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1

Lumiracoxib, a highly selective COX-2 inhibitor.  

PubMed

Lumiracoxib Prexige, Novartis AG) is a highly selective inhibitor of cyclooxygenase-2 that has been approved in 22 countries including the UK for analgesic therapy in chronic and acute pain. For patients with osteoarthritis, the recommended initial dose is 100 or 200 mg once daily, in one or two divided doses. In patients with primary dysmenorrhea, or following dental or orthopedic surgery with moderate-to-severe acute pain, the recommended dose is 400 mg once daily. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) tested the efficacy and gastrointestinal safety of the drug against two traditional nonselective nonsteroidal anti-inflammatory drugs, naproxen and ibuprofen. The results from this trial demonstrated that lumiracoxib reduces gastrointestinal ulcer complication rates by 66% overall and 79% among nonaspirin users in a population without gastroprotection. Lumiracoxib was not associated with a statistically significant difference in cardiovascular morbidity and mortality compared with nonselective nonsteroidal anti-inflammatory drugs. However, in view of the ongoing debate about the safety of cyclooxygenase-2 inhibitors, the use of this drug class should be limited to patients with increased risk of gastrointestinal complications until results of randomized trials in cardiovascular high-risk populations are published. PMID:20477653

Jeger, Raban V; Greenberg, Jeffrey D; Ramanathan, Krishnan; Farkouh, Michael E

2005-05-01

2

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships  

PubMed Central

Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships. PMID:24250402

Zarghi, Afshin; Arfaei, Sara

2011-01-01

3

Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX2) inhibitors  

Microsoft Academic Search

BACKGROUND: Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade. METHODS: We conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were

Randall E Harris; Joanne Beebe-Donk; Galal A Alshafie

2006-01-01

4

COX-2 Inhibitors and Gastric Cancer  

PubMed Central

The evidence that cyclooxygenase-2 (COX-2) is upregulated and plays an important role in carcinogenesis of gastric cancer has triggered the topic of COX-2 inhibitors as chemopreventive agents for gastric cancer. Studies find that COX-2 inhibitors are associated not only with chemoprophylactic effects, but also with chemotherapeutic potentials in gastric cancer. Both COX-dependent and COX-independent pathways have a role in the anticancer efficiency of COX-2 inhibitors. However, enthusiasm is thwarted by the potential toxicity, that is, gastrointestinal toxicity of nonselective COX-2 inhibitors and cardiovascular risk of selective COX-2 inhibitors. Therefore, more studies are needed to develop new targeted antitumor agents (such as prostaglandin E receptor antagonist) and to define fundamental questions such as optimal treatment regimens, integration of cotherapy, and careful selection of candidates. PMID:25371669

Wang, Zhen; Chen, Jun-qiang; Liu, Jin-lu

2014-01-01

5

Outcome trials of COX2 selective inhibitors: global safety evaluation does not promise benefits  

Microsoft Academic Search

Background. Gastrointestinal toxicity is the most frequent adverse effect associated with nonsteroidal anti-inflammatory drug use. The most clinically relevant side effects of this toxicity are ulcer complications, including perforation, obstruction, or bleeding. Selective cyclooxygenase (COX-2) inhibitors (coxibs) have been proposed as a safer alternative to traditional, nonsteroidal anti-inflammatory drugs and they are currently widely used in clinical practice. The aim

Jorge Gomez Cerezo; Rubin Lubomirov Hristov; Antonio J. Carcas Sansuán; Juan J. Vázquez Rodríguez

2003-01-01

6

Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX2) inhibitors  

Microsoft Academic Search

BACKGROUND: Epidemiologic and laboratory investigations suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against colon cancer perhaps due at least in part to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade. METHODS: We conducted a case control study of colon cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A

Randall E Harris; Joanne Beebe-Donk; Galal A Alshafie

2008-01-01

7

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. PMID:19788894

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

2009-01-01

8

TCDD?induced chick cardiotoxicity is abolished by a selective cyclooxygenase?2 (COX?2) inhibitor NS398.  

PubMed

Halogenated aromatic hydrocarbons, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are known to cause severe heart defects in avian species. However, the mechanism of TCDD-induced chick cardiovascular toxicity is unclear. In this study, we investigated cyclooxygenase-2 (COX-2) as a possible mechanism of TCDD-induced cardiotoxicity. Fertile chicken eggs were injected with TCDD and a COX-2 selective inhibitor, NS398, and we investigated chick heart failure on day 10. We found that the chick heart to body weight ratio and atrial natriuretic factor mRNA expression were increased, but this increase was abolished with treatment of NS398. In addition, the morphological abnormality of an enlarged ventricle resulting from TCDD exposure was also abolished with co-treatment of TCDD and NS398. Our results suggested that TCDD-induced chick heart defects are mediated via the nongenomic pathway and that they do not require the genomic pathway. PMID:24658325

Fujisawa, Nozomi; Nakayama, Shouta M M; Ikenaka, Yoshinori; Ishizuka, Mayumi

2014-09-01

9

Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis  

Microsoft Academic Search

Objectives To investigate the cost effectiveness of cyclo-oxygenase-2 (COX 2) selective inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs), and the addition of proton pump inhibitors to these treatments, for people with osteoarthritis.Design An economic evaluation using a Markov model and data from a systematic review was conducted. Estimates of cardiovascular and gastrointestinal adverse events were based on data from three

Nicholas Latimer; Joanne Lord; Robert L Grant; Rachel O’Mahony; John Dickson; Philip G Conaghan

2009-01-01

10

Effects of nimesulide, a selective COX-2 inhibitor, on cardiovascular function in 2 rat models of diabetes.  

PubMed

Cyclooxygenase-2 (COX-2) has been found to be activated in diabetes. We investigated whether nimesulide (selective COX-2 inhibitor) alters cardiovascular responses to adrenaline in 2 rat models of diabetes. Wistar rats (5-week old) were continuously fed a normal or high-fructose diet (60% of caloric intake). At week 2, half of the rats in each diet regimen were given streptozotocin (STZ) (60 mg/kg, intravenously). At week 6, cardiovascular effects of adrenaline (6 and 16 × 10 mol·kg·min, intravenously) were measured in 4 groups of thiobutabarbital-anesthetized rats (control, fructose, STZ, and fructose-streptozotocin [F-STZ]) before and after the injection of nimesulide (3 mg/kg, intravenously). Both the STZ and F-STZ groups exhibited hyperglycemia and significantly (P < 0.05) reduced left ventricular contractility, mean arterial pressure, arterial and venous resistance, and mean circulatory filling pressure (index of venous tone) responses to adrenaline, relative to the control and fructose groups. Nimesulide did not affect responses in the control and fructose groups but increased the venous and, to a less extent, arterial constriction to adrenaline in both the groups of diabetic rats. The cardiac contractile responses, however, were not altered after nimesulide treatment. The results show that nimesulide partially restored arterial and venous constriction to adrenaline in rats with STZ- and F-STZ-induced diabetes. PMID:24621649

Leung, Joanne Y T; Pang, Catherine C Y

2014-07-01

11

Assessment of Alloxan-Induced Diabetic Rats as a Periodontal Disease Model Using a Selective Cyclooxygenase (COX)-2 Inhibitor  

PubMed Central

Several recent studies have reported that alloxan-treated rats with long-term hyperglycemia can develop naturally occurring periodontal disease (PD). Our previous studies detected dental caries in the same model. Therefore, these two lesions of different etiologies are expected to occur concurrently. In this study, we evaluated the use of diabetic rats as a PD model by employing a selective COX-2 inhibitor reported to be effective against PD. Six-week-old female F344 rats were divided into 3 groups: intact rats (control), alloxan-induced diabetic rats fed a standard diet (AL) and alloxan-induced diabetic rats fed a diet containing 0.01% etodolac (AL+Et). The animals were euthanized at 26 weeks of age, and their oral tissues were examined histopathologically. Gingivitis, marginal periodontitis and alveolar bone resorption were markedly enhanced along with dental caries in the AL group compared with the control group. However, the COX-2 inhibitor had no effect on periodontal inflammation in the AL+Et group. In addition, in the AL group, periodontitis was notably nonexistent around the normal molars, and gingivitis was scarcely worse than that in the control group. In the diabetic rats, the progression of periodontal inflammation was closely correlated with the severity of adjacent dental caries, and marginal periodontitis was frequently continuous with apical periodontitis. In conclusion, an alloxan-induced diabetic rat is not a model of PD but of dental caries. It is probable that in this model, hyperglycemia may enable crown caries to progress to apical periodontitis, while the associated inflammation may rostrally expand to surrounding periodontal tissue. PMID:25352713

Nakahara, Yutaka; Ozaki, Kiyokazu; Sano, Tomoya; Kodama, Yasushi; Matsuura, Tetsuro

2014-01-01

12

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

13

NS-398, a selective COX-2 inhibitor, inhibits proliferation of IL-1{beta}-stimulated vascular smooth muscle cells by induction of {eta}{omicron}-1  

SciTech Connect

We investigated whether NS-398, a selective inhibitor of COX-2, induces HO-1 in IL-1{beta}-stimulated vascular smooth muscle cells (VSMC). NS-398 reduced the production of PGE{sub 2} without modulation of expression of COX-2 in IL-1{beta}-stimulated VSMC. NS-398 increased HO-1 mRNA and protein in a dose-dependent manner, but inhibited proliferation of IL-1{beta}-stimulated VSMC. Furthermore, SnPPIX, a HO-1 inhibitor, reversed the effects of NS-398 on PGE{sub 2} production, suggesting that COX-2 activity can be affected by HO-1. Hemin, a HO-1 inducer, also reduced the production of PGE{sub 2} and proliferation of IL-1{beta}-stimulated VSMC. CORM-2, a CO-releasing molecule, but not bilirubin inhibited proliferation of IL-1{beta}-stimulated VSMC. NS-398 inhibited proliferation of IL-1{beta}-stimulated VSMC in a HbO{sub 2}-sensitive manner. In conclusion, NS-398 inhibits proliferation of IL-1{beta}-stimulated VSMC by HO-1-derived CO. Thus, NS-398 may facilitate the healing process of vessels in vascular inflammatory disorders such as atherosclerosis.

Choi, Hyoung Chul [Department of Pharmacology and Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Kim, Hee Sun [Department of Microbiology and Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Lee, Kwang Youn [Department of Pharmacology and Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Chang, Ki Churl [Department of Pharmacology School of Medicine, and Institute of Health Sciences, Gyeongsang National University, Jinju 660-751 (Korea, Republic of)], E-mail: kcchang@gnu.kr; Kang, Young Jin [Department of Pharmacology and Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)], E-mail: yjkang@med.yu.ac.kr

2008-11-28

14

Synthesis, biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents.  

PubMed

A novel series of pyrazole derivatives were synthesized and evaluated in vivo for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Among all compounds, 5a, and 5b showed comparable anti-inflammatory activity to Nimesulide, the standard drug taken for the studies. In silico (docking) studies were carried out to investigate the theoretical binding mode of the compounds to target the cyclooxygenase (COX-2) using Autodock 4.2. PMID:24893208

Tewari, Ashish Kumar; Singh, Ved Prakash; Yadav, Pratima; Gupta, Garima; Singh, Amit; Goel, Raj Kumar; Shinde, Pravin; Mohan, C Gopi

2014-10-01

15

COX2 selective NSAID decreases bone ingrowth in vivo  

Microsoft Academic Search

Whether non-steroidal anti-inflammatory drug (NSAID)––induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the

Stuart Goodman; Ting Ma; Michael Trindade; Takashi Ikenoue; Ippe Matsuura; Neal Wong; Nora Fox; Mark Genovese; Don Regula

2002-01-01

16

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

17

Selective COX2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease  

Microsoft Academic Search

Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that

Rosario Sánchez-Pernaute; Andrew Ferree; Oliver Cooper; Meixiang Yu; Anna-Liisa Brownell; Ole Isacson

2004-01-01

18

Synthesis and biologic evaluation of substituted 5-methyl-2-phenyl-1H-pyrazol-3(2H)-one derivatives as selective COX-2 inhibitors: molecular docking study.  

PubMed

The present study reported the synthesis and biologic evaluation of new pyrazolone derivatives for COX-2 inhibitory activities and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model as well as in vitro using HRBC membrane stabilization and protein denaturation method. Eight derivatives showed pronounced COX-2 inhibition, and 5a, 5d, and 5f exhibited the highest COX-2 inhibition. The derivatives were further evaluated for antioxidant activity wherein 5a and 5b showed potent free radical-scavenging activity against DPPH, nitric oxide, and hydrogen peroxide radicals. Molecular docking study revealed the binding orientations of pyrazolone derivatives into the active sites of COX-2 and thereby helps to design the potent inhibitors. PMID:24636540

Dube, Pritam N; Bule, Shweta S; Mokale, Santosh N; Kumbhare, Manoj R; Dighe, Pravin R; Ushir, Yogesh V

2014-10-01

19

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

20

Antiproliferative effect of two novel COX-2 inhibitors on human keratinocytes.  

PubMed

Selective COX-2 inhibitors (COXib) belonging to the class of diaryl heterocycles (e.g., celecoxib, rofecoxib, etc.), are devoid of the undesirable effects due to their capacity to inhibit selectively inducible (COX-2), responsible for inflammatory effects but not constitutive cyclooxygenase-1 (COX-1)(COX); responsible for cytoprotective effects on gastric mucosa. In addition, several reports have identified an increased risk of cardiovascular events associated with the use of COXib. We have developed a new series of anti-inflammatory agents (1,5-diarylpyrrole-3-alkoxyethyl esters and ethers). To evaluate the effect of two 1,5-diarylpyrrole-3-alkoxyethyl ethers, VA441 and VA428 (up to 100 ?M), respectively, in comparison with two well known COXib, celecoxib and rofecoxib, on HaCaT cell (keratinocytes) proliferation and toxicity. Crucial molecules in cell cycle progression, i.e. NF?B and ERK as targets/mediators and cyclin D1 and p21 Cip1/Kip as final effectors were evaluated by Western blot, immunohystochemistry and q-PCR analysis. Both compounds, VA441 and VA428, showed a strong inhibition of cell proliferation, and did not exhibit cytotoxicity. The anti-proliferative effect was accompanied by a strong activation of ERK and induction of the cell cycle inhibitor p21. In addition, there was a clear inhibition of the transcription factor NF-?B and downregulation of cyclin D1, with enforced inhibition of the HaCaT cell cycle progression. These data suggest that compounds VA441 and VA428, along with their role in inhibiting COX-2 and inflammation, could have a possible therapeutic (topical and systemic) use against skin proliferative disorders, such as psoriasis. PMID:23454135

Sticozzi, Claudia; Belmonte, Giuseppe; Cervellati, Franco; Di Capua, Angela; Maioli, Emanuela; Cappelli, Andrea; Giordani, Antonio; Biava, Mariangela; Anzini, Maurizio; Valacchi, Giuseppe

2013-05-13

21

Brain activity for chronic knee osteoarthritis: dissociating evoked from spontaneous pain and modulation by COX2inhibitor treatment  

E-print Network

and modulation by COX2inhibitor treatment PH 071 IASP 2010 Montreal Funded by NIH NINDS NS35115, Endo 06510 INTRODUCTION Osteoarthritis (OA) is the most common type of arthritis, and a leading threshold determinations. Treatments for OA have included COX2inhibitors (COX2i), but the effects

Apkarian, A. Vania

22

COX-2 inhibitors and the heart: are all coxibs the same?  

PubMed Central

The selective COX?2 inhibitors (coxibs) were originally developed to minimise the adverse effects of conventional non?steroidal anti?inflammatory drugs (NSAIDs) while maintaining the same analgesic and anti?inflammatory properties. Many large studies confirmed the improved gastric side effect profile of coxibs compared with non?selective NSAIDs; however, reports of increased cardiovascular morbidity and mortality followed, and the manufacturer Merck was forced to withdraw rofecoxib (Vioxx) from the market. Other coxibs have also either perished or had restrictions placed on their use. However, there seem to be significant differences between coxibs regarding their cardiovascular profiles, and the evidence for a class effect is dubious. In this paper, the current body of knowledge regarding the cardiovascular toxicities of coxibs is reviewed. The take home message for prescribing NSAIDs and those coxibs still on the market seems to be one of caution rather than contraindication, except in patients with significant cardiovascular risk factors. PMID:16597810

Sooriakumaran, P

2006-01-01

23

Is Australia's national medicines policy failing? The case of COX-2 inhibitors.  

PubMed

Australia has a National Medicines Policy with aims that include quality use of medicines, but policy stakeholders failed to protect Australia from the COX-2 (cyclo-oxygenase-2) inhibitor disaster. Drug regulators did not warn prescribers appropriately about potential cardiovascular risks. The Pharmaceutical Benefits Scheme did not limit unjustified drug expenditures on COX-2 inhibitors. Drug companies ran intense and misleading promotional campaigns on COX-2 inhibitors without adequate controls. Independent drug information was insufficient to counter the effects of the millions of dollars spent on advertising. Core elements of the National Medicines Policy--in particular the drug approval process, the post-marketing surveillance system, the control of drug promotion, and the quality of independent drug information--require major reappraisal if we want to avoid similar disasters in the future. PMID:18072318

Vitry, Agnes; Lexchin, Joel; Mansfield, Peter R

2007-01-01

24

Nimesulide, a COX2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis  

Microsoft Academic Search

BACKGROUND: Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2

M. L. Hull; A. Prentice; D. Y. Wang; R. P. Butt; S. C. Phillips; S. K. Smith; D. S. Charnock-Jones

2005-01-01

25

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. PMID:17996418

Strauss, Kenneth I.

2008-01-01

26

O-desmethylquinine as a cyclooxygenase-2 (COX-2) inhibitors using AutoDock Vina  

NASA Astrophysics Data System (ADS)

Computational approach was employed to evaluate the biological activity of novel cyclooxygenase-2 COX-2 inhibitor, O-desmethylquinine, in comparison to quinine as common inhibitor which can also be used an agent of antipyretic, antimalaria, analgesic and antiinflamation. The molecular models of the compound were constructed and optimized with the density function theory with at the B3LYP/6-31G (d,p) level using Gaussian 09 program. Molecular docking studies of the compounds were done to obtain the COX-2 complex structures and their binding energies were analyzed using the AutoDock Vina. The results of docking of the two ligands were comparable and cannot be differentiated from the energy scoring function with AutoDock Vina.

Damayanti, Sophi; Mahardhika, Andhika Bintang; Ibrahim, Slamet; Chong, Wei Lim; Lee, Vannajan Sanghiran; Tjahjono, Daryono Hadi

2014-10-01

27

Direct-to-consumer advertising of COX-2 inhibitors: effect on appropriateness of prescribing.  

PubMed

Spending on direct-to-consumer advertising (DTCA) of prescription drugs has increased dramatically in the past several years. An unresolved question is whether such advertising leads to inappropriate prescribing. In this study, the authors use survey and administrative data to determine the association of DTCA with the appropriate prescribing of cyclooxygenase-2 (COX-2) inhibitors for 1,382 patients. Treatment with either a COX-2 or a traditional nonsteroidal anti-inflammatory drug (NSAID) was defined as appropriate or not according to three different definitions of gastrointestinal risk. Patients who saw or heard a COX-2 advertisement and asked their physician about the advertised drug were significantly more likely to be prescribed a COX-2 (versus a NSAID, as recommended by evidence-based guidelines) than all other patients. Findings also suggest that some patients may benefit from DTCA. The authors discuss the need for balanced drug information for consumers, increased physician vigilance in prescribing appropriately, and further study of DTCA. PMID:16177457

Spence, Michele M; Teleki, Stephanie S; Cheetham, T Craig; Schweitzer, Stuart O; Millares, Mirta

2005-10-01

28

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

29

Synthesis and evaluation of 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides as COX-2 and serotonin reuptake inhibitors.  

PubMed

Based on the positive effects of COX-2 inhibitors on depressive symptoms and the desirable physicochemical and biological properties of the morpholine group, a series of novel 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides were designed, synthesized, and tested for their COX-2 inhibitory and serotonin reuptake inhibitory activities in vitro. The structure-activity relationships of the 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides as dual COX-2 and serotonin reuptake inhibitors were determined and discussed in detail. The biological assays indicated that five of the compounds possess good COX-2 selectivity (selectivity index COX-1/COX-2 42.8-158.1). The compound 2-[2-(4-benzyloxyphenyl)morpholino]ethyl 2-(4-iso-butylphenyl)-propanoate hydrochloride (1k) shows better COX-2 inhibitory activity (IC50 ?=?0.78?µM) than ibuprofen (IC50 ?=?7.6?µM), and it simultaneously possesses favorable serotonin reuptake inhibitory activity. PMID:24243443

Dou, Jie; Shi, Lei; Hu, Aixi; Dong, Minyu; Xu, Jiangping; Liu, Ailin; Jiang, Yiping

2014-02-01

30

Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation  

PubMed Central

Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Here we utilized medicinal chemistry and in vivo analytical and behavioral pharmacological approaches to demonstrate a key role for COX-2 in the regulation of endocannabinoid (eCB) levels in vivo. A novel pharmacological strategy involving “substrate-selective” inhibition of COX-2 was used to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2reducedanxiety-like behaviors in mice via increasede CB signaling. These data elucidate a key role for COX-2 in the regulation of eCB signaling and suggest substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential. PMID:23912944

Hermanson, Daniel J.; Hartley, Nolan D.; Gamble-George, Joyonna; Brown, Naoko; Shonesy, Brian C.; Kingsley, Phillip J.; Colbran, Roger J.; Reese, Jeffrey

2013-01-01

31

Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors.  

PubMed

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a-d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50's in 1.79-4.35?M range; COX-2 selectivity index (SI)=6.8-16.7 range). Compound 3b emerged as most potent (COX-2 IC50=1.79?M; COX-1 IC50 >30?M) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5h) in comparison to celecoxib (51.44% inhibition of edema at 5h) in carrageenan-induced rat paw edema assay. Structure-activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1. PMID:25219899

Grover, Jagdeep; Kumar, Vivek; Sobhia, M Elizabeth; Jachak, Sanjay M

2014-10-01

32

Effect of the COX2 Inhibitor Celecoxib on Behavioural and Immune Changes in an Olfactory Bulbectomised Rat Model of Depression  

Microsoft Academic Search

Background: The olfactory bulbectomised (OBX) rat model is a chronic model of depression in which behavioural and neuroimmunoendocrine changes are reversed only after chronic antidepressant treatment. The cyclooxygenase 2 (COX-2) inhibitor celecoxib has been shown to improve the depressive symptoms in patients with major depression. Methods: The association between blood and brain immunological and behavioural changes in chronic treatment with

Aye Mu Myint; Harry W. M. Steinbusch; Liam Goeghegan; Dirk Luchtman; Yong Ku Kim; Brian E. Leonard

2007-01-01

33

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

34

Pimarane Cyclooxygenase 2 (COX-2) Inhibitor and its StructureActivity Relationship  

E-print Network

activities, although the inhibitory potency was not satisfactory. Our docking study9 revealed that the COX-2. *Corresponding author. Tel.: +82-02-880-7875; fax: +82-02-888- 0649; e-mail: ygsuh@plaza.snu.ac.kr #12

Suh, Young-Ger

35

Recent Methodologies toward the Synthesis of Valdecoxib: A Potential 3,4-diarylisoxazolyl COX-2 Inhibitor  

PubMed Central

Non-steroidal anti-inflammatory drugs are widely used therapeutic agents in the treatment of inflammation, pain and fever. Cyclooxygenase catalyzes the initial step of biotransformation of arachidonic acid to prostanoids, and exist as three distinct isozymes; COX-I, COX-II and COX-III. Selective COX-II inhibitors are a class of potential anti-inflammatory, analgesic, and antipyretic drugs with reduced gastrointestinal (GI) side effects compared to nonselective inhibitors. 3,4-diarylisoxazole scaffold is recurrently found in a wide variety of NSAIDs, protein kinase inhibitors, hypertensive agents, and estrogen receptor (ER) modulators. In the present review, we document on the recent synthetic strategies of 3,4-diarylisoxazolyl scaffolds of valdecoxib and its relevant structural analogues. PMID:20724040

Dadiboyena, Sureshbabu; Nefzi, Adel

2011-01-01

36

Ulcer formation with low-dose enteric-coated aspirin and the effect of COX2 selective inhibition: A double-blind trial  

Microsoft Academic Search

Background & Aims: We assessed the risk of ulcers with low-dose aspirin and the interaction of low-dose aspirin with a COX-2 selective inhibitor in a double-blind trial that compared placebo, low-dose aspirin, rofecoxib + low-dose aspirin, and ibuprofen. Methods: Osteoarthritis patients ?50 years of age without ulcers or erosive esophagitis at baseline endoscopy were assigned randomly to placebo, enteric-coated aspirin

Loren Laine; Eric S. Maller; Chang Yu; Hui Quan; Thomas Simon

2004-01-01

37

Neuronal and nonneuronal COX-2 expression confers neurotoxic and neuroprotective phenotypes in response to excitotoxin challenge.  

