzat; Martín Montecino; Giancarlo V. de Ferrari; Moray Campbell

2011-01-01

355

Briarane diterpenes diminish COX-2 expression in human colon adenocarcinoma cells.  

PubMed

Exploration of a soft coral (Briareum sp.) from Vanuatu led to the isolation of three new briaranes, designated brialalepolides A (1), B (2), and C (3). Compounds 2 and 3 reduced the expression of COX-2 in human colon adenocarcinoma cells, as well as in murine macrophage cells. This is significant because the metabolic products of COX-2 have been implicated in the pathogenesis of colon cancer and other diseases. PMID:21438584

Joyner, P Matthew; Waters, Amanda L; Williams, Russell B; Powell, Douglas R; Janakiram, Naveena B; Rao, Chinthalapally V; Cichewicz, Robert H

2011-03-25

356

Phenotypes of the COXdeficient mice indicate physiological and pathophysiological roles for COX1 and COX2  

Microsoft Academic Search

The development of mice deficient in either cyclooxygenase-1 (COX-1) or COX-2, as well as mice deficient in both COX isoforms, has provided models to elucidate the physiological and pathophysiological roles of these enzymes. The findings obtained with the COX-deficient mice suggest that COX-2 may be more important than COX-1 for supplying prostaglandins (PGs) to maintain tissue homeostasis. Furthermore, both isoforms

Charles D Loftin; Howard F Tiano; Robert Langenbach

2002-01-01

357

Single crystal growth and superconductivity of Ca(Fe1-xCox)2As2  

SciTech Connect

We report the single crystal growth of Ca(Fe1-xCox)2As2 (0 <= x <= 0.082) from Sn flux. The temperature-composition phase diagram is mapped out based on the magnetic susceptibility and electrical transport measurements. Phase diagram of Ca(Fe1-xCox)2As2 is qualitatively different from those of Sr and Ba, it could be due to both the charge doping and structural tuning effects associated with Co substitution.

Hu, Rongwei; Ran, Sheng; Budko, Serguei; Straszheim, Warren E.; Canfield, Paul C.

2012-05-18

358

COX2 over-expression correlates with VEGF and tumour angiogenesis in canine mammary cancer  

Microsoft Academic Search

This study was designed to investigate the possible roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in canine mammary cancer angiogenesis. Immunohistochemistry was performed on 70 tumours (28 benign and 42 malignant) in order to detect COX-2 and VEGF expression. Microvessel density (MVD) was determined by CD31 immunolabelling to assess tumour angiogenesis.There was a significantly higher expression of

Felisbina L. Queiroga; Isabel Pires; Margarida Parente; Hugo Gregório; Carlos S. Lopes

2011-01-01

359

Triazaspirodimethoxybenzoyls as Selective Inhibitors of Mycobacterial Lipoamide Dehydrogenase  

SciTech Connect

Mycobacterium tuberculosis (Mtb) remains the leading single cause of death from bacterial infection. Here we explored the possibility of species-selective inhibition of lipoamide dehydrogenase (Lpd), an enzyme central to Mtb's intermediary metabolism and antioxidant defense. High-throughput screening of combinatorial chemical libraries identified triazaspirodimethoxybenzoyls as high-nanomolar inhibitors of Mtb's Lpd that were noncompetitive versus NADH, NAD{sup +}, and lipoamide and >100-fold selective compared to human Lpd. Efficacy required the dimethoxy and dichlorophenyl groups. The structure of an Lpd-inhibitor complex was resolved to 2.42 {angstrom} by X-ray crystallography, revealing that the inhibitor occupied a pocket adjacent to the Lpd NADH/NAD{sup +} binding site. The inhibitor did not overlap with the adenosine moiety of NADH/NAD{sup +} but did overlap with positions predicted to bind the nicotinamide rings in NADH and NAD{sup +} complexes. The dimethoxy ring occupied a deep pocket adjacent to the FAD flavin ring where it would block coordination of the NADH nicotinamide ring, while the dichlorophenyl group occupied a more exposed pocket predicted to coordinate the NAD{sup +} nicotinamide. Several residues that are not conserved between the bacterial enzyme and its human homologue were predicted to contribute both to inhibitor binding and to species selectivity, as confirmed for three residues by analysis of the corresponding mutant Mtb Lpd proteins. Thus, nonconservation of residues lining the electron-transfer tunnel in Mtb Lpd can be exploited for development of species-selective Lpd inhibitors.

Bryk, Ruslana; Arango, Nancy; Venugopal, Aditya; Warren, J. David; Park, Yun-Hee; Patel, Mulchand S.; Lima, Christopher D.; Nathan, Carl (Weill-Med); (SKI); (SUNYB)

2010-06-25

360

Thyroid hormone regulates renocortical COX-2 and PGE2 expression in the late gestation fetal sheep.  