PubMed

Treating acute brain injuries with COX-2 inhibitors can produce both neuroprotective and neurotoxic effects. This study investigated the role of COX-2 in modulating acute brain injury induced by excitotoxic neural damage. Intrastriatal injection of excitotoxin (RS)-(tetrazole-5yl) glycine elicited COX-2 expression in two distinct groups of cells. cortical neurons surrounding the lesion and vascular cells in the lesion core. The vascular COX-2 was expressed in two cell types, endothelial cells and monocytes. Selective deletion of COX-2 in vascular cells in Tie2Cre Cox-2(flox/flox) mice did not affect the induction of COX-2 in neurons after the excitotoxin injection but resulted in increased lesion volume, indicating a neuroprotective role for the COX-2 expressed in the vascular cells. Selective deletion of monocyte COX-2 in LysMCre Cox-2(flox/flox) mice did not reduce COX-2-dependent neuroprotection, suggesting that endothelial COX-2 is sufficient to confer neuroprotection. Pharmacological inhibition of COX-2 activity in Tie2Cre Cox-2(flox/flox) mice reduced lesion volume, indicating a neurotoxic role for the COX-2 expressed in neurons. Furthermore, COX-2-dependent neurotoxicity was mediated, at least in part, via the activation of the EP1 receptor. These results show that Cox-2 expression induced in different cell types can confer opposite effects. PMID:24375716

An, Ying; Belevych, Natalya; Wang, Yufen; Zhang, Hao; Herschman, Harvey; Chen, Qun; Quan, Ning

2014-04-01

38

Prescription channeling of COX2 inhibitors and traditional nonselective nonsteroidal anti-inflammatory drugs: a population-based case–control study  

Microsoft Academic Search

This pharmacoepidemiologic study was conducted to determine whether risk factors for upper gastrointestinal bleeding influenced the prescription of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at the time when COX-2 inhibitors were first included in the formulary of reimbursed medications. A population-based case–control study was conducted in which the prevalence of risk factors and the medical histories

Yola Moride; Thierry Ducruet; Jean-François Boivin; Nicholas Moore; Sylvie Perreault; Sean Zhao

2005-01-01

39

Hepatic Ischemia and Reperfusion Injury in the Absence of Myeloid Cell-Derived COX-2 in Mice  

PubMed Central

Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2?M/?M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2?M/?M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2?M/?M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2?M/?M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2?M/?M and WT mice. COX-2?M/?M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2?M/?M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype. PMID:24819536

Duarte, Sergio; Kato, Hiroyuki; Kuriyama, Naohisa; Suko, Kathryn; Ishikawa, Tomo-o; Busuttil, Ronald W.; Herschman, Harvey R.; Coito, Ana J.

2014-01-01

40

A COX-2 inhibitor reduces muscle soreness, but does not influence recovery and adaptation after eccentric exercise.  

PubMed

The aim of this study was to investigate the effect of a cyclooxygenase (COX)-2 inhibitor on the recovery of muscle function, inflammation, regeneration after, and adaptation to, unaccustomed eccentric exercise. Thirty-three young males and females participated in a double-blind, placebo-controlled experiment. Seventy unilateral, voluntary, maximal eccentric actions with the elbow flexors were performed twice (bouts 1 and 2) with the same arm, separated by 3 weeks. The test group participants were administered 400 mg/day of celecoxib for 9 days after bout 1. After both bouts 1 and 2, concentric and isometric force-generating capacity was immediately reduced (approximately 40-50%), followed by the later appearance of muscle soreness and increased serum creatine kinase levels. Radiolabelled autologous leukocytes (detected by scintigraphy) and monocytes/macrophages (histology) accumulated in the exercised muscles, simultaneously with increased satellite cell activity. These responses were reduced and recovery was faster after bout 2 than 1, demonstrating a repeated-bout effect. No differences between the celecoxib and placebo groups were detected, except for muscle soreness, which was attenuated by celecoxib. In summary, celecoxib, a COX-2 inhibitor, did not detectably affect recovery of muscle function or markers of inflammation and regeneration after unaccustomed eccentric exercise, nor did the drug influence the repeated-bout effect. However, it alleviated muscle soreness. PMID:19522751

Paulsen, G; Egner, I M; Drange, M; Langberg, H; Benestad, H B; Fjeld, J G; Hallén, J; Raastad, T

2010-02-01

41

COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity.  

PubMed

Endocannabinoids (eCBs) are important endogenous lipid mediators in synaptic transmission and plasticity and are oxygenated by cyclooxygenase-2 (COX-2) to form new types of prostaglandins. However, little is known about whether COX-2 oxidative metabolism of eCBs and their metabolites alter synaptic signaling. Here we demonstrate that increased COX-2 expression significantly enhances basal synaptic transmission and augments long-term potentiation (LTP) in the mouse hippocampus. This augmentation was inhibited in the presence of a selective COX-2 inhibitor or with deletion of the COX-2 gene. The CB(1) receptor-mediated depolarization-induced suppression of inhibition (DSI) was diminished when COX-2 expression was increased either with lipopolysaccharide (LPS) stimulation or transgenic neuronal over-expression of COX-2. Conversely, DSI was potentiated when COX-2 activity was pharmacologically or genetically inhibited. Interestingly, COX-2 oxidative metabolites of eCBs elevated LTP, an effect opposite to that of their parent molecules 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA). In addition, the ERK/MAPK and IP(3) pathways were found to mediate PGE(2)-G-induced enhancement of LTP. Our results indicate that COX-2 oxidative metabolism of eCBs is an important signaling pathway in modulation of synaptic transmission and plasticity. PMID:18295507

Yang, Hongwei; Zhang, Jian; Andreasson, Katrin; Chen, Chu

2008-04-01

42

Synthesis of heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)-(arylmethyloxy)amine COX-2 inhibitors: effects on the inhibitory activity of the replacement of the cyclopentene central core with pyrazole, thiophene or isoxazole ring.  

PubMed

Several heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)-(arylmethyloxy)amine COX-2 inhibitors, in which the cyclopentene moiety was replaced by pyrazole, thiophene or isoxazole ring, were synthesized, in order to verify the influence of the different nature of the central core on the COX inhibitory properties of these kinds of molecules. Among the compounds tested, only the 3-(p-methylsulfonylphenyl) substituted thiophene derivatives 17 and 22, showed a certain COX-2 inhibitory activity, accompanied by an appreciable COX-2 versus COX-1 selectivity. Only one of the 1-(p-methylsulfonylphenyl)pyrazole compounds (16) displayed a modest inhibitory activity towards both type of isoenzymes, while the pyrazole 1-(p-aminosulfonylphenyl) substituted 12 proved to be significantly active only towards COX-1. All the isoxazole derivatives were inactive on both COX isoforms. PMID:12620660

Balsamo, Aldo; Coletta, Isabella; Guglielmotti, Angelo; Landolfi, Carla; Mancini, Francesca; Martinelli, Adriano; Milanese, Claudio; Minutolo, Filippo; Nencetti, Susanna; Orlandini, Elisabetta; Pinza, Mario; Rapposelli, Simona; Rossello, Armando

2003-02-01

43

A review of the efficacy, safety, and cost-effectiveness of COX-2 inhibitors for Africa and the Middle East region.  

PubMed

Despite an increasingly sophisticated understanding of pain mechanisms, acute and chronic pain remain undertreated throughout the world. This situation reflects the large gap that exists between evidence and practice in pain management and is typified by inappropriate use of nonsteroidal anti-inflammatory drugs (NSAIDs). The scientific evidence around these drugs continues to expand at a high rate, yet physicians are often unaware of best practice. To address this gap among physicians in Africa and the Middle East, an Expert Panel meeting was convened with representatives from the region. The principal objective of the meeting was to review the latest guidelines on the management of acute and chronic pain and to review the efficacy, safety, and cost-effectiveness of cyclooxygenase-2 (COX-2) inhibitors in these settings. The main outcome of this review process was a number of consensus statements concerning the definitions of acute and chronic pain, and the efficacy, safety and cost-effectiveness of traditional nonselective NSAIDs (nsNSAIDs) and selective COX-2 inhibitors (coxibs). The panel agreed that nsNSAIDs and coxibs are effective analgesics with similar efficacy for acute pain; for chronic musculoskeletal pain, NSAIDs are significantly more effective than either placebo or paracetamol. Coxibs offer important safety advantages over nsNSAIDs, including gastrointestinal safety and preservation of platelet function; notably, the cardiovascular safety of coxibs has been the subject of much recent debate. Furthermore, the panel agreed there is substantial evidence to indicate that cost savings can be achieved by using celecoxib in patients at moderate to high risk of gastrointestinal adverse events, even in countries with moderate healthcare expenditures. PMID:22931375

Zeidan, Anwar Z; Al Sayed, Bashar; Bargaoui, Naceur; Djebbar, Mourad; Djennane, Malik; Donald, Royden; El Deeb, Khamis; Joudeh, Raed A; Nabhan, Abdullah; Schug, Stephan A

2013-04-01

44

Post-training intrahippocampal infusion of the COX2 inhibitor celecoxib impaired spatial memory retention in rats  

Microsoft Academic Search

In this study, we investigated the effects of intrahippocampal infusion of indomethacin as a non-selective cyclooxygenase inhibitor and celecoxib as a selective cyclooxygenase-2 inhibitor on spatial memory in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained 4 trials. Tests were performed 48 h after surgery. Bilateral intrahippocampal infusion of

Mohammad Sharifzadeh; Nasser Naghdi; Sara Khosrovani; Seyed Nasser Ostad; Kurdistan Sharifzadeh; Ali Roghani

2005-01-01

45

Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma  

PubMed Central

Background The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. Methods We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). Results The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p?=?0.037), lower CDH-1 mRNA expression (p?=?0.020), and advanced T-classification (p?=?0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p?=?0.041). Conclusions These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC. PMID:24887090

2014-01-01

46

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. PMID:22038825

Lin, You-Min; Sarna, Sushil K.

2012-01-01

47

Specific COX-2 inhibitor NS398 induces apoptosis in human liver cancer cell line HepG2 through BCL-2  

PubMed Central

AIM: To evaluate the effects of NS-398, a cyclooxygenase-2 (COX-2) inhibitor, on the proliferation and apoptosis of HepG2 cells. METHODS: The effects of NS-398 on the proliferation of HepG2 cells were evaluated by MTT. DNA fragmentation gel analysis was used to analyze the apoptotic cells. DNA ploidy and apoptotic cell percentage were calculated by flow cytometry. The expression of COX-2 and Bcl-2 mRNA was identified by competitive RT-PCR. Furthermore, expression level of Bcl-2 was detected using Western blot in HepG2 after treated with NS-398. RESULTS: NS-398 inhibited cell proliferation and induced apoptosis of HepG2 cells in a concentration-dependent manner. DNA ploidy analysis showed that S phase cells were significantly decreased with increase of NS-398 concentration. The quiescent G0/G1 phase was accumulated with decrease of Bcl-2 mRNA. Whereas NS-398 had no effect on the expression of COX-2 mRNA, and no correlations were found between COX-2 mRNA and HepG2 cell proliferation and apoptosis induced by NS-398 (r = 0.056 and r = 0.119, respectively). Bcl-2 protein level was inhibited after treated with NS-398. CONCLUSION: NS-398 significantly inhibits the proliferation and induces apoptosis of HepG2 cells. Mechanisms involved may be accumulation of quiescent G0/G1 phase and decrease of Bcl-2 expression. PMID:15633216

Huang, Dong-Sheng; Shen, Ke-Zhen; Wei, Jian-Feng; Liang, Ting-Bo; Zheng, Shu-Sen; Xie, Hai-Yang

2005-01-01

48

Effect of Specific and Non-Specific Inhibition of COX2 on Renal Oxygenation before and after Water Diuresis  

Microsoft Academic Search

Background\\/Aims: Water diuresis usually increases medullary oxygenation as a result of increased medullary synthesis of prostaglandins, but it is not clear whether this involves activation of cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). Methods: The effects of celecoxib, a selective inhibitor of COX-2, and of ibuprofen, a non-specific inhibitor of COX-1 and COX-2, upon renal oxygenation during water diuresis were studied in

Scott Gilbert; Chun Zuo; Franklin H. Epstein

2005-01-01

49

Impact of 5-lipoxygenase inhibitors on the spatiotemporal distribution of inflammatory cells and neuronal COX-2 expression following experimental traumatic brain injury in rats.  

PubMed

The inflammatory response following traumatic brain injury (TBI) contributes to neuronal death with poor outcome. Although anti-inflammatory strategies were beneficial in the experimental TBI, clinical translations mostly failed, probably caused by the complexity of involved cells and mediators. We recently showed in a rat model of controlled cortical impact (CCI) that leukotriene inhibitors (LIs) attenuate contusion growth and improve neuronal survival. This study focuses on spatiotemporal characteristics of macrophages and granulocytes, typically involved in inflammatory processes, and neuronal COX-2 expression. Effects of treatment with LIs (Boscari/MK-886), started prior trauma, were evaluated by quantifying CD68(+), CD43(+) and COX-2(+) cells 24h and 72h post-CCI in the parietal cortex (PC), CA3 region, dentate gyrus (DG) and visual/auditory cortex (v/aC). Correlations were applied to identify intercellular relationships. At 24h, untreated animals showed granulocyte invasion in all regions, decreasing towards 72h. Macrophages increased from 24h to 72h post-CCI in PC and v/aC. COX-2(+) neurones showed no temporal changes, except of an increase in the CA3 region at 72h. Treatment reduced granulocytes at 24h in the pericontusional zone and hippocampus, and macrophages at 72h in the PC and v/aC. COX-2 expression remained unaffected by LIs, except of time-specific changes in the DG (increase/decrease at 24/72h). Interrelations confirmed concomitant cellular reactions beyond the initial trauma site. In conclusion, LIs attenuated the cellular inflammatory response following CCI. Future studies have to clarify region-specific effects and explore the potential of a clinically more relevant therapeutic approach applying LIs after CCI. PMID:23268351

Härtig, Wolfgang; Michalski, Dominik; Seeger, Gudrun; Voigt, Cornelia; Donat, Cornelius K; Dulin, Julia; Kacza, Johannes; Meixensberger, Jürgen; Arendt, Thomas; Schuhmann, Martin U

2013-03-01

50

Flavocoxid, a dual inhibitor of COX-2 and 5-LOX of natural origin, attenuates the inflammatory response and protects mice from sepsis  

PubMed Central

Introduction Cecal ligation and puncture (CLP) is an inflammatory condition that leads to multisystemic organ failure. Flavocoxid, a dual inhibitor of cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX), has been shown in vitro to possess antiinflammatory activity in lipopolysaccharide (LPS)-stimulated rat macrophages by reducing nuclear factor (NF)-?B activity and COX-2, 5-LOX and inducible nitric oxide synthase (iNOS) expression. The aim of this study was to evaluate the effects of flavocoxid in a murine model of CLP-induced polymicrobial sepsis. Methods C57BL/6J mice were subjected to CLP or sham operation. In a first set of experiments, an intraperitoneal injection of flavocoxid (20 mg/kg) or vehicle was administered 1 hour after surgery and repeated every 12 hours. Survival rate was monitored every 24 hours throughout 120 hours. Furthermore, additional groups of sham and CLP mice were killed 18 hours after surgical procedures for blood-sample collection and the lung and liver were collected for biomolecular, biochemical and histopathologic studies. Results COX-2, 5-LOX, tumor necrosis factor-? (TNF-?), interleukin (IL)-6, IL-10, extracellular-regulated-kinase 1/2 (ERK), JunN-terminal kinase (JNK), NF-?B, and ?-arrestin 2 protein expression were evaluated in lung and liver with Western blot analysis. In addition, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), cytokines, and lipoxin A4 serum content were measured with an enzyme-linked immunosorbent assay (ELISA). Flavocoxid administration improved survival, reduced the expression of NF-?B, COX-2, 5-LOX, TNF-? and IL-6 and increased IL-10 production. Moreover, flavocoxid inhibited the mitogen-activated protein kinases (MAPKs) pathway, preserved ?-arrestin 2 expression, reduced blood LTB4, PGE2, TNF-? and IL-6, and increased IL-10 and lipoxin A4 serum levels. The treatment with flavocoxid also protected against the histologic damage induced by CLP and reduced the myeloperoxidase (MPO) activity in the lung and liver. Conclusions Flavocoxid protects mice from sepsis, suggesting that this dual inhibitor may represent a promising approach in such a life-threatening condition. PMID:22356547

2012-01-01

51

Cardiovascular Effects of the Selective Cyclooxygenase2 Inhibitors  

Microsoft Academic Search

The data that have accumulated in recent years underscore the importance of carefully weighing the risks and benefits of traditional\\u000a NSAIDs and COX-2 selective inhibitors before making therapeutic decisions for the management of chronic arthritis. In clinical\\u000a practice, the majority of patients with moderate to severe arthritis who might benefit from NSAID or COX-2 therapy are likely\\u000a to be elderly

WILLIAM B. WHITE

52

Synergistic Effect of COX-2 Inhibitor on Paclitaxel-Induced Apoptosis in the Human Ovarian Cancer Cell Line OVCAR-3  

PubMed Central

Purpose Celecoxib, a highly selective cyclooxygenase-2 inhibitor, regulates apoptosis of several types of human cancer cells. The purpose of this study was to investigate whether celecoxib in combination with paclitaxel modulates apoptosis of ovarian cancer cells, and to identify the signal pathway by which celecoxib mediates apoptosis. Materials and Methods OVCAR-3 cells were exposed to paclitaxel (20 µM) in the absence or presence of celecoxib (10 µM). Cell viability was evaluated using a Cell Counting Kit-8 assay. Apoptosis was evaluated using Annexin-V/7-aminoactinomycin D staining and a cellular DNA fragmentation enzyme-linked immunosorbent assay. Caspase-3, -9, and cleavage of poly ADP-ribose polymerase (PARP) were determined by western blotting. Expression of nuclear factor-?B (NF-?B) and vascular endothelial growth factor (VEGF) and Akt activation were assessed using reverse transcriptase-polymerase chain reaction and western blotting. Results Celecoxib enhanced paclitaxel-induced growth inhibition of OVCAR-3 cells. Celecoxib significantly increased paclitaxel-induced apoptosis of OVCAR-3 cells. Pretreatment with celecoxib also increased activation of caspase-9, -3 and cleaved PARP following paclitaxel-treatment. Exposure of OVCAR-3 cells to celecoxib in combination with paclitaxel resulted in downregulation of NF-?B activation and VEGF expression. Furthermore, combining celecoxib and paclitaxel inhibited phosphorylation of Akt. Conclusion OVCAR-3 cells were sensitized to paclitaxel-induced apoptosis by celecoxib through downregulation of NF-?B and Akt activation, suggesting that celecoxib may work synergistically with paclitaxel to inhibit different targets and ultimately produce anticancer effects. Combining celecoxib with paclitaxel may prove beneficial in the clinical treatment of ovarian cancer. PMID:24520227

Kim, Hee Jung; Yim, Ga Won; Nam, Eun Ji

2014-01-01

53

Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2  

PubMed Central

In gastrointestinal conditions such as bowel obstruction, pseudo-obstruction, and idiopathic megacolon, the lumen of affected bowel segments is distended and its motility function impaired. Our hypothesis is that mechanical stretch of the distended segments alters gene expression of cyclooxygenase-2 (COX-2), which impairs motility function. Partial obstruction was induced with a silicon band in the distal colon of rats for up to 7 days, and wild-type and COX-2 gene-deficient mice for 4 days. Mechanical stretch was mimicked in vitro in colonic circular muscle strips and in primary culture of colonic circular smooth muscle cells (SMC) with a Flexercell system. The rat colonic circular muscle contractility was significantly decreased in the distended segment oral to obstruction, but not in the aboral segment. This change started as early as day 1 and persisted for at least 7 days after obstruction. The expression of COX-2 mRNA and protein increased dramatically also in the oral, but not aboral, segment. The upregulation of COX-2 expression started at 12 h and the effect persisted for 7 days. At 24 h after obstruction, the COX-2 mRNA level in the oral segment increased 26-fold compared with controls. This was not accompanied by any significant increase of myeloperoxidase or inflammatory cytokines. Immunohistochemical studies showed that COX-2 was selectively induced in the colonic SMC. In vitro stretch of colonic muscle strips or cultured SMC drastically induced COX-2 expression. Incubation of circular muscle strips from obstructed segment with COX-2 inhibitor NS-398 restored the contractility. The impairment of muscle contractility in obstructed colon was attenuated in the COX-2 gene-deficient mice. In conclusion, mechanical stretch in obstruction induces marked expression of COX-2 in the colonic SMC, and stretch-induced COX-2 plays a critical role in the suppression of smooth muscle contractility in bowel obstruction. PMID:21051526

Lin, You-Min; Powell, Don W.; Sarna, Sushil K.

2011-01-01

54

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. PMID:21886896

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

2011-01-01

55

Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa  

Microsoft Academic Search

In addition to inhibiting cyclooxygenase (COX)-1-derived prostanoid biosynthesis, aspirin acetylates COX-2, enabling the conversion of arachidonic acid to 15(R)-epi lipoxin A4, or aspirin-triggered lipoxin (ATL). Selective COX-2 inhibitors block ATL formation and exacerbate mucosal injury in rats treated with aspirin. In the present study, we have examined whether inhibition of COX-2 activity in healthy volunteers taking aspirin exacerbates gastric mucosal

Stefano Fiorucci; Luca Santucci; John L. Wallace; Marco Sardina; Mario Romano; Piero del Soldato; Antonio Morelli

2003-01-01

56

Effect of a Selective Cyclooxygenase2 Inhibitor on Renal Scarring  

Microsoft Academic Search

Background: Scarring is one of the steps of excessive wound healing, causing dysfunction of the involved tissues and clinically poor cosmetics. The aim of this study was to examine the effect of a highly selective cyclooxygenase-2 (COX-2) inhibitor on renal scar formation in experimental pyelonephritis. Materials and Methods: Four groups of 10 Balb\\/C mice were formed. In groups I and

Hasan Fehmi Kucuk; Necmi Kurt; Levent Kaptanoglu; Huseyin Akyol; Oguzhan Aziz Torlak; Elif Colak

2006-01-01

57

Incidence and possible risk factors for clinical upper gastrointestinal events in patients taking selective cyclooxygenase-2 inhibitors: A prospective, observational, cohort study in Taiwan  

Microsoft Academic Search

Background: Use of selective cyclooxygenase (COX)-2 inhibitors is associated with a better gastrointestinal (GI) safety profile than use of other NSAIDs. However, the risk factors for clinical upper GI events (symptomatic ulcers and ulcer complications) in COX-2 inhibitor users have been rarely evaluated in the past.Objective: The aim of this study was to assess the annual incidence of and identify

Kuo-Wei Hsiang; Tseng-Shing Chen; Hsiao-Yi Lin; Jiing-Chyuan Luo; Ching-Liang Lu; Han-Chieh Lin; Kuei-Chuan Lee; Full-Young Chang; Shou-Dong Lee

2010-01-01

58

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

59

COX-1 and COX-2 expression in osteoid osteomas.  

PubMed

Osteoid osteoma is a benign bone forming neoplasm that is characterized by its small size (less than 2 cm), self-limited growth, and the tendency to cause extensive reactive changes in the adjacent tissue. The lesion classically presents with severe pain at night that is dramatically relieved by NSAIDs. The tumor has been shown to express very high levels of prostaglandins, particularly PGE2 and PGI2. The high local levels of these prostaglandins are presumed to be the cause of the intense pain seen in patients with this lesion. One generally accepted form of treatment is the prolonged use of NSAIDs. Since the cyclooxygenases are thought to be the source of these prostaglandins, and the central target of NSAIDs, we evaluated the expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in osteoid osteoma tissues from patients following surgery. In the 12 specimens examined we found that the tumor osteoblasts had strong immunohistochemical staining for COX-2, while the staining in the surrounding host osteoblasts in the reactive bone was scant. Significant COX-1 staining was also detected in both tumor and host osteoblasts. For comparison we examined the COX expression in human fracture callus, fibrous dysplasia, osteoblastoma, osteofibrous dysplasia, and myositis ossificans. With the exception of fracture callus, very limited amounts of COX-2 could be detected in these tissues. Taken together, we conclude that the increased production of prostaglandins by osteoid osteomas implicates that COX-2 is one of the mediators of this condition. These findings suggest that the newly selective COX-2 inhibitors could be used to more safely treat osteoid osteomas. PMID:11853083

Mungo, David V; Zhang, Xinping; O'Keefe, Regis J; Rosier, Randy N; Puzas, J Edward; Schwarz, Edward M

2002-01-01

60

COX-2 signaling and cancer: new players in old arena.  

PubMed

Cancer is a leading cause of death worldwide. The expression of COX-2 and prostaglandins has not only been associated with various types of cancer but is also directly proportional to their aggressiveness including metastasis. Thus, inhibition of COX-2 activity has been one of the preferred targets for cancer reduction. Broad spectrum inhibition of all forms of COX (using NSAIDs) is associated with various side effects ranging from gastric ulceration to renal problems. Even specific COX-2 inhibitors (COXIBs) are associated with side effects like myocardial infarction. Alternative strategies including siRNA technology are also not very victorious due to their off-target associated problems. Thus, there is an urgent need for the development of strategies where COX-2 activity may be reduced without inducing any side effects. One of the approaches for designing novel inhibitors may be to target various molecules downstream of COX-2. In this review, we have tried to cover the basic biology of COX-2 and its association with different types of cancer. Various generations of COX-2 inhibitors have been covered with their merits and demerits. Possible exploitation of novel targets like EP receptors, mPGES and various other downstream molecules which can be utilized for a better COX-2 signaling inhibition and thus efficient cancer reduction with minimal side effects has been discussed. PMID:24467618

Misra, Shashank; Sharma, Kulbhushan

2014-03-01

61

IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells  

SciTech Connect

COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.

Zhu, Yingting, E-mail: yitizhu@yahoo.com [University of Arizona Arizona Cancer Center Tissue Tech Inc, 7000 SW 97th Avenue Suite 212, Miami, FL 33173 (United States) [University of Arizona Arizona Cancer Center Tissue Tech Inc, 7000 SW 97th Avenue Suite 212, Miami, FL 33173 (United States); Tissue Tech Inc, Miami, FL 33173 (United States); Zhu, Min; Lance, Peter [University of Arizona Arizona Cancer Center Tissue Tech Inc, 7000 SW 97th Avenue Suite 212, Miami, FL 33173 (United States)] [University of Arizona Arizona Cancer Center Tissue Tech Inc, 7000 SW 97th Avenue Suite 212, Miami, FL 33173 (United States)

2012-11-15

62

COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial  

PubMed Central

Summary Background COX-2 is overexpressed in some cancers, including prostate cancer; however, little is known about the effect of COX-2 overexpression on outcome in radiation-treated patients with prostate cancer. We aimed to study COX-2 overexpression and outcome in a well-defined cohort of men who received treatment with short-term androgen deprivation (STAD) plus radiotherapy or long-term androgen deprivation (LTAD) plus radiotherapy. Methods Men with prostate cancer who had participated in the Radiation Therapy Oncology Group (RTOG) 92-02 trial and for whom sufficient diagnostic tissue was available for immunohistochemical staining and image analysis of COX-2 expression were enrolled in this study. Patients in the 92-02 trial had been randomly assigned to treatment with STAD plus radiotherapy or LTAD plus radiotherapy. Multivariate analyses by Cox proportional hazards models were done to assess whether associations existed between COX-2 staining intensity and the RTOG 92-02 primary endpoints of biochemical failure (assessed by the American Society for Therapeutic Radiology and Oncology [ASTRO] and Phoenix criteria), local failure, distant metastasis, cause-specific mortality, overall mortality, and any failure. Findings 586 patients with sufficient diagnostic tissue for immunohistochemical staining and image analysis of COX-2 expression were included in this study. In the multivariate analyses, the intensity of COX-2 staining as a continuous covariate was an independent predictor of distant metastasis (hazard ratio [HR] 1.181 [95% CI 1.077–1.295], p=0.0004); biochemical failure by two definitions (ASTRO HR 1.073 [1.018–1.131], p=0.008; Phoenix HR 1.073 [1.014–1.134], p=0.014); and any failure (HR 1.068 [1.015–1.124], p=0.011). The higher the expression of COX-2, the greater the chance of failure. As a dichotomous covariate, COX-2 overexpression seemed to be most discriminating of outcome for those who received STAD compared with those who received LTAD. Interpretation To our knowledge, this is the first study to establish an association of COX-2 expression with outcome in patients with prostate cancer who have had radiotherapy. Increasing COX-2 expression was significantly associated with biochemical failure, distant metastasis, and any failure. COX-2 inhibitors might improve patient response to radiotherapy in those treated with or without androgen deprivation. Our findings suggest that LTAD might overcome the effects of COX-2 overexpression. Therefore, COX-2 expression might be useful in selecting patients who need LTAD. PMID:17881290

Khor, Li-Yan; Bae, Kyounghwa; Pollack, Alan; Hammond, M Elizabeth; Grignon, David J; Venkatesan, Varagur M; Rosenthal, Seth A; Ritter, Mark A; Sandler, Howard M; Hanks, Gerald E; Shipley, William U; Dicker, Adam P

2007-01-01

63

The role of chemoprevention by selective cyclooxygenase-2 inhibitors in colorectal cancer patients - a population-based study  

PubMed Central

Background There are limited population-based studies focusing on the chemopreventive effects of selective cyclooxygenase-2 (COX-2) inhibitors against colorectal cancer. The purpose of this study is to assess the trends and dose–response effects of various medication possession ratios (MPR) of selective COX-2 inhibitor used for chemoprevention of colorectal cancer. Methods A population-based case–control study was conducted using the Taiwan Health Insurance Research Database (NHIRD). The study comprised 21,460 colorectal cancer patients and 79,331 controls. The conditional logistic regression was applied to estimate the odds ratios (ORs) for COX-2 inhibitors used for several durations (5 years, 3 years, 1 year, 6 months and 3 months) prior to the index date. Results In patients receiving selective COX-2 inhibitors, the OR was 0.51 (95% CI=0.29~0.90, p=0.021) for an estimated 5-year period in developing colorectal cancer. ORs showing significant protection effects were found in 10% of MPRs for 5-year, 3-year, and 1-year usage. Risk reduction against colorectal cancer by selective COX-2 inhibitors was observed as early as 6 months after usage. Conclusion Our results indicate that selective COX-2 inhibitors may reduce the development of colorectal cancer by at least 10% based on the MPRs evaluated. Given the limited number of clinical reports from general populations, our results add to the knowledge of chemopreventive effects of selective COX-2 inhibitors against cancer in individuals at no increased risk of colorectal cancer. PMID:23217168

2012-01-01

64

Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells.  

PubMed

Malignant gliomas are heavily infiltrated by immature myeloid cells that mediate immunosuppression. Agonistic CD40 monoclonal antibody (mAb) has been shown to activate myeloid cells and promote antitumor immunity. Our previous study has also demonstrated blockade of cyclooxygenase-2 (COX-2) reduces immunosuppressive myeloid cells, thereby suppressing glioma development in mice. We therefore hypothesized that a combinatory strategy to modulate myeloid cells via two distinct pathways, i.e., CD40/CD40L stimulation and COX-2 blockade, would enhance anti-glioma immunity. We used three different mouse glioma models to evaluate therapeutic effects and underlying mechanisms of a combination regimen with an agonist CD40 mAb and the COX-2 inhibitor celecoxib. Treatment of glioma-bearing mice with the combination therapy significantly prolonged survival compared with either anti-CD40 mAb or celecoxib alone. The combination regimen promoted maturation of CD11b(+) cells in both spleen and brain, and enhanced Cxcl10 while suppressing Arg1 in CD11b(+)Gr-1(+) cells in the brain. Anti-glioma activity of the combination regimen was T-cell dependent because depletion of CD4(+) and CD8(+) cells in vivo abrogated the anti-glioma effects. Furthermore, the combination therapy significantly increased the frequency of CD8(+) T-cells, enhanced IFN-?-production and reduced CD4(+)CD25(+)Foxp3(+) T regulatory cells in the brain, and induced tumor-antigen-specific T-cell responses in lymph nodes. Our findings suggest that the combination therapy of anti-CD40 mAb with celecoxib enhances anti-glioma activities via promotion of type-1 immunity both in myeloid cells and T-cells. PMID:24878890

Kosaka, Akemi; Ohkuri, Takayuki; Okada, Hideho

2014-08-01

65

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. PMID:15655513

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

66

Effusanin E Suppresses Nasopharyngeal Carcinoma Cell Growth by Inhibiting NF-?B and COX-2 Signaling  

PubMed Central

Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC) cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-?B proteins. Moreover, effusanin E abrogated the binding of NF-?B to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-?B-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate) had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-?B/COX-2 (lipopolysaccharides) abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-?B and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma. PMID:25333664

Zhuang, Mingzhu; Zhao, Mouming; Qiu, Huijuan; Shi, Dingbo; Wang, Jingshu; Tian, Yun; Lin, Lianzhu; Deng, Wuguo

2014-01-01

67

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. PMID:16519514

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

2008-01-01

68

Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE2 synthesis and COX-2 expression.  

PubMed

Cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) can potentially affect most of the events in cancer development, including promotion of proliferation, resistance to apoptosis, angiogenesis, immune suppression and invasion. However, worldwide attention has predominantly centered on the cardiovascular toxicity of selective COX-2 inhibitors. Paeonol is a major active extract from the root bark of Paeonia suffruticosa Andrews with anti?inflammatory, anti-oxidant, anti-allergic, anti-oxidation and antitumor effects. In the present study, we investigated the underlying mechanisms of paeonol in inducing apoptosis and aimed to ascertain whether its antitumor effect is associated with a reduction in COX-2 expression and a decrease in the levels of PGE2 in colorectal cancer cells. We observed that paeonol inhibited cell proliferation and induced apoptosis in a dose- and time-dependent manner in colorectal cancer cells, which was associated with a reduction in COX-2 expression and PGE2 synthesis. Treatment with the selective COX-2 inhibitor, celecoxib, or transient transfection of colorectal cancer cells with COX-2 siRNA, also inhibited cell proliferation and induced apoptosis. Western blot analysis showed that paeonol inhibited the activation of NF-?B, an upstream regulator of COX-2, and its translocation to the nucleus. Treatment with increasing doses of paeonol led to increased expression of pro-apoptotic factor Bax and decreased expression of anti-apoptotic factor Bcl-2. Caspase-3 and caspase-9 were activated, and paeonol induced loss of mitochondrial membrane potential, suggesting that the apoptosis induced by paeonol was mediated by mitochondrial pathways. In addition, paeonol significantly suppressed tumor growth in a xenograft tumor mouse model in a dose-dependent manner. Our findings indicate that paeonol exerts an antitumor effect on human colorectal cancer cells by inhibiting PGE2 production and COX-2 expression. We expect that paeonol may replace selective COX-2 inhibitors due to their toxic effects, and may offer a new strategy for the therapy of colorectal cancer. PMID:25322760

Li, Ming; Tan, Shi-Yun; Wang, Xiao-Fan

2014-12-01

69

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

70

Survivin expression in in situ and invasive breast cancer relates to COX2 expression and DCIS recurrence  

Microsoft Academic Search

In lung cancer cyclooxygenase-2 (COX-2) expression has been reported to stabilise survivin, an inhibitor of apoptosis (IAP) which prevents cell death by blocking activated caspases. COX-2 expression limits the ubiquitination of survivin, protecting it from degradation. To determine if COX-2 expression in breast cancer showed an association with survivin expression, we assessed the levels of each protein in ductal carcinoma

N Barnes; P Haywood; P Flint; W F Knox; N J Bundred

2006-01-01

71

COX-2 Protects against Atherosclerosis Independently of Local Vascular Prostacyclin: Identification of COX-2 Associated Pathways Implicate Rgl1 and Lymphocyte Networks  

PubMed Central

Cyxlo-oxygenase (COX)-2 inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased cardiovascular side effects, including myocardial infarction. We and others have shown that COX-1 and not COX-2 drives vascular prostacyclin in the healthy cardiovascular system, re-opening the question of how COX-2 might regulate cardiovascular health. In diseased, atherosclerotic vessels, the relative contribution of COX-2 to prostacyclin formation is not clear. Here we have used apoE?/?/COX-2?/? mice to show that, whilst COX-2 profoundly limits atherosclerosis, this protection is independent of local prostacyclin release. These data further illustrate the need to look for new explanations, targets and pathways to define the COX/NSAID/cardiovascular risk axis. Gene expression profiles in tissues from apoE?/?/COX-2?/? mice showed increased lymphocyte pathways that were validated by showing increased T-lymphocytes in plaques and elevated plasma Th1-type cytokines. In addition, we identified a novel target gene, rgl1, whose expression was strongly reduced by COX-2 deletion across all examined tissues. This study is the first to demonstrate that COX-2 protects vessels against atherosclerotic lesions independently of local vascular prostacyclin and uses systems biology approaches to identify new mechanisms relevant to development of next generation NSAIDs. PMID:24887395

Kirkby, Nicholas S.; Lundberg, Martina H.; Wright, William R.; Warner, Timothy D.; Paul-Clark, Mark J.; Mitchell, Jane A.

2014-01-01

72

Overexpression of Cyclooxygenase-2 in Malignant Peripheral Nerve Sheath Tumor and Selective Cyclooxygenase-2 Inhibitor-Induced Apoptosis by Activating Caspases in Human Malignant Peripheral Nerve Sheath Tumor Cells  

PubMed Central

Background Cyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST. Methods We evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1. Results Overexpression of COX-2 (?50% positive cells) was observed in 29 cases (65.9%), was significantly associated with a poor overall survival (P?=?0.0495), and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis. Conclusions Selective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses. PMID:24516579

Hakozaki, Michiyuki; Tajino, Takahiro; Konno, Shinichi; Kikuchi, Shinichi; Yamada, Hitoshi; Yanagisawa, Michiro; Nishida, Jun; Nagasawa, Hiroyuki; Tsuchiya, Takashi; Ogose, Akira; Abe, Masafumi; Hojo, Hiroshi

2014-01-01

73

Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats.  

PubMed

Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg(-1)·day(-1), 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2 (·-) production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-?B subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-?B inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-?B and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones. PMID:24727493

Pérez-Girón, Jose V; Palacios, Roberto; Martín, Angela; Hernanz, Raquel; Aguado, Andrea; Martínez-Revelles, Sonia; Barrús, María T; Salaices, Mercedes; Alonso, María J

2014-06-01

74

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

75

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

76

Radiation-induced non-targeted response in vivo: role of the TGF?-TGFBR1-COX-2 signalling pathway  

PubMed Central

Background: Previous studies from our group and others have shown that cyclooxygenase-2 (COX-2) has an essential role in radiation-induced non-targeted responses and genomic instability in vivo. However, the signalling pathways involved in such effects remain unclear. Methods: A 1?cm2 area (1?cm × 1?cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5?Gy of 300?keV X-rays. Nimesulide, a selective COX-2 inhibitor, was given to mice for five consecutive days before irradiation. Changes in transforming growth factor-beta (TGF-?) and TGF-? receptor type-1 (TGFBR1) mediated signalling pathways, in the out of radiation field lung and liver tissues were examined. Results: While the plasma level of cytokines remained unchanged, the expression of TGF-? and its receptors was elevated in non-targeted lung tissues after partial body irradiation. In contrast to the predominant expression of TGF-? in stromal and alveolar cells, but not in bronchial epithelial cells, TGF-? receptors, especially TGFBR1 were significantly elevated in non-targeted bronchial epithelial cells, which is consistent with the induction of COX-2. The different expression levels of TGFBR1 between liver and lung resulted in a tissue specific induction of COX-2 in these two non-targeted tissues. Multiple TGF-? induced signalling pathways were activated in the non-targeted lung tissues. Conclusion: The TGF?-TGFBR1-COX-2 Signalling Pathway has a critical role in radiation-induced non-targeted response in vivo. PMID:23412109

Chai, Y; Lam, R K K; Calaf, G M; Zhou, H; Amundson, S; Hei, T K

2013-01-01

77

Lasiodin Inhibits Proliferation of Human Nasopharyngeal Carcinoma Cells by Simultaneous Modulation of the Apaf-1/Caspase, AKT/MAPK and COX-2/NF-?B Signaling Pathways  

PubMed Central

Rabdosia serra has been widely used for the treatment of the various human diseases. However, the antiproliferative effects and underlying mechanisms of the compounds in this herb remain largely unknown. In this study, an antiproliferative compound against human nasopharyngeal carcinoma (NPC) cells from Rabdosia serra was purified and identified as lasiodin (a diterpenoid). The treatment with lasiodin inhibited cell viability and migration. Lasiodin also mediated the cell morphology change and induced apoptosis in NPC cells. The treatment with lasiodin induced the Apaf-1 expression, triggered the cytochrome-C release, and stimulated the PARP, caspase-3 and caspase-9 cleavages, thereby activating the apoptotic pathways. The treatment with lasiodin also significantly inhibited the phosphorylations of the AKT, ERK1/2, p38 and JNK proteins. The pretreatment with the AKT or MAPK-selective inhibitors considerably blocked the lasiodin-mediated inhibition of cell proliferation. Moreover, the treatment with lasiodin inhibited the COX-2 expression, abrogated NF-?B binding to the COX-2 promoter, and promoted the NF-?B translocation from cell nuclei to cytosol. The pretreatment with a COX-2-selective inhibitor abrogated the lasiodin-induced inhibition of cell proliferation. These results indicated that lasiodin simultaneously activated the Apaf-1/caspase-dependent apoptotic pathways and suppressed the AKT/MAPK and COX-2/NF-?B signaling pathways. This study also suggested that lasiodin could be a promising natural compound for the prevention and treatment of NPC. PMID:24845412

Lin, Lianzhu; Deng, Wuguo; Tian, Yun; Chen, Wangbing; Wang, Jingshu; Fu, Lingyi; Shi, Dingbo; Zhao, Mouming; Luo, Wei

2014-01-01

78

Lasiodin inhibits proliferation of human nasopharyngeal carcinoma cells by simultaneous modulation of the Apaf-1/caspase, AKT/MAPK and COX-2/NF-?B signaling pathways.  

PubMed

Rabdosia serra has been widely used for the treatment of the various human diseases. However, the antiproliferative effects and underlying mechanisms of the compounds in this herb remain largely unknown. In this study, an antiproliferative compound against human nasopharyngeal carcinoma (NPC) cells from Rabdosia serra was purified and identified as lasiodin (a diterpenoid). The treatment with lasiodin inhibited cell viability and migration. Lasiodin also mediated the cell morphology change and induced apoptosis in NPC cells. The treatment with lasiodin induced the Apaf-1 expression, triggered the cytochrome-C release, and stimulated the PARP, caspase-3 and caspase-9 cleavages, thereby activating the apoptotic pathways. The treatment with lasiodin also significantly inhibited the phosphorylations of the AKT, ERK1/2, p38 and JNK proteins. The pretreatment with the AKT or MAPK-selective inhibitors considerably blocked the lasiodin-mediated inhibition of cell proliferation. Moreover, the treatment with lasiodin inhibited the COX-2 expression, abrogated NF-?B binding to the COX-2 promoter, and promoted the NF-?B translocation from cell nuclei to cytosol. The pretreatment with a COX-2-selective inhibitor abrogated the lasiodin-induced inhibition of cell proliferation. These results indicated that lasiodin simultaneously activated the Apaf-1/caspase-dependent apoptotic pathways and suppressed the AKT/MAPK and COX-2/NF-?B signaling pathways. This study also suggested that lasiodin could be a promising natural compound for the prevention and treatment of NPC. PMID:24845412

Lin, Lianzhu; Deng, Wuguo; Tian, Yun; Chen, Wangbing; Wang, Jingshu; Fu, Lingyi; Shi, Dingbo; Zhao, Mouming; Luo, Wei

2014-01-01

79

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

80

Comprehensive analysis of kinase inhibitor selectivity  

Microsoft Academic Search

We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases

Mindy I Davis; Jeremy P Hunt; Sanna Herrgard; Pietro Ciceri; Lisa M Wodicka; Gabriel Pallares; Michael Hocker; Daniel K Treiber; Patrick P Zarrinkar

2011-01-01

81

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

82

Albumin-induced podocyte injury and protection are associated with regulation of COX-2.  

PubMed

Albuminuria is both a hallmark and a risk factor for progressive glomerular disease, and results in increased exposure of podocytes to serum albumin with its associated factors. Here in vivo and in vitro models of serum albumin-overload were used to test the hypothesis that albumin-induced proteinuria and podocyte injury directly correlate with COX-2 induction. Albumin induced COX-2, MCP-1, CXCL1, and the stress protein HSP25 in both rat glomeruli and cultured podocytes, whereas B7-1 and HSP70i were also induced in podocytes. Podocyte exposure to albumin induced both mRNA and protein and enhanced the mRNA stability of COX-2, a key regulator of renal hemodynamics and inflammation, which renders podocytes susceptible to injury. Podocyte exposure to albumin also stimulated several kinases (p38 MAPK, MK2, JNK/SAPK, and ERK1/2), inhibitors of which (except JNK/SAPK) downregulated albumin-induced COX-2. Inhibition of AMPK, PKC, and NF?B also downregulated albumin-induced COX-2. Critically, albumin-induced COX-2 was also inhibited by glucocorticoids and thiazolidinediones, both of which directly protect podocytes against injury. Furthermore, specific albumin-associated fatty acids were identified as important contributors to COX-2 induction, podocyte injury, and proteinuria. Thus, COX-2 is associated with podocyte injury during albuminuria, as well as with the known podocyte protection imparted by glucocorticoids and thiazolidinediones. Moreover, COX-2 induction, podocyte damage, and albuminuria appear mediated largely by serum albumin-associated fatty acids. PMID:24918154

Agrawal, Shipra; Guess, Adam J; Chanley, Melinda A; Smoyer, William E

2014-12-01

83

Intracellular gene transfer in action: Dual transcription and multiple silencings of nuclear and mitochondrial cox2 genes in legumes  

PubMed Central

The respiratory gene cox2, normally present in the mitochondrion, was previously shown to have been functionally transferred to the nucleus during flowering plant evolution, possibly during the diversification of legumes. To search for novel intermediate stages in the process of intracellular gene transfer and to assess the evolutionary timing and frequency of cox2 transfer, activation, and inactivation, we examined nuclear and mitochondrial (mt) cox2 presence and expression in over 25 legume genera and mt cox2 presence in 392 genera. Transfer and activation of cox2 appear to have occurred during recent legume evolution, more recently than previously inferred. Many intermediate stages of the gene transfer process are represented by cox2 genes in the studied legumes. Nine legumes contain intact copies of both nuclear and mt cox2, although transcripts could not be detected for some of these genes. Both cox2 genes are transcribed in seven legumes that are phylogenetically interspersed with species displaying only nuclear or mt cox2 expression. Inactivation of cox2 in each genome has taken place multiple times and in a variety of ways, including loss of detectable transcripts or transcript editing and partial to complete gene loss. Phylogenetic evidence shows about the same number (3–5) of separate inactivations of nuclear and mt cox2, suggesting that there is no selective advantage for a mt vs. nuclear location of cox2 in plants. The current distribution of cox2 presence and expression between the nucleus and mitochondrion in the studied legumes is probably the result of chance mutations silencing either cox2 gene. PMID:10570164

Adams, Keith L.; Song, Keming; Roessler, Philip G.; Nugent, Jacqueline M.; Doyle, Jane L.; Doyle, Jeff J.; Palmer, Jeffrey D.