PubMed

Cyclooxygenase 2 (COX-2) is important for development of the fetal kidney. Precisely how renal COX-2 expression is regulated in fetal life is unclear. The hypothesis that thyroid hormone positively regulates COX-2 and PGE(2) levels in the late gestation fetal kidney cortex was tested. Sham, thyroidectomized (TX), and TX + thyroid hormone replacement (R) fetal sheep were studied. TX was performed at 120 days gestational age (dGA). TX + R fetuses were continuously infused with thyroxine from 3 days after surgery until study completion. Fetal kidney cortex was obtained at 137 dGA for measurement of renal cyclooxygenase type-2 (COX-2) protein and PGE(2) metabolites. Renocortical COX-2 and PGE(2) levels were significantly lower in TX compared with sham and TX + R fetuses. There were no differences between sham and TX + R fetuses. These findings demonstrate that thyroid hormone positively regulates renal COX-2 and PGE(2) expression in the late gestation fetal sheep kidney. PMID:18579848

Carey, Luke C; Valego, Nancy K; Chen, Kai; Rose, James C

2008-07-01

361

LY294002 inhibits glucocorticoid-induced COX2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism  

Microsoft Academic Search

Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K\\/AKT

Haipeng Sun; Beibei Xu; Elena Sheveleva; Qin M. Chen

2008-01-01

362

Involvement of COX2 in VEGF-induced angiogenesis via P38 and JNK pathways in vascular endothelial cells  

Microsoft Academic Search

Objective: Cyclooxygenase-2 (COX-2) is induced by hypoxic stimuli and is also involved in the process of angiogenesis. We previously demonstrated that vascular endothelial growth factor (VEGF) is one of the principal factors produced by hypoxic myocytes and is responsible for the induction of COX-2 expression in endothelial cells. Yet the signaling pathways by which VEGF modulates COX-2 gene expression are

GuiFu Wu; Jincai Luo; Jamal S. Rana; Roger Laham; Frank W. Sellke; Jian Li

363

Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors  

Microsoft Academic Search

Background:Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies, although the frequency and severity varies among the different agents. Inhibitors targeting vascular endothelial growth factor receptor (VEGFR) often inhibit other kinases, which may contribute to their adverse-event profiles.Methods:Kinase selectivity of pazopanib, sorafenib, and sunitinib was evaluated in a panel of 242 kinases. Cellular potency was measured using

R Kumar; M-C Crouthamel; D H Rominger; R R Gontarek; P J Tummino; R A Levin; A G King

2009-01-01

364

Quercetin inhibits IL-1?-induced proliferation and production of MMPs, COX-2, and PGE2 by rheumatoid synovial fibroblast.  

PubMed

This study was aimed to determine the effects of quercetin on the interleukin-1? (IL-1?)-induced proliferation of rheumatoid synovial fibroblasts (RASFs) and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX), and prostaglandin E2 (PGE2) by RASFs. The proliferation and apoptosis of RASFs was evaluated with CCK-8 reagent and flow cytometry in the presence of IL-1with CCK-8 reagquercetin. The expression of MMPs, IL-1? enhanced the expression of MMP-1, MMP-3, tissue inhibitor of metalloproteinase (TIMP)-1, COXs, PGE2, and intracellular mitogen-activated protein kinase (MAPK) signalings including phosphorylated extracellular signal-regulated kinase (p-ERK), p-p38, phosphorylated c-Jun N-terminal kinase (p-JNK), and nuclear factor kB (NF-kB) were examined by immunoblotting or semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in conditions as described above. Quercetin inhibits unstimulated and IL-1?-induced proliferation of RASFs and MMP-1, 3, COX-2 messenger ribonucleic acid and protein expression, PGE2 production induced with IL-1?. Quercetin also inhibits the phosphorylation of ERK-1/2, p38, JNK and activation of NF-kB by IL-1ed. These results indicate that quercetin inhibits synovial fibroblasts proliferation and MMPs, COX-2, and PGE2 production, which involved joint destruction in rheumatoid arthritis (RA), and suggest that it might be a new therapeutic agent for management of RA. PMID:22592909

Sung, Myung-Soon; Lee, Eun-Gyeong; Jeon, Hyun-Soon; Chae, Han-Jung; Park, Seoung Ju; Lee, Yong Chul; Yoo, Wan-Hee

2012-08-01

365

Aromatic-turmerone attenuates invasion and expression of MMP-9 and COX-2 through inhibition of NF-?B activation in TPA-induced breast cancer cells.  