1999-01-01

84

A cohort study to evaluate cardiovascular risk of selective and nonselective cyclooxygenase inhibitors (COX-Is) in arthritic patients attending orthopedic department of a tertiary care hospital  

PubMed Central

Background: Cyclooxygenase-2 inhibitors (COX-2-Is) have recently been concerned in the occurrence of adverse cardiovascular (CV) events. Rofecoxib and valdecoxib has been withdrawn from the market, but celecoxib, etoricoxib and parecoxib continues to be used. Other nonsteroidal anti-inflammatory drugs (NSAIDs) may also increase the risk of CV events. However, clinical trial databases for COX-2-Is had created lots of controversies regarding cardiovascular safety of selective and nonselective cyclooxygenase inhibitors (COX-Is). This study was, conducted to assess and compare the CV risk of COX-Is in arthritic patients over a period of time. Materials and Methods: In this prospective cohort study adult arthritics of either sex those were freshly diagnosed or taking COX-Is for < 3 months; were included. Patients were grouped into nonselective and selective COX-2-I groups with reference to treatment they received. The CV risk factors like blood pressure (BP), blood sugar level (BSL), lipid profile, body mass index (BMI) were assessed and compared; demography of CV risk factors was also studied. Data obtained was analysed using Student's ‘t’-test of OpenEpi statistical software. Results: Study clearly revealed that all NSAIDs exhibit variable CV risk; however, selective COX-2-Is found to exhibit more CV risk. BMI, BP and lipid profile; the potential CV risk factors, showed significant impairment in selective COX-2-Is group; P < 0.01, P < 0.001 and P < 0.05, respectively, compared to baseline and P < 0.05 vs. nonselective COX-Is for BMI. Conclusions: This study portrays the potential CV risk of selective COX-2-Is; confirms and re-evaluate the results of earlier studies in this regard.

Bhosale, Uma A.; Quraishi, Nilofar; Yegnanarayan, Radha; Devasthale, Dileep

2014-01-01

85

Attenuation of Proinflammatory Responses by S-[6]-Gingerol via Inhibition of ROS/NF-Kappa B/COX2 Activation in HuH7 Cells  

PubMed Central

Introduction. Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S-[6]-Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor ?B (NF?B) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S-[6]-gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1? to establish an in vitro hepatic inflammatory model. Results. S-[6]-Gingerol attenuated IL1?-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S-[6]-gingerol reduced IL1?-induced COX2 upregulation as well as NF?B activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NF?B inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1?-induced overexpression of COX2. Of particular note, the protective effect of S-[6]-gingerol against the IL1?-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1?-induced inflammatory insults through inhibition of the ROS/NF?B/COX2 pathway. PMID:23843863

McGrath, Kristine C. Y.; Tran, Van H.; Li, Yi-Ming; Duke, Colin C.; Roufogalis, Basil D.; Heather, Alison K.

2013-01-01

86

Sphingosine-1-phosphate induces thrombin receptor PAR-4 expression to enhance cell migration and COX-2 formation in human monocytes.  

PubMed

Thrombin is not only a central factor in blood coagulation but also stimulates inflammatory processes, including monocyte responses, via activation of PARs. The signaling lipid S1P is a major determinant of monocyte function. Here, we established an interaction between S1P and human monocyte responses to thrombin. S1P induced PAR-1 and PAR-4 mRNA and total protein expression in human monocytes and U937 cells in a concentration (0.1-10 ?M)- and time (1-24 h)-dependent manner, respectively. However, only PAR-4 cell-surface expression was increased significantly by S1P, whereas PAR-1 remained unaffected. This response was associated with activation of the Akt, Erk, and p38 pathway and induction of COX-2 but not COX-1. PAR-4-mediated induction of COX-2 was prevented by the PI3K inhibitor LY (10 ?M). Preincubation of human monocytes with S1P (1 ?M; 16 h) resulted in an enhanced chemotaxis toward thrombin or to selective AP for PAR-4 but not PAR-1. Furthermore, down-regulation of PAR-4 transcription with siRNA attenuated the chemotactic response to thrombin and AP4. In conclusion, S1P enhances monocyte responses to thrombin via up-regulation of PAR-4 expression, which promotes cell migration and COX-2 abundance. This mechanism may facilitate monocyte recruitment to sites of vessel injury and inflammation. PMID:24990321

Mahajan-Thakur, Shailaja; Sostmann, Björn D; Fender, Anke C; Behrendt, Daniel; Felix, Stephan B; Schrör, Karsten; Rauch, Bernhard H

2014-10-01

87

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. PMID:22919060

Guo, C. M.; Kasaraneni, N.

2012-01-01

88

Macrophages induce COX-2 expression in breast cancer cells: role of IL-1? autoamplification.  

PubMed

Tumor-associated macrophages and high levels of cyclooxygenase-2 (COX-2) are associated with poor prognosis in breast cancer patients, but their potential interdependence has not been evaluated. The objective of this study was to determine whether macrophages regulate COX-2 expression in breast cancer cells. For this purpose, THP-1 cells were cocultured with HCC1954 breast cancer cells. Coculture led to increased COX-2 expression in the HCC1954 cells and elevated prostaglandin E(2) levels in conditioned media. Similar results were observed when THP-1 cells were incubated with HCC1937 breast cancer cells or when human monocyte-derived macrophages were cocultured with HCC1954 cells. Coculture triggered production of reactive oxygen species (ROS) in HCC1954 cells. COX-2 induction was blocked in cells preincubated with an reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor or by silencing p67PHOX, a subunit of NADPH oxidase. ROS production triggered activation of Src and mitogen-activated protein kinases (MAPKs). Blocking Src or MAPK activities or antagonizing the activator protein-1 (AP-1) transcription factor attenuated COX-2 induction in HCC1954 cells. Coculture caused rapid induction of interleukin-1? (IL-1?) in both breast cancer cells and macrophages. Increased IL-1? expression was blocked by an interleukin-1 receptor antagonist (IL-1Ra), suggesting autocrine and paracrine effects. Importantly, macrophage-induced COX-2 expression was blocked in HCC1954 cells preincubated with IL-1Ra or anti-IL-1? IgG. Together, these results indicate that macrophage-mediated induction of COX-2 in breast cancer cells is a consequence of IL-1?-mediated stimulation of ROS?Src?MAPK?AP-1 signaling. IL-1?-dependent induction of COX-2 in breast cancer cells provides a mechanism whereby macrophages contribute to tumor progression and potential therapeutic targets in breast cancer. PMID:21310944

Hou, Zhe; Falcone, Domenick J; Subbaramaiah, Kotha; Dannenberg, Andrew J

2011-05-01

89

Investigating the Selectivity of Metalloenzyme Inhibitors  

PubMed Central

The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors, in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY) was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe3+ from holo-transferrin to gauge the ability of the inhibitors to access Fe3+ from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity. PMID:24074025

Day, Joshua A.; Cohen, Seth M.

2013-01-01

90

Ultraviolet C Irradiation Induces Different Expression of Cyclooxygenase 2 in NIH 3T3 Cells and A431 Cells: The Roles of COX-2 Are Different in Various Cell Lines  

E-print Network

caused cell growth inhibition and induced cell death after exposure for 24–36 h. The growth of NIH 3T3 cells was significantly suppressed at 24 h after UVC irradiation whereas the proliferation of A431 cells was inhibited until 36 h after UVC irradiation. UVC irradiation increased COX-2 expression and such up-regulation reached a maximum during 3–6 h in NIH 3T3 cells. In contrast, UVC-induced COX-2 reached a maximum after 24–36 h in A431 cells. Measuring prostaglandin E2 (PGE2) level showed a biphasic profile that PGE2 release was rapidly elevated in 1–12 h after UVC irradiation and increased again at 24 h in both cell lines. Treatment with the selective COX-2 inhibitor, SC-791, during maximum expression of COX-2 induction, attenuated the UVC induced-growth inhibition in NIH 3T3 cells. In contrast, SC-791 treatment after UVC irradiation enhanced death of A431 cells. These data showed that the patterns of UVC-induced PGE2 secretion from NIH 3T3 cells and A431 cells were similar despite the differential profile in UVC-induced COX-2 up-regulation.

Ming-hong Tai; Chien-hui Weng; Dir-pu Mon; Chun-yi Hu; Ming-hsiu Wu

2012-01-01

91

Oxidative Stress Mediates Chemical Hypoxia- Induced Injury and Inflammation by Activating NF-?b-COX-2 Pathway in HaCaT Cells  

PubMed Central

Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl2), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms. Exposure of HaCaT cells to CoCl2 reduced cell viability and caused overproduction of reactive oxygen species (ROS) and oversecretion of interleukin-6 (IL-6) and interleukin-8 (IL-8). Importantly, CoCl2 exposure elicited overexpression of cyclooxygenase-2 (COX-2) and phosphorylation of nuclear factor-kappa B (NF-?B) p65 subunit. Inhibition of COX-2 by NS-398, a selective inhibitor of COX-2, significantly repressed the cytotoxicity, as well as secretion of IL-6 and IL-8 induced by CoCl2. Inhibition of NF-?B by PDTC (a selective inhibitor of NF-?B) or genetic silencing of p65 by RNAi (Si-p65), attenuated not only the cytotoxicity and secretion of IL-6 and IL-8, but also overexpression of COX- 2 in CoCl2-treated HaCaT cells. Neutralizing anti-IL-6 or anti-IL-8 antibody statistically alleviated CoCl2-induced cytotoxicity in HaCaT cells. N-acetyl-L-cysteine (NAC), a well characterized ROS scavenger, obviously suppressed CoCl2-induced cytotoxicity in HaCaT cells, as well as secretion of IL-6 and IL-8. Additionally, NAC also repressed overexpression of COX-2 and phosphorylation of NF-?B p65 subunit induced by CoCl2 in HaCaT cells. In conclusion, our results demonstrated that oxidative stress mediates chemical hypoxia-induced injury and inflammatory response through activation of NF-?B–COX-2 pathway in HaCaT cells. PMID:21533553

Yang, Chuntao; Ling, Hongzhong; Zhang, Meifen; Yang, Zhanli; Wang, Xiuyu; Zeng, Fanqin; Wang, Chuhuai; Feng, Jianqiang

2011-01-01

92

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

93

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

94

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

95

Selective serotonin reuptake inhibitor exposure.  

PubMed

Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them more desirable than other antidepressants. The prognosis in animals that receive treatment is excellent. In one retrospective study, there were no deaths in 313 SSRI-poisoned dogs. No characteristic or classic histopathologic lesions result from SSRI toxicosis. Differential diagnoses for SSRI overdose must include ingestions of other serotonergic medications such as phenylpiperidine opioids (fentanyl and tramadol), mirtazapine, buspirone, amitraz, and chlorpheniramine. PMID:23796482

Fitzgerald, Kevin T; Bronstein, Alvin C

2013-02-01

96

NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure  

PubMed Central

The nuclear factor of activated T cells (NFAT) transcription factors are regulated by calcium/calcineurin signals and play important roles in T cells, muscle, bone, and neural tissue. NFAT is expressed in the epidermis, and although recent data suggest that NFAT is involved in the skin’s responses to ultraviolet radiation (UVR), the wavelengths of radiation that activate NFAT and the biological function of UV-activated NFAT remain undefined. We demonstrate that NFAT transcriptional activity is preferentially induced by UVB wavelengths in keratinocytes. The derived action spectrum for NFAT activation indicates that NFAT transcriptional activity is inversely associated with wavelength. UVR also evoked NFAT2 nuclear translocation in a parallel wavelength-dependent fashion and both transcriptional activation and nuclear translocation were inhibited by the calcineurin inhibitor cyclosporin A. UVR also evoked NFAT2 nuclear translocation in three-dimensional skin equivalents. Evidence suggests that COX-2 contributes to UV-induced carcinogenesis. Inhibiting UV-induced NFAT activation in keratinocytes, reduced COX-2 protein induction, and increased UV-induced apoptosis. COX-2 luciferase reporters lacking functional NFAT binding sites were less responsive to UVR, highlighting that NFAT is required for UV-induced COX-2 induction. Taken together, these data suggest that the proinflammatory, antiapoptotic, and procarcinogenic functions of UV-activated COX-2 may be mediated, in part, by upstream NFAT signaling. Flockhart, R. J., Diffey, B. L., Farr, P. M., Lloyd, J., Reynolds, N. J. NFAT regulates induction of COX-2 and apoptosis of keratinocytes in response to ultraviolet radiation exposure. PMID:18708588

Flockhart, R. J.; Diffey, B. L.; Farr, P. M.; Lloyd, J.; Reynolds, N. J.

2008-01-01

97

A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors.  

PubMed Central

Cyclo-oxygenase (COX) enzymes are the targets for non-steroidal anti-inflammatory drugs (NSAIDs). These drugs demonstrate a variety of inhibitory mechanisms, which include simple competitive, as well as slow binding and irreversible inhibition. In general, most NSAIDs inhibit COX-1 and -2 by similar mechanisms. A unique class of diarylheterocyclic inhibitors has been developed that is highly selective for COX-2 by virtue of distinct inhibitory mechanisms for each isoenzyme. Several of these inhibitors, with varying selectivity, have been utilized to probe the mechanisms of COX inhibition. Results from analysis of both steady-state and time-dependent inhibition were compared. A generalized mechanism for inhibition, consisting of three sequential reversible steps, can account for the various types of kinetic behaviour observed with these inhibitors. PMID:11463341

Walker, M C; Kurumbail, R G; Kiefer, J R; Moreland, K T; Koboldt, C M; Isakson, P C; Seibert, K; Gierse, J K

2001-01-01

98

Selective cyclooxygenase-2 silencing mediated by engineered E. coli and RNA interference induces anti-tumour effects in human colon cancer cells  

PubMed Central

Background: Cyclooxygenase-2 (COX-2) overexpression is strongly associated with colorectal tumourigenesis. It has been demonstrated that the chronic use of non-steroidal anti-inflammatory drugs (COX inhibitors) partially protects patients from colorectal cancer (CRC) development and progression but induces severe cardiovascular side effects. New strategies for selective COX-2 blockade are required. Methods: We developed an improved technique, based on RNA interference (RNAi), to gain a selective COX-2 silencing in CRC cells by a tumour-dependent expression of anti-COX-2 short-hairpin RNA (shCOX-2). Anti-COX-2 shRNA-expressing vectors were delivered in CRC cells (in vitro) and in colon tissues (ex vivo) using engineered Escherichia coli strains, capable of invading tumour cells (InvColi). Results: A highly tumour-dependent shCOX-2 expression and a significant COX-2 silencing were observed in CRC cells following InvColi strain infection. Cyclooxygenase-2 silencing was associated with a strong reduction in both proliferative and invasive behaviour of tumour cells. We also demonstrated a pivotal role of COX-2 overexpression for the survival of CRC cells after bacterial infection. Moreover, COX-2 silencing was achieved ex vivo by infecting colon tissue samples with InvColi strains, leading to anti-inflammatory and anti-tumour effects. Conclusion: Our RNAi/InvColi-mediated approach offers a promising tool for a highly selective COX-2 blockade in vitro and in vivo. PMID:20717114

Strillacci, A; Griffoni, C; Lazzarini, G; Valerii, M C; Di Molfetta, S; Rizzello, F; Campieri, M; Moyer, M P; Tomasi, V; Spisni, E

2010-01-01

99

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

100

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. PMID:22747786

2012-01-01

101

Simultaneous Targeting of COX-2 and AKT Using Selenocoxib-1-GSH to Inhibit Melanoma  

PubMed Central

Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting COX-2, PI3K/Akt and MAPK signaling pathways that are deregulated in up to 70% of sporadic melanoma might be an effective treatment but no agent of this type exists. To develop a single drug inhibiting COX-2 and PI3K/Akt signaling (and increasing MAPK pathway activity to inhibitory levels as a result of Akt inhibition), a selenium-containing glutathione (GSH) analog of celecoxib, called selenocoxib-1-GSH was synthesized. It killed melanoma cells with an average IC50 of 7.66 µmol/L compared to control celecoxib at 55.6 µmol/L. The IC50 range for normal cells was 36.3–41.2 µmol/L compared to 7.66 µmol/L for cancer cells. Selenocoxib-1-GSH reduced xenografted tumor development by ~70% with negligible toxicity by targeting COX-2, like celecoxib, and having new inhibitory properties acting as a PI3K/Akt inhibitor (and MAPK pathway activator to inhibitory levels due to Akt inhibition). The consequence of this inhibitory activity was an ~80% decrease in cultured cell proliferation and a ~200% increase in apoptosis following 24 hours treatment with 15.5 µmol/L of drug. Thus, this study details development of selenocoxib-1-GSH, which is a non-toxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development. PMID:23112250

Gowda, Raghavendra; Madhunapantula, SubbaRao V.; Desai, Dhimant; Amin, Shantu; Robertson, Gavin P.

2012-01-01

102

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

2006-01-01

103

Rescue of Impaired Fracture Healing in COX-2?/? Mice via Activation of Prostaglandin E2 Receptor Subtype 4  

PubMed Central

Although the essential role of cyclooxygenase (COX)-2 in fracture healing is known, the targeted genes and molecular pathways remain unclear. Using prostaglandin E2 receptor (EP)2 and EP4 agonists, we examined the effects of EP receptor activation in compensation for the lack of COX-2 during fracture healing. In a fracture-healing model, COX-2?/? mice showed delayed initiation and impaired endochondral bone repair, accompanied by a severe angiogenesis deficiency. The EP4 agonist markedly improved the impaired healing in COX-2?/? mice, as evidenced by restoration of bony callus formation on day 14, a near complete reversal of bone formation, and an approximately 70% improvement of angiogenesis in the COX-2?/? callus. In comparison, the EP2 agonist only marginally enhanced bone formation in COX-2?/? mice. To determine the differential roles of EP2 and EP4 receptors on COX-2-mediated fracture repair, the effects of selective EP agonists on chondrogenesis were examined in E11.5 long-term limb bud micromass cultures. Only the EP4 agonist significantly increased cartilage nodule formation similar to that observed during prostaglandin E2 treatment. The prostaglandin E2/EP4 agonist also stimulated MMP-9 expression in bone marrow stromal cell cultures. The EP4 agonist further restored the reduction of MMP-9 expression in the COX-2?/? fracture callus. Taken together, our studies demonstrate that EP2 and EP4 have differential functions during endochondral bone repair. Activation of EP4, but not EP2 rescued impaired bone fracture healing in COX-2?/? mice. PMID:19628768

Xie, Chao; Liang, Bojian; Xue, Ming; Lin, Angela S.P.; Loiselle, Alayna; Schwarz, Edward M.; Guldberg, Robert E.; O'Keefe, Regis J.; Zhang, Xinping

2009-01-01

104

Inhibitors Selective for Mycobacterial Versus Human Proteasomes  

SciTech Connect

Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M.?tuberculosis and act as selective suicide-substrate inhibitors of the M.?tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.

Lin, G.; Li, D; Sorio de Carvalho, L; Deng, H; Tao, H; Vogt, G; Wu, K; Schneider, J; Chidawanyika, T; et. al.

2009-01-01

105

Ezetimibe: a selective inhibitor of cholesterol absorption  

Microsoft Academic Search

Ezetimibe is a novel selective cholesterol absorption inhibitor that eectively blocks intestinal absorption of dietary and biliary cholesterol. Ezetimibe undergoes glu- curonidation to a single metabolite and is localized in the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of ezetimibe and the glucuro- nide ensures repeated delivery to the site of action and limits peripheral exposure. Ezetimibe does

A. L. Catapano

2001-01-01

106

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1? and TNF-?  

PubMed Central

Objective Excessive mechanical stress on synovial joints causes osteoarthritis (OA) and results in the production of prostaglandin E2 (PGE2), a key molecule in arthritis, by synovial fibroblasts. However, the relationship between arthritis-related molecules and mechanical stress is still unclear. The purpose of this study was to examine the synovial fibroblast response to cyclic mechanical stress using an in vitro osteoarthritis model. Method Human synovial fibroblasts were cultured on collagen scaffolds to produce three-dimensional constructs. A cyclic compressive loading of 40 kPa at 0.5 Hz was applied to the constructs, with or without the administration of a cyclooxygenase-2 (COX-2) selective inhibitor or dexamethasone, and then the concentrations of PGE2, interleukin-1? (IL-1?), tumour necrosis factor-? (TNF-?), IL-6, IL-8 and COX-2 were measured. Results The concentrations of PGE2, IL-6 and IL-8 in the loaded samples were significantly higher than those of unloaded samples; however, the concentrations of IL-1? and TNF-? were the same as the unloaded samples. After the administration of a COX-2 selective inhibitor, the increased concentration of PGE2 by cyclic compressive loading was impeded, but the concentrations of IL-6 and IL-8 remained high. With dexamethasone, upregulation of PGE2, IL-6 and IL-8 was suppressed. Conclusion These results could be useful in revealing the molecular mechanism of mechanical stress in vivo for a better understanding of the pathology and therapy of OA. Cite this article: Bone Joint Res 2014;3:280–8. PMID:25237168

Shimomura, K.; Kanamoto, T.; Kita, K.; Akamine, Y.; Nakamura, N.; Mae, T.; Yoshikawa, H.; Nakata, K.

2014-01-01

107

Original article Selection of cholesterol absorption inhibitors devoid  

E-print Network

Original article Selection of cholesterol absorption inhibitors devoid of secondary intestinal 1997) Summary ― The digestive tolerance of cholesterol absorption inhibitors, which requires group. The first derivative was a potent inhibitor of cholesterol absorption and a potent

Paris-Sud XI, Université de

108

Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice  

PubMed Central

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein–coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type–specific GPR109A expression in Gpr109a–/– mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid–induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin. PMID:20664170

Hanson, Julien; Gille, Andreas; Zwykiel, Sabrina; Lukasova, Martina; Clausen, Bjorn E.; Ahmed, Kashan; Tunaru, Sorin; Wirth, Angela; Offermanns, Stefan

2010-01-01

109

Potential impact of selective cyclooxygenase-2 inhibitors on bone metabolism in health and disease  

Microsoft Academic Search

Prostaglandins are potent local regulators of bone cell function and may play a critical role in both physiologic and pathologic changes in the human skeleton. The availability of cyclooxygenase-2 (COX-2)–specific inhibitors, which are likely to be used frequently and for long periods because of their improved safety profile, mandates an investigation of their possible effects on bone. This is particularly

Lawrence G Raisz

2001-01-01

110

A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin  

PubMed Central

Both nonsteroidal anti-inflammatory drugs, such as ibuprofen, and the prototypical selective cyclooxygenase (Cox)-2 inhibitors DuP-697 and NS-398 block the inhibition of Cox-1 by aspirin in vitro. However, clinical studies have shown that the Cox-2 selective drugs (or coxibs) rofecoxib and etoricoxib, at therapeutic doses, do not interfere with the antiplatelet effect of aspirin, in contrast to ibuprofen. Here, we have evaluated the relative potential of ibuprofen and various coxibs to interfere with the inactivation of Cox-1 by aspirin by using purified enzyme and calcium ionophore-activated human platelets. The irreversible inactivation of Cox-1 by aspirin can be antagonized by ibuprofen and coxibs, albeit with widely different potencies. The rank order of potencies for this process (ibuprofen > celecoxib > valdecoxib > rofecoxib > etoricoxib) parallels that obtained for the inhibition of Cox-1-mediated thromboxane B2 production by calcium ionophore-stimulated platelets. The antagonism of aspirin therefore likely involves a competition at the enzyme active site. The EC50 value for the antagonism against 10 ?M aspirin for each drug is ?10- to 40-fold lower than the corresponding IC50 value for inhibition of platelet Cox-1 activity, consistent with the much weaker initial binding of aspirin to Cox-1 as compared with arachidonic acid. These results show that a low affinity for Cox-1 and a high degree of Cox-2 selectivity confers a low potential to block aspirin inhibition of platelet Cox-1, consistent with the results of clinical studies. PMID:11717412

Ouellet, Marc; Riendeau, Denis; Percival, M. David

2001-01-01

111

Radiosynthesis of a ¹?F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo.  

PubMed

The radiosynthesis of 3-(4-[(18)F]fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole [(18)F]-3 as potential PET radiotracer for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo is described. [(18)F]-3 was prepared by McMurry cyclization of a (18)F-labeled intermediate with low valent titanium and zinc via a two-step procedure in a remote controlled synthesizer unit including HPLC purification and solid phase extraction. In this way [(18)F]-3 was synthesized in 80 min synthesis time in 10% total decay corrected yield from [(18)F]fluoride in radiochemical purity >98% and a specific activity of 74-91 GBq/?mol (EOS). [(18)F]-3 was evaluated in vitro using pro-inflammatory stimulated THP-1 and COX-2 expressing tumor cell lines (FaDu, A2058, HT-29), where the radiotracer uptake was shown to be consistent with up regulated COX-2 expression. The stability of [(18)F]-3 was determined by incubation in rat whole blood and plasma in vitro and by metabolite analysis of arterial blood samples in vivo, showing with 75% of original compound after 60 min an acceptable high metabolic stability. However, no substantial tumor accumulation of [(18)F]-3 could be observed by dynamic small animal PET studies on HT-29 tumor-bearing mice in vivo. This may be due to the only moderate COX-1/COX-2 selectivity of 3 as demonstrated by both cellular and enzymatic cyclooxygenase inhibition assay in vitro. Nevertheless, the new approach first using McMurry cyclization in (18)F-chemistry gives access to (18)F-labeled diarylsubstituted heterocycles that hold promise as radiolabeled COX-2 inhibitors. PMID:22560838

Kniess, Torsten; Laube, Markus; Bergmann, Ralf; Sehn, Fabian; Graf, Franziska; Steinbach, Joerg; Wuest, Frank; Pietzsch, Jens

2012-06-01

112

Selective Water-Soluble Gelatinase Inhibitor Prodrugs  

PubMed Central

SB-3CT (1), a selective and potent thiirane-based gelatinase inhibitor, is effective in animal models of cancer metastasis and stroke; however, it is limited by poor aqueous solubility and extensive metabolism. We addressed these issues by blocking the primary site of metabolism and capitalizing on a prodrug strategy to achieve >5000-fold increased solubility. The amide prodrugs were quantitatively hydrolyzed in human blood to a potent gelatinase inhibitor, ND-322 (3). The arginyl amide prodrug (ND-478, 5d) was metabolically stable in mouse, rat, and human liver microsomes. Both 5d and 3 were non-mutagenic in the Ames II mutagenicity assay. The prodrug 5d showed moderate clearance of 0.0582 L/min/kg, remained mostly in the extracellular fluid compartment (Vd = 0.0978 L/kg), and had a terminal half-life of >4 h. The prodrug 5d had superior pharmacokinetic properties than 3, making the thiirane class of selective gelatinase inhibitors suitable for intravenous administration in treatment of acute gelatinase-dependent diseases. PMID:21866961

Gooyit, Major; Lee, Mijoon; Schroeder, Valerie A.; Ikejiri, Masahiro; Suckow, Mark A.; Mobashery, Shahriar; Chang, Mayland

2011-01-01

113

Castanospermine-glucosides as selective disaccharidase inhibitors.  

PubMed

Castanospermine (CS) is a potent but non-selective inhibitor of many glycohydrolases including the intestinal disaccharidases. Several CS-glucosides were synthesized to investigate the effect of an attached glucopyranosyl residue on the potency and selectivity of CS toward inhibition of intestinal disaccharidases. 8 alpha-glucosyl-CS and 7 alpha-glucosyl-CS were nearly as potent against sucrase activity as CS (IC50 values = 30, 40, and 20 nM respectively) but were 1/50 or less as potent as CS against lactase and trehalase activities. 8 beta-glucosyl-CS was 1/20 to 1/140 as potent as CS and 1 alpha-glucosyl-CS was 1/57 to 1/1500 as potent as CS against disaccharidase activities. 1 alpha-glc-CS was less selective than CS, whereas the other CS-glucosides were more selective. 7 alpha-glc-CS and 8 alpha-glc-CS were the most sucrase selective and were particularly ineffective against trehalase and lactase activities. 8 beta-glc-CS was similar to CS except for relatively weaker trehalase inhibition. In summary, selectivity toward certain disaccharidases was achieved by glucosylation of CS hydroxyls. However, a simple structural comparison of the CS-glucoside to a disaccharide substrate did not reliably predict which disaccharidase would be more inhibited by the CS-glucoside. PMID:2337410

Rhinehart, B L; Robinson, K M; King, C H; Liu, P S

1990-05-15

114

Mechano-transcription of COX-2 is a common response to lumen dilation of the rat gastrointestinal tract  

PubMed Central

Background In obstructive bowel disorders (OBDs) such as achalasia, pyloric stenosis, and bowel obstruction, the lumen of the affected segments is markedly dilated and the motility function is significantly impaired. We tested the hypothesis that mechanical stress in lumen dilation leads to induction of cyclo-oxygenase-2 (COX-2) in smooth muscle throughout the gastrointestinal (GI) tract, contributing to motility dysfunction. Methods Lumen dilation was induced in vivo with obstruction bands (12 × 3 mm) applied over the lower esophageal sphincter (LES), the pyloric sphincter, and the ileum in rats for 48 hr. Mechanical stretch in vivo was also emulated by balloon distension of the distal colon. Direct stretch of muscle strips from the esophagus, gastric fundus, and ileum was mimicked in an in vitro tissue culture system. Key Results Partial obstruction in the LES, pylorus, and ileum significantly increased expression of COX-2 mRNA and protein in the muscularis externae of the dilated segment oral to the occlusions, but not in the aboral segment. Direct stretch of the lumen in vivo or of muscle strips in vitro markedly induced COX-2 expression. The smooth muscle contractility was significantly suppressed in the balloon distended segments. However, treatment with COX-2 inhibitor NS-398 restored the contractility. Furthermore, in vivo administration of NS-398 in gastric outlet obstruction significantly improved gastric emptying. Conclusions & Inferences Mechanical dilation of the gut lumen by occlusion or direct distension induces gene expression of COX-2 throughout the GI tract. Mechanical stress-induced COX-2 contributes to motility dysfunction in conditions with lumen dilation. PMID:22489918

Lin, You-Min; Li, Feng; Shi, Xuan-Zheng

2014-01-01

115

Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent  

PubMed Central

The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet-derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I–IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I–III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-?B. We found that resveratrol efficiently reversed the PMA-induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced I?B phosphorylation in siSirt1-transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-?B signal transduction inhibitor independent of Sirt1. PMID:22523472

Annabi, Borhane; Lord-Dufour, Simon; Vézina, Amélie; Béliveau, Richard

2012-01-01

116

Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhibitor.  

PubMed

Although highly selective cyclooxygenase (COX)-2 inhibitors have been shown to be less toxic to the gastrointestinal tract than conventional non-steroidal anti-inflammatory drugs (NSAIDs), their overall safety profile is questioned. Since different selective COX-2 inhibitors were found to be associated with increased cardiovascular thrombotic events, the thrombotic hazard may be a class effect. Furthermore, warnings have been issued regarding serious skin and hypersensitivity reactions associated with valdecoxib. Lumiracoxib is a novel COX-2 selective inhibitor (coxib) with improved biochemical selectivity over that of currently available coxibs. It is structurally distinct from other drugs in the class and has weakly acidic properties. Clinical studies support a once-daily dosing regimen, despite its relatively short plasma elimination half-life (3 - 6 h). In randomised, controlled clinical trials, lumiracoxib 100 - 200 mg/day has been shown to be superior to placebo in patients with symptomatic osteoarthritis, with clinical efficacy similar to diclofenac 150 mg/day, celecoxib 200 mg/day or rofecoxib 25 mg/day. Furthermore, lumiracoxib 200 - 400 mg/day appeared to be effective in patients with rheumatoid arthritis. In patients with acute pain related to primary dysmenorrhoea, dental or orthopaedic surgery, lumiracoxib 400 mg/day was found to be at least as effective as standard doses of traditional NSAIDs and other coxibs. Endoscopic studies have indicated that lumiracoxib is associated with a rate of gastroduodenal ulcer formation that is significantly lower than with ibuprofen and does not differ from celecoxib. In the Therapeutic Arthritis Research and Gastrointestinal Trial, which enrolled 18,325 patients with osteoarthritis, the cumulative 1-year incidence of ulcer complications (primary end point) was significantly reduced by approximately threefold on lumiracoxib 400 mg/day compared with naproxen 1000 mg/day or ibuprofen 2400 mg/day (0.32 versus 0.91%). Reduction in ulcer complications was more pronounced in the population not taking low-dose aspirin (0.2 versus 0.92%, respectively). Conversely, the gastrointestinal advantage of lumiracoxib was abrogated in patients receiving low-dose aspirin (0.69 versus 0.88%, respectively, p = 0.49). Regarding cardiovascular events contributing to the trialists' composite end point (myocardial infarction, stroke or cardiovascular death), there was no significant difference between lumiracoxib (0.65%) versus combined comparator NSAIDs (0.55%). Similarly, no significant difference was recorded in rates of myocardial infarction (clinical and silent) between the lumiracoxib (0.25%) and the combined NSAID (0.19%) treatment groups. Liver function test abnormalities were more frequent with lumiracoxib (2.57%) than with the comparator NSAIDs (0.63%). Whether or not this would result in an increased risk of clinical hepatitis in the real world setting is unforeseeable. PMID:15882125

Bannwarth, Bernard; Berenbaum, Francis

2005-04-01

117

Cell-type-specific roles for COX-2 in UVB-induced skin cancer.  

PubMed

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

Jiao, Jing; Mikulec, Carol; Ishikawa, Tomo-o; Magyar, Clara; Dumlao, Darren S; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey

2014-06-01

118

Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors.  

PubMed

3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a known selective cyclooxygenase-1 (COX-1) inhibitor, was used to design a new series of 3,4-diarylisoxazoles in order to improve its biochemical COX-1 selectivity and antiplatelet efficacy. Structure-activity relationships were studied using human whole blood assays for COX-1 and COX-2 inhibition in vitro, and results showed that the simultaneous presence of 5-methyl (or -CF3), 4-phenyl, and 5-chloro(-bromo or -methyl)furan-2-yl groups on the isoxazole core was essential for their selectivity toward COX-1. 3g, 3s, 3d were potent and selective COX-1 inhibitors that affected platelet aggregation in vitro through the inhibition of COX-1-dependent thromboxane (TX) A2. Moreover, we characterized their kinetics of COX-1 inhibition. 3g, 3s, and 3d were more potent inhibitors of platelet COX-1 and aggregation than P6 (named 6) for their tighter binding to the enzyme. The pharmacological results were supported by docking simulations. The oral administration of 3d to mice translated into preferential inhibition of platelet-derived TXA2 over protective vascular-derived prostacyclin (PGI2). PMID:23651359

Vitale, Paola; Tacconelli, Stefania; Perrone, Maria Grazia; Malerba, Paola; Simone, Laura; Scilimati, Antonio; Lavecchia, Antonio; Dovizio, Melania; Marcantoni, Emanuela; Bruno, Annalisa; Patrignani, Paola

2013-06-13

119

COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status  

PubMed Central

Background Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Method Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Results Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1?, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-?B, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Conclusions Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue. PMID:21668942

2011-01-01

120

Aspirin-Induced COX2 Overexpression in Monocytes of Aspirin-Intolerant Patients  

Microsoft Academic Search

Background: We hypothesize that alternate regulation of cyclooxygenase-2 (COX-2) may predispose patients to aspirin-induced exacerbations.Therefore, we want to examine the dynamics of COX-2 up-regulation in whole blood monocytes in the presence and absence of aspirin. Methods: COX-2 expression was evaluated by flow cytometry through intracellular staining of whole blood monocytes with antiCOX-2 antibodies. Enzyme up-regulation was monitored after in vitrostimulation

Tina Morgan; Nissera Bajrovic; Mira Silar; Mitja Kosnik; Peter Korosec

2009-01-01

121

COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice.  

PubMed

It was hypothesized that cyclooxygenase-2 (COX-2) activity promotes urine concentrating ability through stimulation of vasopressin (AVP) release after water deprivation (WD). COX-2-deficient (COX-2(-/-), C57BL/6) and wild-type (WT) mice were water deprived for 24 h, and water balance, central AVP mRNA and peptide level, AVP plasma concentration, and AVP-regulated renal transport protein abundances were measured. In male COX-2(-/-), basal urine output and water intake were elevated while urine osmolality was decreased compared with WT. Water deprivation resulted in lower urine osmolality, higher plasma osmolality in COX-2(-/-) mice irrespective of gender. Hypothalamic AVP mRNA level increased and was unchanged between COX-2(-/-) and WT after WD. AVP peptide content was higher in COX-2(-/-) compared with WT. At baseline, plasma AVP concentration was elevated in conscious chronically catheterized COX-2(-/-) mice, but after WD plasma AVP was unchanged between COX-2(-/-) and WT mice (43 ± 11 vs. 70 ± 16 pg/ml). Renal V2 receptor abundance was downregulated in COX-2(-/-) mice. Medullary interstitial osmolality increased and did not differ between COX-2(-/-) and WT after WD. Aquaporin-2 (AQP2; cortex-outer medulla), AQP3 (all regions), and UT-A1 (inner medulla) protein abundances were elevated in COX-2(-/-) at baseline and further increased after WD. COX-2(-/-) mice had elevated plasma urea and creatinine and accumulation of small subcapsular glomeruli. In conclusion, hypothalamic COX-2 activity is not necessary for enhanced AVP expression and secretion in response to water deprivation. Renal medullary COX-2 activity negatively regulates AQP2 and -3. The urine concentrating defect in COX-2(-/-) is likely caused by developmental glomerular injury and not dysregulation of AVP or collecting duct aquaporins. PMID:21880835

Nørregaard, Rikke; Madsen, Kirsten; Hansen, Pernille B L; Bie, Peter; Thavalingam, Sugarna; Frøkiær, Jørgen; Jensen, Boye L

2011-12-01

122

Overexpression of COX-2 in human osteosarcoma cells decreases proliferation and increases apoptosis.  

PubMed

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 cell numbers by 50% to 70% compared with controls. Decreased proliferation in COX-2-overexpressing cells was associated with cell cycle prolongation in G(2)-M. Apoptosis, measured by both Annexin V binding assay and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining, was increased in cells overexpressing COX-2, and the increase was not reversed by treatment with NS-398, indicating that the effects were not mediated by prostaglandins. Retroviral COX-2 overexpression in two other human osteosarcoma cell lines, U2OS and TE85, also decreased cell viability. However, in the human colon carcinoma HCT-116 cell line, which is deficient in COX-2, retroviral overexpression of COX-2, at similar efficiency as in Saos-2 cells, increased resistance to apoptosis. Reactive oxygen species (ROS), measured by flow cytometry, were increased by COX-2 overexpression in Saos-2 cells but not in HCT-116 cells. Inhibition of peroxidase activity, but not of COX activity, blocked the ROS increase. Antioxidants blocked the increase in ROS and the increase in apoptosis due to COX-2 overexpression in Saos-2 cells. Our results suggest that (a) COX-2 overexpression in osteosarcoma cells may increase resistance to tumorigenesis by increasing ROS to levels that decrease cell viability and (b) the effects of COX-2 overexpression are cell type/tissue dependent. PMID:16818639

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

2006-07-01

123

Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NF?B/c-Jun/AP-1-Dependent Pathway  

PubMed Central

Background: Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation. However, the molecular mechanisms by which Cr(VI) causes cancers are not well understood. Objectives: We evaluated cyclooxygenase-2 (COX-2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells. Methods: We used the luciferase reporter assay and Western blotting to determine COX-2 induction by Cr(VI). We used dominant negative mutant, genetic knockout, gene knockdown, and chromatin immunoprecipitation approaches to elucidate the signaling pathway leading to COX-2 induction. Results: We found that Cr(VI) exposure induced COX-2 expression in both normal human bronchial epithelial cells and mouse embryonic fibroblasts in a concentration- and time-dependent manner. Deletion of IKK? [inhibitor of transcription factor NF?B (I?B) kinase ?; an upstream kinase responsible for nuclear factor ?B (NF?B) activation] or overexpression of TAM67 (a dominant-negative mutant of c-Jun) dramatically inhibited the COX-2 induction due to Cr(VI), suggesting that both NF?B and c-Jun/AP-1 pathways were required for Cr(VI)-induced COX-2 expression. Our results show that p65 and c-Jun are two major components involved in NF?B and AP-1 activation, respectively. Moreover, our studies suggest crosstalk between NF?B and c-Jun/AP-1 pathways in cellular response to Cr(VI) exposure for COX-2 induction. Conclusion: We demonstrate for the first time that Cr(VI) is able to induce COX-2 expression via an NF?B/c-Jun/AP-1–dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis. PMID:22472290

Zuo, Zhenghong; Cai, Tongjian; Li, Jingxia; Zhang, Dongyun; Yu, Yonghui

2012-01-01

124

PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons.  

PubMed

The oxygenation of endogenous cannabinoids (eCBs) 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide by cyclooxygenase-2 (COX-2) produces novel types of prostanoids: prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). However, the physiological function of COX-2 oxidative metabolites of eCBs is still unclear. Here we demonstrate that PGE2-G, a COX-2 oxidative metabolite of 2-AG, induced a concentration-dependent increase in the frequency ofminiature inhibitory postsynaptic currents (mIPSCs) in primary cultured hippocampal neurons, an effect opposite to that of 2-AG. This increase was not inhibited by SR141716, a CB1 receptor antagonist, but was attenuated by an IP3 or MAPK inhibitor. In addition, we also examined the effects of other prostanoids derived from COX-2 oxygenation of eCBs on mIPSCs. PGD2-G, PGF2alpha-G and PGD2-EA, but not PGE2-EA or PGF2alpha-EA, also increased the frequency of mIPSCs. The eCB-derived prostanoid-induced responses appeared to be different from those of corresponding arachidonic acid-derived prostanoids, implying that these effects are not mediated via known prostanoid receptors. We further discovered that the inhibition of COX-2 activity reduced inhibitory synaptic activity and augmented depolarization-induced suppression of inhibition (DSI), whereas the enhancement of COX-2 augmented the synaptic transmission and abolished DSI. Our results, which show that COX-2 oxidative metabolites of eCBs exert opposite effects to their parent molecules on inhibitory synaptic transmission, suggest that alterations in COX-2 activity will have significant impact on endocannabinoid signalling in hippocampal synaptic activity. PMID:16484297

Sang, Nan; Zhang, Jian; Chen, Chu

2006-05-01

125

Post-Exposure Therapeutic Efficacy of COX-2 Inhibition against Burkholderia pseudomallei  

PubMed Central

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.

2013-01-01

126

Effect of cyclooxygenase (COX)-2 inhibition on mouse renal interstitial fibrosis.  

PubMed

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. In this study, we investigated the effects of a COX-2 inhibitor, meloxicam, on UUO-induced renal interstitial fibrosis in mice. Serum creatinine, blood urea nitrogen and urinary glucose were significantly increased by UUO. However, all of these changes were attenuated by meloxicam (1mg/kg/day). Masson?s trichrome staining showed that interstitial fibrosis was significantly increased by UUO, but that meloxicam also significantly diminished the area of UUO-induced fibrosis. Heat shock protein (HSP) 47 protein, a collagen-specific molecular chaperone essential for the biosynthesis of collagen molecules, and type IV collagen mRNA were increased in kidneys of UUO mice. Meloxicam reduced the expression of both HSP47 protein and type IV collagen mRNA. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) was increased by UUO, but these changes were inhibited by meloxicam. Collectively, these results suggest that COX-2 may be involved in the expression of HSP47 and type IV collagen through the phosphorylation of ERK and JNK, accelerating renal interstitial fibrosis. PMID:24975097

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

2014-10-01

127

COX-2-dependent stabilization of survivin in non-small cell lung cancer.  

PubMed

Elevated tumor cyclooxygenase 2 (COX-2) expression is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. The mechanism(s) by which COX-2 exerts its cytoprotective effects are not completely understood but may be due to an imbalance of pro- and anti-apoptotic gene expression. To analyze COX-2-dependent gene expression and apoptosis, we created cell lines constitutively expressing COX-2 cDNA in sense and antisense orientations. Whereas COX-2 sense cells have significantly heightened resistance to radiation and drug-induced apoptosis, COX-2 antisense cells are highly sensitive to apoptosis induction. We found that the expression of the anti-apoptotic protein survivin correlated positively with COX-2 expression. A COX-2-dependent modulation of survivin ubiquitination led to its stabilization in COX-2 overexpressing cells, and this effect was replicated by exogenous PGE2 treatment of parental tumor cells. In contrast to previous studies in other cell types, in nonsmall cell lung cancer cells survivin was expressed in a cell cycle-independent manner. When established in SCID mice in vivo, COX-2 antisense-derived tumors had significantly decreased survivin levels while COX-2 sense-derived tumors demonstrated elevated levels compared with controls. In accord with these findings, survivin and COX-2 were frequently upregulated and co-expressed in human lung cancers in situ. PMID:14597555

Krysan, Kostyantyn; Merchant, Farrukh H; Zhu, Li; Dohadwala, Mariam; Luo, Jie; Lin, Ying; Heuze-Vourc'h, Nathalie; Põld, Mehis; Seligson, David; Chia, David; Goodglick, Lee; Wang, Hejing; Strieter, Robert; Sharma, Sherven; Dubinett, Steven

2004-01-01

128

Upregulation of fibronectin expression by COX-2 is mediated by interaction with ELMO1  

PubMed Central

Engulfment and cell motility 1 (ELMO1), a bipartite guanine nucleotide exchange factor (GEF) for the small GTPase Rac 1, was identified as a susceptibility gene for glomerular disease. Here, we reported that ELMO1 interacted with COX-2 in human mesangial cells. Furthermore, we identified ELMO1 as a posttranslational regulator of COX-2 activity. We demonstrated that COX-2 cyclooxygenase activity increased fibronectin promoter activity. The protein-protein interaction between ELMO1 and COX-2 increased the cyclooxygenase activity of COX-2 and, correspondingly, fibronectin expression. We also found that ET625, the dominant negative form of ELMO1 lacking Rac1 activity, interacted with COX-2, increased cyclooxygenase activity of COX-2 and enhanced COX-2-mediated fibronectin upregulation. To further rule out Rac1 as an ELMO1-mediated regulator of COX-2 activity, we employed the constitutive active Rac1, Rac1Q63E, and demonstrated that Rac1 signaling has no effect on COX-2-mediated fibronectin promoter activity. These results suggest that ELMO1 contributes to the development of glomerular injury through serving as a regulator of COX-2 activity. The interaction of ELMO1 with COX-2 could play an important role in the development and progression of renal glomerular injury. PMID:20732417

Yang, Chen; Sorokin, Andrey

2010-01-01

129

The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts.  