PubMed

Recent evidence suggests that breast cancer is one of the most common forms of malignancy in females, and metastasis from the primary cancer site is the main cause of death. Aromatic (ar)-turmerone is present in Curcuma longa and is a common remedy and food. In the present study, we investigated the inhibitory effects of ar-turmerone on expression and enzymatic activity levels of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase (MMP)-9 and cyclooxygenaase-2 (COX-2) in breast cancer cells. Our data indicated that ar-turmerone treatment significantly inhibited enzymatic activity and expression of MMP-9 and COX-2 at non-cytotoxic concentrations. However, the expression of tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, MMP-2, and COX-1 did not change upon ar-turmerone treatment. We found that ar-turmerone inhibited the activation of NF-?B, whereas it did not affect AP-1 activation. Moreover, The ChIP assay revealed that in vivo binding activities of NF-?B to the MMP-9 and COX-2 promoter were significantly inhibited by ar-turmerone. Our data showed that ar-turmerone reduced the phosphorylation of PI3K/Akt and ERK1/2 signaling, whereas it did not affect phosphorylation of JNK or p38 MAPK. Thus, transfection of breast cancer cells with PI3K/Akt and ERK1/2 siRNAs significantly decreased TPA-induced MMP-9 and COX-2 expression. These results suggest that ar-turmerone suppressed the TPA-induced up-regulation of MMP-9 and COX-2 expression by blocking NF-?B, PI3K/Akt, and ERK1/2 signaling in human breast cancer cells. Furthermore, ar-turmerone significantly inhibited TPA-induced invasion, migration, and colony formation in human breast cancer cells. PMID:22740037

Park, Sun Young; Kim, Young Hun; Kim, YoungHee; Lee, Sang-Joon

2012-12-01

366

A profiling platform for the identification of selective metalloprotease inhibitors.  

PubMed

Although proteases represent an estimated 5% to 10% of potential drug targets, inhibitors for metalloproteases (MPs) account for only a small proportion of all approved drugs, failures of which have typically been associated with lack of selectivity. In this study, the authors describe a novel and universal binding assay based on an actinonin derivative and show its binding activities for several MPs and its lack of activity toward all the non-MPs tested. This newly developed assay would allow for the rapid screening for inhibitors of a given MP and for the selectivity profiling of the resulting hits. The assay has successfully enabled for the first time simultaneous profiling of 8 well-known inhibitors against a panel of selected MPs. Previously published activities for these inhibitors were confirmed, and the authors have also discovered new molecular targets for some of them. The authors conclude that their profiling platform provides a generic assay solution for the identification of novel metalloprotease inhibitors as well as their selectivity profiling using a simple and homogeneous assay. PMID:18349423

Antczak, Christophe; Radu, Constantin; Djaballah, Hakim

2008-03-18

367

Regulation of COX-2-mediated signaling by ?3 type IV noncollagenous domain in tumor angiogenesis  

PubMed Central

Human ?3 chain, a noncollagenous domain of type IV collagen [?3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of ?3(IV)NC1 to ?V?3 and ?3?1 integrins. ?3(IV)NC1 binds ?V?3 integrin, leading to translation inhibition by inhibiting focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathways. In the present study, we evaluated the role of ?3?1 and ?V?3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on ?3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by ?3(IV)NC1 in endothelial cells, only ?3?1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of ?3(IV)NC1 to ?3?1 integrin leads to inhibition of COX-2–mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating I?B?/NF?B axis, and is independent of ?V?3 integrin. Furthermore, ?3 integrin–null endothelial cells, when treated with ?3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in ?3 integrin–null endothelial cells, indicating that regulation of COX-2 by ?3(IV)NC1 is mediated by integrin ?3?1. Our in vitro and in vivo findings demonstrate that ?3?1 integrin is critical for ?3(IV)NC1-mediated inhibition of COX-2–dependent angiogenic signaling and inhibition of tumor progression.

Boosani, Chandra Shekhar; Mannam, Arjuna P.; Cosgrove, Dominic; Silva, Rita; Hodivala-Dilke, Kairbaan M.; Keshamouni, Venkateshwar G.

2007-01-01

368

Acyl chain-dependent effect of lysophosphatidylcholine on cyclooxygenase (COX)-2 expression in endothelial cells  

PubMed Central

Objective Previously we identified palmitoyl-, oleoyl- linoleoyl-, and arachidonoyl-lysophosph-atidylcholine (LPC 16:0, 18:1, 18:2 and 20:4) as the most prominent LPC species generated by endothelial lipase (EL). In the present study, we examined the capacity of those LPC to modulate expression of cyclooxygenase (COX)-2 in vascular endothelial cells. Methods & results LPC 16:0 and 20:4 promoted both COX