PubMed

Mouse embryonic fibroblasts (MEFs) are multi-potent progenitor cells (MPCs), can differentiate into different lineages, such as osteogenic, and adipogenic. PTEN, a tumor suppressor, may be involved in regulating bone development through interacting with COX-2. BMP9, the most potent osteogenic BMPs, can up-regulate COX-2 in MPCs. Whether PTEN is involved in BMP9 induced osteogenic differentiation in MPCs remains unknown. The goal of this investigation is to identify the effect of PTEN on BMP9-induced osteogenic differentiation in MPCs and dissect the possible mechanism underlay this. We found that BMP9 down-regulates PTEN, and PTEN inhibitor (VO) effectively increases different osteogenic markers induced by BMP9 in MEFs. Exogenous expression of PTEN inhibits BMP9 induced ectopic bone formation apparently. Mechanistically, we found that VO can enhance BMP9 induced BMPs/Smads signaling prominently without no substantial effects on cell cycle. Further analysis indicates that VO can promote BMP9-induced expression of COX-2 in MEFs, which can be eliminated by PI3K inhibitor. Additionally, COX-2 knockdown abolishes the effect of VO on BMP9-induced ALP activities in MEFs. Our findings suggest that PTEN plays an important role in regulating BMP9 induced osteogenic differentiation in MPCs, which may be mediated by PTEN/PI3K/Akt signaling to modulate the expression of COX-2. PMID:25176064

Huang, Jun; Yuan, Shuang-Xue; Wang, Dong-Xu; Wu, Qiu-Xiang; Wang, Xing; Pi, Chang-Jun; Zou, Xiang; Chen, Liang; Ying, Liang-Jun; Wu, Ke; Yang, Jun-Qing; Sun, Wen-Juan; Deng, Zhong-Liang; He, Bai-Cheng

2014-12-01

130

Considerations in Selecting Protease Inhibitor Therapy  

Microsoft Academic Search

Over the past 10 years, highly active antiretroviral therapy that included a protease inhibitor has played a significant role in reducing morbidity and mortality among HIV-infected individuals. The early protease inhibitors were associated, however, with some significant limitations that posed major obstacles to their use - limited potency, difficult side effects, high regimen complexity and potential for cross-resis- tance. Important

Brian A. Boyle; Richard A. Elion; Graeme J. Moyle; Calvin J. Cohen

2004-01-01

131

miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells  

SciTech Connect

Highlights: •Pancreatic cancer cells express low miR-143 levels and elevated p-MEK, p-MAPK and RREB1. •MEK inhibitors U0126 and PD98059 increase miR-143 expression. •miR-143 decreases COX-2 mRNA stability and expression and PGE{sub 2}. •miR-143 decreases p-p38MAPK, p-MEK, p-MAPK and RREB1 expression. -- Abstract: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3?-untranslated region (3?-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E{sub 2} (PGE{sub 2}) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 ?M of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE{sub 2} levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE{sub 2}, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.

Pham, Hung [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States) [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States); Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073 (United States); Ekaterina Rodriguez, C.; Donald, Graham W.; Hertzer, Kathleen M.; Jung, Xiaoman S.; Chang, Hui-Hua; Moro, Aune; Reber, Howard A.; Hines, O. Joe [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States)] [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States); Eibl, Guido, E-mail: geibl@mednet.ucla.edu [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States)] [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States)

2013-09-13

132

Butein downregulates phorbol 12-myristate 13-acetate-induced COX2 transcriptional activity in cancerous and non-cancerous breast cells  

Microsoft Academic Search

Butein is a flavonoid isolated from the bark of Rhus verniciflua Stokes and the flowers of Butea monosperma, and is known to be a potential therapeutic drug for treating inflammation and cancer. Cyclooxygenase (COX) converts arachidonic acid to prostanoids, and increased expression of its isoform COX-2 has been observed in breast cancer tissues. It has been suggested that COX inhibitors

Grace Tak Yi Lau; Hui Huang; Shu-mei Lin; Lai K. Leung

2010-01-01

133

The pharmacogenetics of the selective serotonin reuptake inhibitors  

Microsoft Academic Search

Citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs), which are thought to act as antidepressants through their ability to inhibit presynaptic serotonin reuptake in the brain. The elimination of the SSRIs proceeds predominantly via oxidation catalyzed by cytochrome P450 in the liver. Paroxetine and fluoxetine are potent inhibitors of cytochrome P4502D6 and hence may cause serious

K. Brøsen

1993-01-01

134

COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis  

PubMed Central

Background Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. Methods The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n?=?92), ampullary cancer (AC, n?=?62) and distal bile duct cancer (DBC, n?=?76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. Results COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p?=?0.043 in PC, p?=?0.011 in AC, p?=?0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p?=?0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p?=?0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model. Conclusions COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis. PMID:24950702

2014-01-01

135

Anti-inflammatory activity of sertaconazole nitrate is mediated via activation of a p38-COX-2-PGE2 pathway.  

PubMed

Sertaconazole nitrate is an antifungal agent that exhibits anti-inflammatory activity; however, the mechanism for this action was unknown. We investigated the cellular mechanisms by which sertaconazole exerts its anti-inflammatory activity in keratinocytes and human peripheral blood mononuclear cells (PBMCs). Paradoxically, sertaconazole was found to activate the proinflammatory p38 mitogen-activated protein kinase. Treatment with sertaconazole also resulted in the induction of cyclooxygenase-2 (COX-2) and the subsequent release of prostaglandin E2 (PGE2). Knocking down p38 in keratinocytes using small interfering RNA resulted in an inhibition of sertaconazole-induced PGE2 release confirming that activation of p38 was required for PGE2 production. Additionally, in stimulated keratinocytes and human PBMCs, sertaconazole was found to suppress the release of cytokines. Treatment with anti-PGE2 antiserum or the COX-2 inhibitor NS398 reversed the inhibitory effects of sertaconazole on the release of proinflammatory cytokines, linking endogenous PGE2 with the anti-inflammatory effects. Finally, in an in vivo mouse model of tetradecanoyl phorbol acetate (TPA)-induced dermatitis, the sertaconazole-mediated inhibition of TPA-induced ear edema was reversed by NS398. Biochemical analysis of tissue biopsies revealed increase in PGE2 levels in sertaconazole-treated mice. Thus, activation of the p38-COX-2-PGE2 pathway by agents such as sertaconazole provides anti-inflammatory therapeutic benefits. PMID:17637821

Sur, Runa; Babad, Jeffrey M; Garay, Michelle; Liebel, Frank T; Southall, Michael D

2008-02-01

136

Butein downregulates phorbol 12-myristate 13-acetate-induced COX-2 transcriptional activity in cancerous and non-cancerous breast cells.  

PubMed

Butein is a flavonoid isolated from the bark of Rhus verniciflua Stokes and the flowers of Butea monosperma, and is known to be a potential therapeutic drug for treating inflammation and cancer. Cyclooxygenase (COX) converts arachidonic acid to prostanoids, and increased expression of its isoform COX-2 has been observed in breast cancer tissues. It has been suggested that COX inhibitors can be used as chemopreventive agents against breast carcinogenesis. This study examined the potential suppressive effect of the flavonoid on phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in the non-tumorigenic MCF-10A and cancerous MCF-7 breast cells. Immunoblot and mRNA analyses revealed that butein at or below 10 ?M significantly inhibited PMA-induced COX-2 expression in these breast cells. The blocking of the PKC signaling pathway appeared to be the underlying mechanism. Butein treatment reduced the amount of phospho-mitogen activated protein kinase (MAPK) ERK-1/2, and the total activity of PKC. Activated ERKs might trigger the transcriptional activation of COX-2. Reporter gene assays as well as electrophoretic mobility shift assays (EMSA) illustrated that butein inhibited transcription of this gene. This study showed that butein down-regulated PMA-induced COX-2 expression in both cancerous and non-cancerous breast cells, and such findings could provide the basis for pharmaceutical development of butein. PMID:20826149

Lau, Grace Tak Yi; Huang, Hui; Lin, Shu-mei; Leung, Lai K

2010-12-01

137

COX2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin  

Microsoft Academic Search

Some previous studies have found worse prognosis among cyclooxygenase-2 (COX-2)-expressing breast cancers. Aspirin and NSAIDs\\u000a inhibit COX-2. Three studies, including ours, have reported a survival advantage among women with breast cancer who take either\\u000a aspirin or NSAIDs. Through this study we hypothesized that in the Nurses’ Health Study (NHS), COX-2 expression would be associated\\u000a with worse prognosis, and aspirin use

Michelle D. Holmes; Wendy Y. Chen; Stuart J. Schnitt; Laura Collins; Graham A. Colditz; Susan E. Hankinson; Rulla M. Tamimi

138

Cyclic tensile force up-regulates BMP-2 expression through MAP kinase and COX-2/PGE2 signaling pathways in human periodontal ligament cells.  

PubMed

Periodontal ligament cells play important roles in the homeostasis of periodontal tissue by mechanical stress derived from mastication, such as tension, compression, fluid shear, and hydrostatic force. In the present study, we showed that cyclic tensile force increased the gene expression level of bone morphogenetic protein (BMP)-2, a crucial regulator of mineralization, in human periodontal ligament cells using real-time PCR. Signaling inhibitors, PD98059/U0126 (extracellular signal-regulated kinase (ERK) inhibitors) and SB203580/SB202190 (p38 inhibitors), revealed that tensile force-mediated BMP-2 expression was dependent on activation of the ERK1/2 and p38 mitogen-activated protein (MAP) kinase pathways. Cyclic tensile force also induced cyclooxygenase-2 (COX-2) gene expression in a manner dependent on ERK1/2 and p38 MAP kinase pathways, and induced prostaglandin E2 (PGE2) biosynthesis. NS-398, a COX-2 inhibitor, significantly reduced tensile force-mediated BMP-2 expression, indicating that PGE2 synthesized by COX-2 may be involved in the BMP-2 induction. The inhibitory effect of NS-398 was completely restored by the addition of exogenous PGE2. However, stimulation with PGE2 alone in the absence of tensile force had no effect on the BMP-2 induction, indicating that some critical molecule(s) other than COX-2/PGE2 may be required for cyclic tensile force-mediated BMP-2 induction. Collectively, the results indicate that cyclic tensile force activates ERK1/2 and p38 MAP kinase signaling pathways, and induces COX-2 expression, which is responsible for the sequential PGE2 biosynthesis and release, and furthermore, mediates the increase in BMP-2 expression at the transcriptional level. PMID:24561081

Suzuki, Risako; Nemoto, Eiji; Shimauchi, Hidetoshi

2014-04-15

139

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

2013-09-01

140

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

141

Mono-, di-, and triaryl substituted tetrahydropyrans as cyclooxygenase-2 and tumor growth inhibitors. Synthesis and biological evaluation.  

PubMed

Rationally designed tetrahydropyrans (THPs) carrying one, two, or three aryl rings and other substituents were synthesized by the allylation of beta-hydroxy ketones followed by iodocyclization. It has been observed that compounds with one aryl ring on THP are moderate inhibitors of cyclooxygenase-1 (COX-1) (IC(50) = 0.3 microM) and cyclooxygenase-2 (IC(50) = 0.17 microM) with poor selectivity index (SI = 2-3) for COX-2. The presence of two aryl rings enhanced their inhibitory activities for COX-2 (IC(50) = 0.9-5.5 nM). Selectivity for COX-2 over COX-1 also increased (SI = 50-1900), while triaryl substituted THPs, along with high inhibition (IC(50) = 0.57-4.0 nM), also exhibited excellent selectivity for COX-2 over COX-1 (SI = 3200-44000). Similar to the experimental results of increased COX-2 inhibition and selectivity with the increase in the size of the molecule, their docking in the active sites of COX-1 and COX-2 also showed same trend. Seven compounds from the category of di- and triaryl substituted THPs exhibited average GI(50) over all the human tumor cell lines in the range 1.6-3.2 microM and showed in vitro therapeutic indices of 8-17. PMID:20387815

Singh, Palwinder; Bhardwaj, Atul

2010-05-13

142

Antitumor properties of taxol in combination with cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on ovarian tumor growth in vivo.  

PubMed

The present study was designed to investigate whether taxol in combination with cyclooxygenase (COX) inhibitors could be superior on inhibitory effect of ovarian cancer growth than taxol alone as drug therapy of mice implanted with human ovarian carcinoma cell line SKOV-3. The animals were treated with 100 mg/ kg celecoxib (a COX-2 selective inhibitor) alone or in combination with 3 mg/kg SC-560 (a COX-1 selective inhibitor) by gavage twice a day, 20mg/kg taxol alone by intraperitoneal (IP) once a week or in combination with celecoxib, or SC-560/celecoxib/taxol for 3 weeks. To test the mechanism of the combination treatment, the index of cell proliferation, expression of cyclin D1, and microvessel density (MVD) in tumor tissues were determined by immunohistochemistry and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. Mean tumor volume in the SC-560/celecoxib/taxol group was first significantly lower than control at day 14 (p < 0.05). In the SC-560/celecoxib/taxol group, the index of cell proliferation and apoptosis and quantification of cyclin D1-postive cells were 6.93%, 69.62%, and 19.14%, respectively, which are statistically significant compared with those of the control group (29.85%, p < 0.001; 32.81% and 36.99%, both p < 0.05). Statistical significance on MVD was observed between the SC-560/celecoxib/taxol (39.57 +/- 4.98) and the control (73.2 +/- 1.96) group (p < 0.001). Our results suggest that the combined antitumor efficacy of taxol and COX inhibitors may be superior to taxol alone as drug therapy against ovarian cancer in mice, and that synergism of the combination treatment in part may be mediated through accelerated apoptosis and suppression of cell proliferation and angiogenesis. PMID:23193911

Li, Wei; Zhai, Lingyun; Tang, Yunxian; Cai, Jiahui; Liu, Meilin; Zhang, Jun

2012-01-01

143

COX-2 but Not mPGES-1 Contributes to Renal PGE2 Induction and Diabetic Proteinuria in Mice with Type-1 Diabetes  

PubMed Central

Prostaglandin E2 (PGE2) has been implicated to play a pathogenic role in diabetic nephropathy (DN) but its source remains unlcear. To elucidate whether mPGES-1, the best characterized PGE2 synthase, was involved in the development of DN, we examined the renal phenotype of mPGES-1 KO mice subjected to STZ-induced type-1 diabetes. After STZ treatment, mPGES-1 WT and KO mice presented the similar onset of diabetes as shown by similar elevation of blood glucose. Meanwhile, both genotypes of mice exhibited similar increases of urinary and renal PGE2 production. In parallel with this comparable diabetic status, the kidney injury indices including the urinary albumin excretion, kidney weight and the kidney histology (PAS staining) did not show any difference between the two genotypes. By Western-blotting and quantitative qRT-PCR, mPGES-1, mPGES-2, cPGES and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) remain unaltered following six weeks of diabetes. Finally, a selective COX-2 inhibitor celecoxib (50 mg/kg/day) was applied to the STZ-treated KO mice, which resulted in significant reduction of urinary albumin excretion (KO/STZ: 141.5±38.4 vs. KO/STZ + Celebrex: 48.7±20.8 ug/24 h, p<0.05) and the blockade of renal PGE2 induction (kidney: KO/STZ: 588.7±89.2 vs. KO/STZ + Celebrex: 340.8±58.7 ug/24 h, p<0.05; urine: KO/STZ 1667.6±421.4 vs. KO/STZ + Celebrex 813.6±199.9 pg/24 h, p<0.05), without affecting the blood glucose levels and urine volume. Taken together, our data suggests that an as yet unidentified prostaglanind E synthase but not mPGES-1 may couple with COX-2 to mediate increased renal PGE2 sythsesis in DN. PMID:24984018

Liu, Shanshan; Liu, Ying; Yang, Tianxin

2014-01-01

144

Allelic variation in the canine Cox-2 promoter causes hypermethylation of the canine Cox-2 promoter in clinical cases of renal dysplasia  

PubMed Central

Background Novel allelic variants in the promoter of the canine cyclooxygenase-2 (Cox-2) gene are associated with renal dysplasia (RD). These variants consist of either deletions of putative SP1 transcription factor-binding sites or insertions of tandem repeats of SP1-binding sites located in the CpG island just upstream of the ATG translation initiation site. The canine Cox-2 gene was studied because Cox-2-deficient mice have renal abnormalities and a pathology that is strikingly similar to RD in dogs. Findings The allelic variants were associated with hypermethylation of the Cox-2 promoter only in clinical cases of RD. The wild-type allele was never methylated, even in clinical cases that were heterozygous for a mutant allele. In cases that were biopsy-negative, the promoter remained unmethylated, regardless of the genotype. Methylated DNA was found in DNA from various adult tissues of dogs with clinical RD. Conclusions The mechanism of action of the allelic variation in the canine Cox-2 promoter most likely involves variation in the extent of epigenetic downregulation of this gene. This epigenetic downregulation must have occurred early in development because methylated Cox-2 promoter DNA sequences are found in various adult tissues. PMID:24708682

2014-01-01

145

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

146

Discovery of a Potent And Selective Aurora Kinase Inhibitor  

SciTech Connect

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

Oslob, J.D.; Romanowski, M.J.; Allen, D.A.; Baskaran, S.; Bui, M.; Elling, R.A.; Flanagan, W.M.; Fung, A.D.; Hanan, E.J.; Harris, S.; Heumann, S.A.; Hoch, U.; Jacobs, J.W.; Lam, J.; Lawrence, C.E.; McDowell, R.S.; Nannini, M.A.; Shen, W.; Silverman, J.A.; Sopko, M.M.; Tangonan, B.T.

2009-05-21

147

Identification of novel, selective and potent Chk2 inhibitors.  

PubMed

A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K(i) values as low as 11 nM for Chk2. Computer modeling studies were employed to comprehend the mechanism of action and SAR of these compounds. PMID:17035018

Larson, Gary; Yan, Shunqi; Chen, Huanming; Rong, Frank; Hong, Zhi; Wu, Jim Zhen

2007-01-01

148

Endomicroscopic Imaging of COX-2 Activity in Murine Sporadic and Colitis-Associated Colorectal Cancer  

PubMed Central

Although several studies propose a chemopreventive effect of aspirin for colorectal cancer (CRC) development, the general use of aspirin cannot be recommended due to its adverse side effects. As the protective effect of aspirin has been associated with an increased expression of COX-2, molecular imaging of COX-2, for instance, during confocal endomicroscopy could enable the identification of patients who would possibly benefit from aspirin treatment. In this pilot trial, we used a COX-2-specific fluorescent probe for detection of colitis-associated and sporadic CRC in mice using confocal microscopy. Following the injection of the COX-2 probe into tumor-bearing APCmin mice or mice exposed to the AOM + DSS model of colitis-associated cancer, the tumor-specific upregulation of COX-2 could be validated with in vivo fluorescence imaging. Subsequent confocal imaging of tumor tissue showed an increased number of COX-2 expressing cells when compared to the normal mucosa of healthy controls. COX-2-expression was detectable with subcellular resolution in tumor cells and infiltrating stroma cells. These findings pose a proof of concept and suggest the use of CLE for the detection of COX-2 expression during colorectal cancer surveillance endoscopy. This could improve early detection and stratification of chemoprevention in patients with CRC. PMID:23401648

Foersch, Sebastian; Neufert, Clemens; Neurath, Markus F.; Waldner, Maximilian J.

2013-01-01

149

Endomicroscopic Imaging of COX-2 Activity in Murine Sporadic and Colitis-Associated Colorectal Cancer.  

PubMed

Although several studies propose a chemopreventive effect of aspirin for colorectal cancer (CRC) development, the general use of aspirin cannot be recommended due to its adverse side effects. As the protective effect of aspirin has been associated with an increased expression of COX-2, molecular imaging of COX-2, for instance, during confocal endomicroscopy could enable the identification of patients who would possibly benefit from aspirin treatment. In this pilot trial, we used a COX-2-specific fluorescent probe for detection of colitis-associated and sporadic CRC in mice using confocal microscopy. Following the injection of the COX-2 probe into tumor-bearing APCmin mice or mice exposed to the AOM + DSS model of colitis-associated cancer, the tumor-specific upregulation of COX-2 could be validated with in vivo fluorescence imaging. Subsequent confocal imaging of tumor tissue showed an increased number of COX-2 expressing cells when compared to the normal mucosa of healthy controls. COX-2-expression was detectable with subcellular resolution in tumor cells and infiltrating stroma cells. These findings pose a proof of concept and suggest the use of CLE for the detection of COX-2 expression during colorectal cancer surveillance endoscopy. This could improve early detection and stratification of chemoprevention in patients with CRC. PMID:23401648

Foersch, Sebastian; Neufert, Clemens; Neurath, Markus F; Waldner, Maximilian J

2013-01-01

150

miR-143 Decreases COX-2 mRNA Stability and Expression in Pancreatic Cancer Cells  

PubMed Central

Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3?-untranslated region (3?-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E2 (PGE2) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 ?M of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26 fold in BxPC-3 and 182 ± 7 and 136 ± 9 fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3 fold in BxPC-3 and 2.5 ± 0.2 fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE2 levels decreased by 39.3 ± 5.0 % in BxPC-3 and 48.0 ± 3.0 % in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE2, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression. PMID:23973710

Pham, Hung; Rodriguez, C. Ekaterina; Donald, Graham. W.; Hertzer, Kathleen M.; Jung, Xiaoman S.; Chang, Hui-Hua; Moro, Aune; Reber, Howard A.; Hines, O. Joe; Eibl, Guido

2013-01-01

151

Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid.  

PubMed

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH(2) to PGE(2) and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC(50) of 1.1 ?M) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10 ?M concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors. PMID:23218602

Lee, Kijae; Pham, Van Chung; Choi, Min Ji; Kim, Kyung Ju; Lee, Kyung-Tae; Han, Seong-Gu; Yu, Yeon Gyu; Lee, Jae Yeol

2013-01-01

152

An update on nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors  

Microsoft Academic Search

Selective inhibitors of the cyclooxygenase-2 enzyme were developed to treat pain and inflammation while reducing the risk\\u000a of the serious gastrointestinal side effects seen with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). The results\\u000a of several clinical trials have demonstrated an apparent increased risk of serious cardiovascular events in patients taking\\u000a the COX-2-selective inhibitors. Although the risk was observed originally with trials

Gary W. Williams

2005-01-01

153

Running title : Inhibitors of CYP2J2 SELECTIVE, COMPETITIVE AND MECHANISM-BASED INHIBITORS OF  

E-print Network

efficiently inhibits the other main vascular CYPs, such as CYP2B6, 2C8, 2C9 and 3A4; however, it could to code for CYPs [2]. The main CYPs implicated in drug metabolism, such as CYP3A4, CYP2C9 or CYP2D61 Running title : Inhibitors of CYP2J2 SELECTIVE, COMPETITIVE AND MECHANISM-BASED INHIBITORS

Paris-Sud XI, Université de

154

Peripheral administration of morphine attenuates postincisional pain by regulating macrophage polarization through COX-2-dependent pathway  

PubMed Central

Background Macrophage infiltration to inflammatory sites promotes wound repair and may be involved in pain hypersensitivity after surgical incision. We recently reported that the development of hyperalgesia during chronic inflammation is regulated by macrophage polarity, often referred to as proinflammatory (M1) or anti-inflammatory (M2) macrophages. Although opioids such as morphine are known to alter the inflammatory milieu of incisional wounds through interactions with immunocytes, the macrophage-mediated effects of morphine on the development of postincisional pain have not been well investigated. In this study, we examined how morphine alters pain hypersensitivity through phenotypic shifts in local macrophages during the course of incision-induced inflammation. Results Local administration of morphine in the early phase, but not in the late phase alleviated mechanical hyperalgesia, and this effect was reversed by clodronate-induced peripheral depletion of local macrophages. At the morphine-injected incisional sites, the number of pro-inflammatory F4/80+iNOS+M1 macrophages was decreased during the course of pain development whereas increased infiltration of wound healing F4/80+CD206+M2 macrophages was observed during the early phase. Morphine increased the gene expression of endogenous opioid, proenkephalin, and decreased the pronociceptive cytokine, interleukin-1?. Heme oxygenase (HO)-1 promotes the differentiation of macrophages to the M2 phenotype. An inhibitor of HO-1, tin protoporphyrin reversed morphine-induced analgesic effects and the changes in macrophage phenotype. However, local expression levels of HO-1 were not altered by morphine. Conversely, cyclooxygenase (COX)-2, primarily produced from peripheral macrophages in acute inflammation states, was up-regulated in the early phase at morphine-injected sites. In addition, the analgesic effects and a phenotype switching of infiltrated macrophages by morphine was reversed by local administration of a COX inhibitor, indomethacin. Conclusions Local administration of morphine alleviated the development of postincisional pain, possibly by altering macrophage polarity at the incisional sites. A morphine-induced shift in macrophage phenotype may be mediated by a COX-2-dependent mechanism. Therefore, ?-opioid receptor signaling in macrophages may be a potential therapeutic target during the early phase of postincisional pain development. PMID:24928142

2014-01-01

155

Ex vivo assay to determine the cyclooxygenase selectivity of non-steroidal anti-inflammatory drugs  

PubMed Central

In this study we describe experiments to establish ex vivo the selectivity of non-steroidal anti-inflammatory drugs (NSAIDs) given in vivo.Anaesthetised (Inactin, 120?mg?kg?1) male Wistar rats (220–250?g) received an i.v. dose of one of the following compounds (dose mg?kg?1): aspirin (20), diclofenac (3), L-745,337 (30), nimesulide (15), salicylate (20), sulindac (10). Blood samples were taken before and up to 6?h after dosing and the plasma obtained from it was tested for its ability to inhibit prostanoid formation in IL-1?-treated A549 cells (COX-2 system) and human washed platelets (COX-1 system). For control the same compounds were also added directly to the assay systems.All drugs, except sodium salicylate, inhibited COX-1 and COX-2 when added directly to the test systems. Plasma from aspirin-treated rats was without effect on either COX-1 or COX-2, consistent with the rapid in vivo metabolism to salicylate. Conversely, plasma from sulindac-treated rats inhibited COX-1 and COX-2 with potencies according with in vivo metabolism to sulindac sulphide. Diclofenac was COX-1/2 non-selective when tested in vitro, but a slightly preferential inhibitor of COX-2 when tested ex vivo. Nimesulide was confirmed as preferential inhibitor of COX-2 both in vitro and ex vivo. L-745,337 was a selective COX-2 inhibitor when tested in vitro or ex vivo.In conclusion, our experiments show clearly (a) NSAIDs inactivation, (b) activation of pro-drugs, and (c) NSAIDs selectivity. Our assay provides useful information about the selectivity of NSAIDs that could be extended by the analysis of plasma samples taken from humans similarly treated with test drugs. PMID:10372826

Giuliano, Francesco; Warner, Timothy D

1999-01-01

156

Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury.  

PubMed

In a previous study, we found that intracerebral administration of excitotoxin (RS)-(tetrazole-5yl) glycine caused increased neural damage in the brain in an endothelial COX-2 deleted mouse line (Tie2Cre COX-2(flox/flox) ). In this study, we investigated whether prostacyclin might mediate this endothelial COX-2-dependent neuroprotection. Administration of excitotoxin into the striatum induced the production of prostacyclin (PGI2) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI2 synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI2 agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI2 synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI2 reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI2 mediated neuroprotection. These results reveal that PGI2 mediates endothelial COX-2 dependent neuroprotection. PMID:24971026

An, Ying; Belevych, Natalya; Wang, Yufen; Zhang, Hao; Nasse, Jason S; Herschman, Harvey; Chen, Qun; Tarr, Andrew; Liu, Xiaoyu; Quan, Ning

2014-01-01

157

Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury  

PubMed Central

In a previous study, we found that intracerebral administration of excitotoxin (RS)-(tetrazole-5yl) glycine caused increased neural damage in the brain in an endothelial COX-2 deleted mouse line (Tie2Cre COX-2flox/flox). In this study, we investigated whether prostacyclin might mediate this endothelial COX-2-dependent neuroprotection. Administration of excitotoxin into the striatum induced the production of prostacyclin (PGI2) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI2 synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI2 agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI2 synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI2 reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI2 mediated neuroprotection. These results reveal that PGI2 mediates endothelial COX-2 dependent neuroprotection. PMID:24971026

An, Ying; Belevych, Natalya; Wang, Yufen; Zhang, Hao; Nasse, Jason S; Herschman, Harvey; Chen, Qun; Tarr, Andrew; Liu, Xiaoyu; Quan, Ning

2014-01-01

158

Citral, a component of lemongrass oil, activates PPAR? and ? and suppresses COX-2 expression.  

PubMed

Lemongrass is a widely used herb as a food flavoring, as a perfume, and for its analgesic and anti-inflammatory purposes; however, the molecular mechanisms of these effects have not been elucidated. Previously, we identified carvacrol from the essential oil of thyme as a suppressor of cyclooxygenase (COX)-2, a key enzyme for prostaglandin synthesis, and also an activator of peroxisome proliferator-activated receptor (PPAR), a molecular target for "lifestyle-related" diseases. In this study, we evaluated the essential oil of lemongrass using our established assays for COX-2 and PPARs. We found that COX-2 promoter activity was suppressed by lemongrass oil in cell-based transfection assays, and we identified citral as a major component in the suppression of COX-2 expression and as an activator of PPAR? and ?. PPAR?-dependent suppression of COX-2 promoter activity was observed in response to citral treatment. In human macrophage-like U937 cells, citral suppressed both LPS-induced COX-2 mRNA and protein expression, dose-dependently. Moreover, citral induced the mRNA expression of the PPAR?-responsive carnitine palmitoyltransferase 1 gene and the PPAR?-responsive fatty acid binding protein 4 gene, suggesting that citral activates PPAR? and ?, and regulates COX-2 expression. These results are important for understanding the anti-inflammatory and anti-lifestyle-related disease properties of lemongrass. PMID:20656057

Katsukawa, Michiko; Nakata, Rieko; Takizawa, Yoshie; Hori, Kazuyuki; Takahashi, Saori; Inoue, Hiroyasu

2010-11-01

159

Carvacrol, a component of thyme oil, activates PPAR? and ? and suppresses COX-2 expression[S  

PubMed Central

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, plays a key role in inflammation and circulatory homeostasis. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors belonging to the nuclear receptor superfamily and are involved in the control of COX-2 expression, and vice versa. Here, we show that COX-2 promoter activity was suppressed by essential oils derived from thyme, clove, rose, eucalyptus, fennel, and bergamot in cell-based transfection assays using bovine arterial endothelial cells. Moreover, from thyme oil, we identified carvacrol as a major component of the suppressor of COX-2 expression and an activator of PPAR? and ?. PPAR?-dependent suppression of COX-2 promoter activity was observed in response to carvacrol treatment. In human macrophage-like U937 cells, carvacrol suppressed lipopolysaccharide-induced COX-2 mRNA and protein expression, suggesting that carvacrol regulates COX-2 expression through its agonistic effect on PPAR?. These results may be important in understanding the antiinflammatory and antilifestyle-related disease properties of carvacrol. PMID:19578162

Hotta, Mariko; Nakata, Rieko; Katsukawa, Michiko; Hori, Kazuyuki; Takahashi, Saori; Inoue, Hiroyasu

2010-01-01

160

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus  

Microsoft Academic Search

During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C

Rudolf K. F. Beran; Ruchi Sharma; Amoreena C. Corsa; Yang Tian; Justin Golde; Greta Lundgaard; William E. Delaney; Weidong Zhong; Andrew E. Greenstein

2012-01-01

161

Selective serotonin reuptake inhibitor-induced urinary incontinence  

Microsoft Academic Search

PURPOSE: Irrespective of its cause, urinary incontinence is a medical condition seriously affecting quality of life and is increasingly recognized. In this study, we examined the association between the use of selective serotonin reuptake inhibitors (SSRIs) and urinary incontinence. METHODS: A retrospective follow-up study among starters with an SSRI was performed to estimate the relative and absolute risk for urinary

K. L. L. Movig; H. G. M. Leufkens; S. V. Belitser; A. W. Lenderink; A. C. G. Egberts

2002-01-01

162

Naringin inhibits growth and induces apoptosis by a mechanism dependent on reduced activation of NF??B/COX?2?caspase-1 pathway in HeLa cervical cancer cells.  

PubMed

Naringin (NRG), a bioflavonoid found in citrus fruit extracts, has been pharmacologically evaluated as a potential anticancer agent. This study confirmed a novel mechanism of the anticancer effects of NRG in the human cervical cancer HeLa cell line (HeLa cells). Exposure of HeLa cells to NRG resulted in growth inhibition, as evidenced by a decrease in cell viability. In addition, NRG treatment induced apoptosis, as indicated by the increased apoptotic percentage and the cleaved caspase-3 expression. Importantly, exposure of the cells to NRG attenuated the expression levels of phosphorylated (p) nuclear factor ?B (NF-?B) p65 subunit, cyclooxygenase-2 (COX-2) and cysteinyl aspartate proteinase-1 (caspase-1). Treatment with PDTC (an inhibitor of NF-?B) or NS-398 (an inhibitor of COX-2) or SC-3069 (an inhibitor of caspase-1) markedly induced growth inhibition and apoptosis. Treatment with PDTC or NS-398 also reduced caspase-1 expression. Interestingly, PDTC treatment blocked the expression of COX-2 and NS-398 reduced the p-NF-?B p65 expression. Taken together, this study provides novel evidence that NRG induces growth inhibition and apoptosis by inhibiting the NF-?B/COX-2-caspase-1 pathway and that a positive interaction between NF-?B and COX-2 pathway contributes to the growth and antiapoptotic effect in HeLa cells. PMID:25174821

Zeng, Lan; Zhen, Yulan; Chen, Yiming; Zou, Lin; Zhang, Ying; Hu, Fen; Feng, Jianqiang; Shen, Jianhua; Wei, Bing

2014-11-01

163

Non-steroidal anti-inflammatory drugs, Cyclooxygenase-2 inhibitors and paracetamol use in Queensland and in the whole of Australia  

PubMed Central

Background Cross national drug utilization studies can provide information about different influences on physician prescribing. This is important for medicines with issues around safety and quality of use, like non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors. To enable comparison of prescription medicine use across different jurisdictions with a range of population sizes, data first need to be compared within Australia to understand whether use in a smaller sub-population may be considered as representative of the total use within Australia. The aim of this study was to compare the utilization of non selective NSAID, COX-2 inhibitors and paracetamol between Queensland and Australia. Method Dispensing data were obtained for concession beneficiaries for Australia for ns-NSAIDs, COX-2 inhibitors and paracetamol subsidized by the PBS over the period 1997–2003. The same data were purchased for Queensland. Data were converted to Defined Daily Dose (DDD)/1000 beneficiaries/day (World Health Organization anatomical therapeutic chemical classification, 2005). Results Total NSAID and paracetamol consumption were similar in Australia and Queensland. Ns-NSAID use decreased sharply with the introduction of COX-2 inhibitors (from approximately 80 to 40 DDD/1000 beneficiaries/day). Paracetamol was constant (approximately 45 DDD/1000 beneficiaries/day). COX-2 inhibitors consumption was initially higher in Queensland than in the whole of Australia. Conclusion Despite initial divergence in celecoxib use between Queensland and Australia, the use of ns-NSAIDs, COX-2 inhibitors and paracetamol overall, in concession beneficiaries, was comparable in Australia and Queensland. PMID:18816393

Barozzi, Nadia; Tett, Susan E

2008-01-01

164

Comparison between two cyclooxygenase inhibitors in an experimental dry eye model in albino rabbits.  

PubMed

The purpose of this study was to compare the topical anti-inflammatory effects of the nonselective cyclooxygenase (COX) inhibitor, ketorolac, with the selective COX-2 inhibitor, nimesulide, in an animal model of dry eye in albino rabbits. All animals were examined by the Schirmer test, tear break-up time (TBUT) and fluorescein corneal staining test. Dry eye model showed significant reduction in tear volume, TBUT, corneal staining and histopathological signs of dryness and inflammation. On treating dry eye model with nimesulide 0.1% eye drops and ketorolac 0.5% eye drops, there were improvements in Schirmer test values, TBUT and fluorescein corneal staining and histopathologically reduced inflammatory reaction, with signs of healing and regeneration. Both nimesulide and ketorolac ameliorate atropine sulphate induced dry eye in albino rabbits. The use of selective COX-2 inhibitor, nimesulide, is preferred to avoid local and systemic side effects which may occur with the use of the nonselective COX inhibitor, ketorolac. PMID:18515226

El-Shazly, Amany Hassan Mohamed; El-Gohary, Amal Ahmad; El-Shazly, Laila Hassan Mohamed; El-Hossary, Ghada Ghanem

2008-06-01

165

Cyclooxygenase-2 inhibitors in colorectal cancer prevention: point.  

PubMed

The limited success of current treatments for most advanced common malignancies highlights the importance of cancer prevention. Clinical trials on cyclooxygenase (COX) inhibitor drugs showed the potential of chemoprevention as a strategy for reducing cancer incidence, although not without associated side effects. The attractiveness of these drugs partly stems from an ability to engage multiple mechanisms of action by their potential to influence multiple components of the carcinogenesis pathway, from initiation to progression. There are two isoforms of the COX enzymes. COX-1 is constitutively expressed in normal tissues and serves as a "housekeeper" of mucosal integrity, whereas COX-2 is an immediate early response gene that is highly inducible by neoplastic and inflammatory stimuli. COX-2 is significantly overexpressed in colorectal neoplasms, making it an attractive therapeutic target. The drug market has been revolutionized by the development of preparations targeted selectively against COX-2, and a proof of concept has been achieved. Chemoprevention of colorectal cancer is already possible with celecoxib, but it is still not the ultimate drug of choice especially because of the cardiovascular risk associated with COX-2 inhibitors. Better patient selection and more effective and safer drugs are needed. Celecoxib is probably best used in a subset of individuals at moderate to high colorectal cancer risk and low risk of cardiovascular disease. PMID:18708371

Arber, Nadir

2008-08-01

166

Cyclooxygenase-2 inhibitors: promise or peril?  

PubMed Central

The discovery of two isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, and the development of COX-2-specific inhibitors as anti-inflammatories and analgesics have offered great promise that the therapeutic benefits of NSAIDs could be optimized through inhibition of COX-2, while minimizing their adverse side effect profile associated with inhibition of COX-1. While COX-2 specific inhibitors have proven to be efficacious in a variety of inflammatory conditions, exposure of large numbers of patients to these drugs in postmarketing studies have uncovered potential safety concerns that raise questions about the benefit/risk ratio of COX-2-specific NSAIDs compared to conventional NSAIDs. This article reviews the efficacy and safety profiles of COX-2-specific inhibitors, comparing them with conventional NSDAIDs. PMID:12467519

Mengle-Gaw, Laurel J; Schwartz, Benjamin D

2002-01-01

167

COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1  

EPA Science Inventory

Cyclooxygenase-2 (COX-2) plays an important role in the inflammatory response induced by physiologic and stress stimuli. Exposure to diesel exhaust particulate matter (DEP) has been shown to induce pulmonary inflammation and exacerbate asthma and chronic obstructive pulmonary dis...

168

NDRG2 Controls COX-2/PGE2-Mediated Breast Cancer Cell Migration and Invasion  

PubMed Central

N-myc downstream-regulated gene 2 (NDRG2), which is known to have tumor suppressor functions, is frequently down-regulated in breast cancers and potentially involved in preventing the migration and invasion of malignant tumor cells. In the present study, we examined the inhibitory effects of NDRG2 overexpression, specifically focusing on the role of cyclooxygenase-2 (COX-2) in the migration of breast cancer cells. NDRG2 overexpression in MDA-MB-231 cells inhibited the expression of the COX-2 mRNA and protein, the transcriptional activity of COX-2, and prostaglandin E2 (PGE2) production, which were induced by a treatment with phorbol-12-myristate-13-acetate (PMA). Nuclear transcription factor-?B (NF-?B) signaling attenuated by NDRG2 expression resulted in a decrease in PMA-induced COX-2 expression. Interestingly, the inhibition of COX-2 strongly suppressed PMA-stimulated migration and invasion in MDA-MB-231-NDRG2 cells. Moreover, siRNA-mediated knockdown of NDRG2 in MCF7 cells increased the COX-2 mRNA and protein expression levels and the PMA-induced COX-2 expression levels. Consistent with these results, the migration and invasion of MCF7 cells treated with NDRG2 siRNA were significantly enhanced following treatment with PMA. Taken together, our data show that the inhibition of NF-?B signaling by NDRG2 expression is able to suppress cell migration and invasion through the down-regulation of COX-2 expression. PMID:25256221

Kim, Myung-Jin; Kim, Hak-Su; Lee, Soo-Hwan; Yang, Young; Lee, Myeong-Sok; Lim, Jong-Seok

2014-01-01

169

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

170

Sumoylation of LAP1 is involved in the HDAC4-mediated repression of COX2 transcription  

Microsoft Academic Search

CEBPB, one of the CEBP family members, is a crucial regulator of gene expression during innate immunity, inflammatory responses and adipogenesis. In this study, the EGF-induced increase of CEBPB mRNA is shown to be coincident with the decrease of COX-2 mRNA. We identified that all of the individual CEBPB isoforms, LAP1, LAP2 and LIP, attenuate EGF-induced COX-2 promoter activity. Although

Wen-Ling Wang; Yi-Chao Lee; Wen-Ming Yang; Wen-Chang Chang; Ju-Ming Wang

2008-01-01

171

COX-2 mediated induction of endothelium-independent contraction to bradykinin in endotoxin-treated porcine coronary artery.  

PubMed

This study examined the vascular effects of bradykinin in health and vascular inflammation comparing responses of isolated pig coronary arteries in the absence and presence of endotoxins. Bradykinin induced contractions in lipopolysaccharide-treated, but not untreated, arterial rings without endothelium. The B2-receptor antagonist HOE140, but not the B1-receptor inhibitor SSR240612, blocked these endothelium-independent contractions in response to bradykinin. The bradykinin-induced contractions were blocked by indomethacin, celecoxib, and terbogrel but not valeryl salicylate, AH6809, AL 8810, or RO1138452. They were attenuated by N-(p-amylcinnamoyl) anthranilic acid, and by diethyldithiocarbamate plus tiron but not by L-NAME. Quantitative reverse-transcription polymerase chain reaction revealed significant upregulations of messenger RNA expressions of B1 receptors, COX-2, and thromboxane A synthase 1 (TBXAS1) following lipopolysaccharide incubation but not of B2 receptors or COX-1. The present data demonstrate that bradykinin induces contractions mediated by the COX-2 pathway in endotoxin-treated pig coronary arteries. These results support differential roles of bradykinin in health and disease. PMID:25192543

More, Amar S; Kim, Hye Min; Zhao, Ru; Khang, Gilson; Hildebrandt, Tobias; Bernlöhr, Christian; Doods, Henri; Lee, Dongwon; Lee, Seung Hee; Vanhoutte, Paul M; Wu, Dongmei

2014-09-01

172

Expression of COX-2 and bcl-2 in oral lichen planus lesions and lichenoid reactions  

PubMed Central

Oral lichen planus and lichenoid reactions are autoimmune type inflammatory conditions of the oral mucosa with similar clinical and histological characteristics. Recent data suggest that oral lichenoid reactions (OLR) present a greater percentage of malignant transformation than oral lichen planus (OLP). Objective To compare the expression of bcl-2 and COX-2 in OLP and OLR. Methods The study population consisted of 65 cases; 34 cases diagnosed as OLR and 31 as OLP. A retrospective study was done, and bcl-2 and COX-2 expression was semiquantitatively analysed. Results Fifty-three per cent (18/34) of the ORL samples tested positive for COX-2, whereas in the OLP group, 81% of the samples (25/31) immunostained positive for COX-2. The Fisher’s exact test for the expression of COX-2 revealed that there are significant differences between the two groups, P = 0.035. With respect to the expression of the bcl-2 protein, 76% (26/34) of the samples were positive in OLR, while 97% (30/31) were positive in the group with OLP. The Fisher’s exact test for the expression of bcl-2 revealed that there are significant statistical differences between the two groups, P = 0.028. Conclusions The expression of bcl-2 and COX-2 was more commonly expressed in OLP when compared with OLR. PMID:24834112

Arreaza, Alven J; Rivera, Helen; Correnti, Maria

2014-01-01

173

Discovery of novel and selective SIRT6 inhibitors.  

PubMed

SIRT6 is an NAD(+)-dependent deacetylase with a role in the transcriptional control of metabolism and aging but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here we report on the identification of the first selective SIRT6 inhibitors by in silico screening. The most promising leads show micromolar IC50s, have significant selectivity for SIRT6 versus SIRT1 and SIRT2, and are active in cells, as shown by increased acetylation at SIRT6 target lysines on histone 3, reduced TNF-? secretion, GLUT-1 upregulation, and increased glucose uptake. Taken together, these results show the value of these compounds as starting leads for the development of new SIRT6-targeting therapeutic agents. PMID:24785705

Parenti, Marco Daniele; Grozio, Alessia; Bauer, Inga; Galeno, Lauretta; Damonte, Patrizia; Millo, Enrico; Sociali, Giovanna; Franceschi, Claudio; Ballestrero, Alberto; Bruzzone, Santina; Del Rio, Alberto; Nencioni, Alessio

2014-06-12

174

Indolocarbazoles: potent, selective inhibitors of human cytomegalovirus replication  

Microsoft Academic Search

In our search for new, safer anti-HCMV agents, we discovered that the natural product Arcyriaflavin A (1a) was a potent inhibitor of HCMV replication in cell culture. A series of analogues (symmetrical indolocarbazoles) was synthesised to investigate structure–activity relationships in this series against a range of herpes viruses (HCMV, VZV, HSV1, and 2). This identified a number of novel, selective

Martin J. Slater; Stuart Cockerill; Robert Baxter; Robert W. Bonser; Kam Gohil; Clare Gowrie; J. Edward Robinson; Edward Littler; Nigel Parry; Roger Randall; Wendy Snowden

1999-01-01

175

ERK1/2/COX-2/PGE2 signaling pathway mediates GPR91-dependent VEGF release in streptozotocin-induced diabetes  

PubMed Central

Purpose Retinal vascular dysfunction caused by vascular endothelial growth factor (VEGF) is the major pathological change that occurs in diabetic retinopathy (DR). It has recently been demonstrated that G protein-coupled receptor 91 (GPR91) plays a major role in both vasculature development and retinal angiogenesis. In this study, we examined the signaling pathways involved in GPR91-dependent VEGF release during the early stages of retinal vascular change in streptozotocin-induced diabetes. Methods Diabetic rats were assigned randomly to receive intravitreal injections of shRNA lentiviral particles targeting GPR91 (LV.shGPR91) or control particles (LV.shScrambled). Accumulation of succinate was assessed by gas chromatography-mass spectrometry (GC-MS). At 14 weeks, the ultrastructure and function of the retinal vessels of diabetic retinas with or without shRNA treatment were assessed using hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), and Evans blue dye permeability. The expression of GPR91, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and cyclooxygenase-2 (COX-2) were measured using immunofluorescence and western blotting. COX-2 and VEGF mRNA were determined by quantitative RT–PCR. Prostaglandin E2 (PGE2) and VEGF secretion were detected using an enzyme-linked immunosorbent assay. Results Succinate exhibited abundant accumulation in diabetic rat retinas. The retinal telangiectatic vessels, basement membrane thickness, and Evans blue dye permeability were attenuated by treatment with GPR91 shRNA. In diabetic rats, knockdown of GPR91 inhibited the activities of ERK1/2 and COX-2 as well as the expression of PGE2 and VEGF. Meanwhile, COX-2, PGE2, and VEGF expression was inhibited by ERK1/2 inhibitor U0126 and COX-2 inhibitor NS-398. Conclusions Our data suggest that hyperglycemia causes succinate accumulation and GPR91 activity in retinal ganglion cells, which mediate VEGF-induced retinal vascular change via the ERK1/2/COX-2/PGE2 pathway. This study highlights the signaling pathway as a potential target for intervention in DR. PMID:25324681

Li, Tingting; Hu, Jianyan; Du, Shanshan; Chen, Yongdong; Wang, Shuai

2014-01-01

176

Neuronal COX-2 expression in human myenteric plexus in active inflammatory bowel disease  

PubMed Central

BACKGROUND—Inflammatory bowel disease (IBD) is associated with changes in colonic motility which may contribute to the pain and diarrhoea associated with exacerbations of this disease. These changes may be mediated by prostaglandins which are increased in this condition. Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) has been found in active IBD although its cellular distribution remains uncertain.?AIMS—To evaluate the cellular distribution of COX-2 in active IBD.?PATIENTS AND METHODS—Using reverse transcription-polymerase chain reaction, in situ hybridisation, and immunohistochemistry, COX-2 expression was evaluated in 12 colectomy specimens from patients with active ulcerative colitis (UC), and six specimens from patients with Crohn's colitis that had failed medical therapy. Histologically normal colon was obtained from 12 patients having resection for colorectal neoplasia and evaluated as above, acting as control specimens.?RESULTS—All specimens expressed COX-2 mRNA, with some 6-8-fold increase in inflamed tissues on densitometric analysis (both UC and Crohn's) compared with controls. In situ hybridisation localised this mRNA to myenteric neural cells, surrounding smooth muscle cells, and inflammatory cells of the lamina propria in the IBD specimens, with some weaker labelling seen in the epithelium. No COX-2 labelling was seen in normal tissues. Immunohistochemistry confirmed these sites of COX-2 expression in all inflamed specimens, with absence of immunoreactivity in control tissues.?CONCLUSIONS—These findings provide the first evidence of COX-2 expression in neural cells of the myenteric plexus in active IBD which, via increased prostaglandin synthesis at this site, may contribute to the dysmotilty seen in this condition.???Keywords: inducible cyclo-oxygenase; prostaglandins; myenteric plexus; inflammatory bowel disease PMID:11247889

Roberts, P; Morgan, K; Miller, R; Hunter, J; Middleton, S

2001-01-01

177

A highly selective telomerase inhibitor limiting human cancer cell proliferation  

PubMed Central

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities. PMID:11742973

Damm, Klaus; Hemmann, Ulrike; Garin-Chesa, Pilar; Hauel, Norbert; Kauffmann, Iris; Priepke, Henning; Niestroj, Claudia; Daiber, Christine; Enenkel, Barbara; Guilliard, Bernd; Lauritsch, Ines; Muller, Elfriede; Pascolo, Emanuelle; Sauter, Gabriele; Pantic, Milena; Martens, Uwe M.; Wenz, Christian; Lingner, Joachim; Kraut, Norbert; Rettig, Wolfgang J.; Schnapp, Andreas

2001-01-01

178

A highly selective telomerase inhibitor limiting human cancer cell proliferation.  

PubMed

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities. PMID:11742973

Damm, K; Hemmann, U; Garin-Chesa, P; Hauel, N; Kauffmann, I; Priepke, H; Niestroj, C; Daiber, C; Enenkel, B; Guilliard, B; Lauritsch, I; Müller, E; Pascolo, E; Sauter, G; Pantic, M; Martens, U M; Wenz, C; Lingner, J; Kraut, N; Rettig, W J; Schnapp, A

2001-12-17

179

Inhibition of phorbol ester-induced COX-2 expression by some edible African plants.  

PubMed

Cancer bush (CB, Sutherlandia frutescens), Devil's claw (DEV, Harpagophytum procumbens), Rooibos tea (RT, Aspalathus linearis), and Bambara groundnut (BB, Vignea subterranean) have been used to treat some malignancies and inflammatory disorders in Africa. However, biochemical basis for chemopreventive effects of these medicinal plants remains unclear. An abnormally elevated expression of cyclooxygenase-2 (COX-2) has been implicated in pathogenesis and progression of carcinogenesis. In the present study, we found that the methanol extracts of CB, DEV, RT, and BB inhibited, to a different extent, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 expression in human breast epithelial (MCF10A) cells and in mouse skin in vivo. To determine the molecular mechanism of COX-2 inhibition by the above medicinal plants, we examined their effects on activation of NF-kappaB which is one of the major transcription factors responsible for regulating COX-2 expression. Methanol extracts of both CB and BB inhibited the DNA binding of NF-kappaB activated by TPA in MCF10A cells in a dose-dependent manner. Based on above findings, CB and BB are likely to inhibit TPA-induced COX-2 expression through suppression of DNA binding of NF-kappaB, which may contribute to the chemopreventive or chemoprotective activity of these African plants. PMID:15630188

Na, Hye-Kyung; Mossanda, Kensese S; Lee, Ji-Yoon; Surh, Young-Joon

2004-01-01

180

Identification of an Adamantyl Azaquinolone JNK Selective Inhibitor  

PubMed Central

3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure–activity relationship of the azaquinolone analogues leading to 4 is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-? challenge models. PMID:24900545

2012-01-01

181

Identification of novel SIRT2-selective inhibitors using a click chemistry approach.  

PubMed

A series of 114 SIRT inhibitor candidates was assembled using 'click chemistry', by reacting two alkynes bearing 2-anilinobenzamide pharmacophore with 57 azide building blocks in the presence of Cu(I) catalyst. Screening identified two SIRT2-selective inhibitors, which were more SIRT2-selective than AGK2, a known SIRT2 inhibitor. These findings will be useful for further development of SIRT2-selective inhibitors. PMID:24675380

Tatum, Prima R; Sawada, Hideyuki; Ota, Yosuke; Itoh, Yukihiro; Zhan, Peng; Ieda, Naoya; Nakagawa, Hidehiko; Miyata, Naoki; Suzuki, Takayoshi

2014-04-15

182

Myricetin blocks lipoteichoic acid-induced COX-2 expression in human gingival fibroblasts.  

PubMed

Periodontitis is an infectious disease caused by microorganisms present in dental bacterial plaque. Lipoteichoic acid (LTA) is a component of the external membrane of Gram-positive bacteria. It causes septic shock. Ingested flavonoids have been reported to directly affect the regulation of cyclooxygenase-2 (COX-2) expression induced by bacterial toxins. In this study, we examined the effects of four flavonoids (luteolin, fisetin, morin and myricetin) on the activation of ERK1/2, p38 and AKT, and on the synthesis of COX-2 in human gingival fibroblasts treated with LTA from Streptococcus sanguinis. We found that luteolin and myricetin blocked AKT and p38 activation and that myricetin blocked LTA-induced COX-2 expression. The results of our study are important for elucidating the mechanism of action of flavonoid regulation of inflammatory responses. PMID:24569980

Gutiérrez-Venegas, Gloria; Luna, Oscar Alonso; Arreguín-Cano, Juan Antonio; Hernández-Bermúdez, Cristina

2014-03-01

183

Postpartum mammary gland involution drives DCIS progression through collagen and COX-2  

PubMed Central

Prognosis of young women’s breast cancer is influenced by reproductive history. Women diagnosed within five years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors characterized by abundant fibrillar collagen, high COX-2 expression, and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2-dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high-risk for postpartum breast cancer would benefit from treatment with NSAIDs during postpartum involution. PMID:21822285

Lyons, Traci R; O’Brien, Jenean; Borges, Virginia; Conklin, Matthew W; Keely, Patricia J; Eliceiri, Kevin W; Marusyk, Andriy; Tan, Aik-Choon; Schedin, Pepper

2014-01-01

184

COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models.  

PubMed

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies. PMID:24964992

Xu, Lihong; Stevens, Janine; Hilton, Mary Beth; Seaman, Steven; Conrads, Thomas P; Veenstra, Timothy D; Logsdon, Daniel; Morris, Holly; Swing, Deborah A; Patel, Nimit L; Kalen, Joseph; Haines, Diana C; Zudaire, Enrique; St Croix, Brad

2014-06-25

185

Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect  

SciTech Connect

Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effect on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-?B dependent. Inhibition of NF-?B reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines. - Highlights: ? Cyclopamine alone but not jervine induces apoptosis in human erythroleukemia cells. ? Cyclopamine and jervine induce COX-2 overexpression. ? COX-2 overexpression is implicated in resistance to cyclopamine-induced apoptosis. ? Apoptotic potential of jervine is restrained by NF-?B pathway activation. ? PKC is involved in cyclopamine-induced apoptosis and COX-2 overexpression.

Ghezali, Lamia; Leger, David Yannick; Limami, Youness [Université de Limoges, FR 3503 GEIST, EA 1069 “Laboratoire de Chimie des Substances Naturelles”, GDR CNRS 3049, Faculté de Pharmacie, Laboratoire de Biochimie et Biologie Moléculaire, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France); Cook-Moreau, Jeanne [Université de Limoges, FR 3503 GEIST, UMR CNRS 7276 “Contrôle de la réponse immune B et lymphoproliférations”, Faculté de Médecine, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France); Beneytout, Jean-Louis [Université de Limoges, FR 3503 GEIST, EA 1069 “Laboratoire de Chimie des Substances Naturelles”, GDR CNRS 3049, Faculté de Pharmacie, Laboratoire de Biochimie et Biologie Moléculaire, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France); Liagre, Bertrand, E-mail: bertrand.liagre@unilim.fr [Université de Limoges, FR 3503 GEIST, EA 1069 “Laboratoire de Chimie des Substances Naturelles”, GDR CNRS 3049, Faculté de Pharmacie, Laboratoire de Biochimie et Biologie Moléculaire, 2 rue du Docteur Marcland, 87025 Limoges Cedex (France)

2013-04-15

186

Flavonoids targeting of I?B phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells  

PubMed Central

Brain endothelial cells play an essential role as structural and functional components of the blood–brain barrier (BBB). Increased BBB breakdown and brain injury are associated with neuroinflammation and are thought to trigger mechanisms involving matrix metalloproteinase upregulation. Emerging evidence also indicates that cyclooxygenase (COX) inhibition limits BBB disruption, but the mechanisms linking metalloproteinase to COX remain unknown. In this study, we sought to investigate the nuclear factor-kappa B (NF-?B) signaling pathway, a common pathway in both the regulation of matrix metalloproteinase-9 (MMP-9) and COX-2 expression, and the inhibitory properties of several chemopreventive flavonoids. Human brain microvascular endothelial cells were treated with a combination of phorbol 12-myristate 13-acetate (PMA), a carcinogen documented to increase MMP-9 and COX-2 through NF-?B, and several naturally occurring flavonoids. Among the molecules tested, we found that fisetin, apigenin, and luteolin specifically and dose-dependently antagonized PMA-induced COX-2 and MMP-9 gene and protein expressions as assessed by qRT-PCR, immunoblotting, and zymography respectively. We further demonstrate that flavonoids impact on I?K-mediated phosphorylation activity as demonstrated by the inhibition of PMA-induced I?B phosphorylation levels. Our results suggest that BBB disruption during neuroinflammation could be pharmacologically reduced by a specific class of flavonoids acting as NF-?B signal transduction inhibitors. PMID:21625419

Tahanian, Elizabeth; Sanchez, Luis Arguello; Shiao, Tze Chieh; Roy, Rene; Annabi, Borhane

2011-01-01

187

Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2.  

PubMed

Recent studies have shown that CXCL1 upregulation in spinal astrocytes is involved in the maintenance of neuropathic pain. However, whether and how CXCL1 regulates inflammatory pain remains unknown. Here we show that intraplantar injection of CFA increased mRNA and protein expressions of CXCL1 and its major receptor CXCR2 in the spinal cord at 6h and 3days after the injection. Immunofluorescence double staining showed that CXCL1 and CXCR2 were expressed in spinal astrocytes and neurons, respectively. Intrathecal injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 attenuated CFA-induced mechanical and heat hypersensitivity on post-CFA day 3. Patch-clamp recordings showed that CXCL1 potentiated NMDA-induced currents in lamina II neurons via CXCR2, and this potentiation was further increased in CFA-treated mice. Furthermore, intrathecal injection of CXCL1 increased COX-2 expression in dorsal horn neurons, which was blocked by pretreatment with SB225002 or MEK (ERK kinase) inhibitor PD98059. Finally, pretreatment with SB225002 or PD98059 decreased CFA-induced heat hyperalgesia and COX-2 mRNA/protein expression and ERK activation in the spinal cord. Taken together, our data suggest that CXCL1, upregulated and released by spinal astrocytes after inflammation, acts on CXCR2-expressing spinal neurons to increase ERK activation, synaptic transmission and COX-2 expression in dorsal horn neurons and contributes to the pathogenesis of inflammatory pain. PMID:24852102

Cao, De-Li; Zhang, Zhi-Jun; Xie, Rou-Gang; Jiang, Bao-Chun; Ji, Ru-Rong; Gao, Yong-Jing

2014-11-01

188

Chemoprevention of Gastric Cancer: Role of COX2 Inhibitors and Other Agents  

Microsoft Academic Search

Despite the decrease in incidence, gastric cancer remains the second leading cause of cancer-related death worldwide. Prevention is likely to be the most effective means of not only reducing the incidence but also mortality from this disease. The term ‘chemoprevention’ has been referred to the prevention of cancer using specific agents to suppress or reverse the carcinogenic process. In recent

Gerardo Nardone; Alba Rocco

2004-01-01

189

Curcumin Alleviates Neuropathic Pain by Inhibiting p300/CBP Histone Acetyltransferase Activity-Regulated Expression of BDNF and Cox-2 in a Rat Model  

PubMed Central

The management of neuropathic pain is still a major challenge because of its unresponsiveness to most common treatments. Curcumin has been reported to play an active role in the treatment of various neurological disorders, such as neuropathic pain. Curcumin has long been recognized as a p300/CREB-binding protein (CBP) inhibitor of histone acetyltransferase (HAT) activity. However, this mechanism has never been investigated for the treatment of neuropathic pain with curcumin. The aim of the present study was to investigate the anti-nociceptive role of curcumin in the chronic constriction injury (CCI) rat model of neuropathic pain. Furthermore, with this model we investigated the effect of curcumin on P300/CBP HAT activity-regulated release of the pro-nociceptive molecules, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (Cox-2). Treatment with 40 and 60 mg/kg body weight curcumin for 7 consecutive days significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, whereas 20 mg/kg curcumin showed no significant analgesic effect. Chromatin immunoprecipitation analysis revealed that curcumin dose-dependently reduced the recruitment of p300/CBP and acetyl-Histone H3/acetyl-Histone H4 to the promoter of BDNF and Cox-2 genes. A similar dose-dependent decrease of BDNF and Cox-2 in the spinal cord was also observed after curcumin treatment. These results indicated that curcumin exerted a therapeutic role in neuropathic pain by down-regulating p300/CBP HAT activity-mediated gene expression of BDNF and Cox-2. PMID:24603592

Zhu, Xiaoyan; Li, Qian; Chang, Ruimin; Yang, Dong; Song, Zongbing; Guo, Qulian; Huang, Changsheng

2014-01-01

190

Ethyl caffeate suppresses NF-kappaB activation and its downstream inflammatory mediators, iNOS, COX-2, and PGE2 in vitro or in mouse skin.  

PubMed

Ethyl caffeate, a natural phenolic compound, was isolated from Bidens pilosa, a medicinal plant popularly used for treating certain inflammatory syndromes. The purpose of this study was to investigate the structural activity, and the anti-inflammatory functions and mechanism(s) of ethyl caffeate. Ethyl caffeate was found to markedly suppress the lipopolysaccharide (LPS)-induced nitric oxide (NO) production (IC(50) = 5.5 microg ml(-1)), mRNA and protein expressions of inducible nitric oxide synthase (iNOS), and prostaglandin E(2) (PGE(2)) production in RAW 264.7 macrophages. Transient gene expression assays using human cox-2 promoter construct revealed that ethyl caffeate exerted an inhibitory effect on cox-2 transcriptional activity in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells. Immunohistochemical studies of mouse skin demonstrated that TPA-induced COX-2 expression was significantly inhibited by ethyl caffeate with a superior effect to that of celecoxib, a nonsteroidal anti-inflammatory drug. The phosphorylation and degradation of inhibitor kappaB (IkappaB) and the translocation of nuclear transcription factor-kappaB (NF-kappaB) into the nucleus, as well as the activation of mitogen-activated protein kinases (MAPKs) induced by LPS in macrophages, were not affected by ethyl caffeate. Ethyl caffeate, however, could inhibit NF-kappaB activation by impairing the binding of NF-kappaB to its cis-acting element. These results suggest that ethyl caffeate suppresses iNOS and COX-2 expressions partly through the inhibition of the NF-kappaB.DNA complex formation. Structure-activity relationship analyses suggested that the catechol moiety and alpha,beta-unsaturated ester group in ethyl caffeate are important and essential structural features for preventing NF-kappaB.DNA complex formation. This study provides an insight into the probable mechanism(s) underlying the anti-inflammatory and therapeutic properties of ethyl caffeate. PMID:16041399

Chiang, Yi-Ming; Lo, Chiu-Ping; Chen, Yi-Ping; Wang, Sheng-Yang; Yang, Ning-Sun; Kuo, Yueh-Hsiung; Shyur, Lie-Fen

2005-10-01

191

Expression of Cyclooxygenase2 (COX2) in Human Invasive Transitional Cell Carcinoma (TCC) of the Urinary Bladder1  

Microsoft Academic Search

Cyclooxygenase (COX)-inhibiting drugs have antitumor activity in ca- nine and rodent models of urinary bladder cancer. Two isoenzymes of COX have been identified, COX-1 and COX-2. The purpose of this study was to characterize COX-1 and COX-2 expression in human invasive transitional cell carcinoma of the urinary bladder by immunohistochem- istry and Western blot analysis. COX-2 was not expressed in

Sulma I. Mohammed; Deborah W. Knapp; David G. Bostwick; Richard S. Foster; Kanwar Nasir; M. Khan; Jaime L. Masferrer; Bryan M. Woerner; Paul W. Snyder; Alane T. Koki

1999-01-01

192

Silibinin modulates TNF-? and IFN-? mediated signaling to regulate COX2 and iNOS expression in tumorigenic mouse lung epithelial LM2 cells.  

PubMed

Silibinin inhibits mouse lung tumorigenesis in part by targeting tumor microenvironment. Tumor necrosis factor-alpha (TNF-?) and interferon-gamma (IFN-?) can be pro- or anti-tumorigenic, but in lung cancer cell lines they induce pro-inflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). Accordingly, here we examined mechanism of silibinin action on TNF-??+?IFN-? (hereafter referred as cytokine mixture) elicited signaling in tumor-derived mouse lung epithelial LM2 cells. Both signal transducers and activators of the transcription (STAT)3 (tyr705 and ser727) and STAT1 (tyr701) were activated within 15?min of cytokine mixture exposure, while STAT1 (ser727) activated after 3?h. Cytokine mixture also activated Erk1/2 and caused an increase in both COX2 and iNOS levels. Pretreatment of cells with a MEK, NF-?B, and/or epidermal growth factor receptor (EGFR) inhibitor inhibited cytokine mixture-induced activation of Erk1/2, NF-?B, or EGFR, respectively, and strongly decreased phosphorylation of STAT3 and STAT1 and expression of COX2 and iNOS. Also, janus family kinases (JAK)1 and JAK2 inhibitors specifically decreased cytokine-induced iNOS expression, suggesting possible roles of JAK1, JAK2, Erk1/2, NF-?B, and EGFR in cytokine mixture-caused induction of COX2 and iNOS expression via STAT3/STAT1 activation in LM2 cells. Importantly, silibinin pretreatment inhibited cytokine mixture-induced phosphorylation of STAT3, STAT1, and Erk1/2, NF-?B-DNA binding, and expression of COX2, iNOS, matrix metalloproteinases (MMP)2, and MMP9, which was mediated through impairment of STAT3 and STAT1 nuclear localization. Silibinin also inhibited cytokine mixture-induced migration of LM2 cells. Together, we showed that STAT3 and STAT1 could be valuable chemopreventive and therapeutic targets within the lung tumor microenvironment in addition to being targets within tumor itself, and that silibinin inhibits their activation as a plausible mechanism of its efficacy against lung cancer. PMID:21882257

Tyagi, Alpna; Agarwal, Chapla; Dwyer-Nield, Lori D; Singh, Rana P; Malkinson, Alvin M; Agarwal, Rajesh

2012-10-01

193

Green Tea Catechins Reduce Invasive Potential of Human Melanoma Cells by Targeting COX-2, PGE2 Receptors and Epithelial-to-Mesenchymal Transition  

PubMed Central

Melanoma is the most serious type of skin disease and a leading cause of death from skin disease due to its highly metastatic ability. To develop more effective chemopreventive agents for the prevention of melanoma, we have determined the effect of green tea catechins on the invasive potential of human melanoma cells and the molecular mechanisms underlying these effects using A375 (BRAF-mutated) and Hs294t (Non-BRAF-mutated) melanoma cell lines as an in vitro model. Employing cell invasion assays, we found that the inhibitory effects of green tea catechins on the cell migration were in the order of (-)-epigallocatechin-3-gallate (EGCG)>(-)-epigallocatechin>(-)-epicatechin-3-gallate>(-)-gallocatechin>(-)-epicatechin. Treatment of A375 and Hs294t cells with EGCG resulted in a dose-dependent inhibition of cell migration or invasion of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2, prostaglandin (PG) E2 and PGE2 receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, also inhibited melanoma cell migration. EGCG inhibits 12-O-tetradecanoylphorbol-13-acetate-, an inducer of COX-2, and PGE2-induced cell migration of cells. EGCG decreased EP2 agonist (butaprost)- and EP4 agonist (Cay10580)-induced cell migration ability. Moreover, EGCG inhibited the activation of NF-?B/p65, an upstream regulator of COX-2, in A375 melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-?B, also inhibited cell migration. Inhibition of melanoma cell migration by EGCG was associated with transition of mesenchymal stage to epithelial stage, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin, cytokeratin and desmoglein 2) and a reduction in the levels of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in A375 melanoma cells. Together, these results indicate that EGCG, a major green tea catechin, has the ability to inhibit melanoma cell invasion/migration, an essential step of metastasis, by targeting the endogenous expression of COX-2, PGE2 receptors and epithelial-to-mesenchymal transition. PMID:22022384

Singh, Tripti; Katiyar, Santosh K.

2011-01-01

194

Elevated COX2 expression and PGE2 production by downregulation of RXR? in senescent macrophages  

SciTech Connect

Highlights: •Downregulation of RXR? in senescent macrophage. •RXR? suppresses NF-?B activity and COX2 expression. •Increased PGE2 production due to downregulation of RXR?. -- Abstract: Increased systemic level of inflammatory cytokines leads to numerous age-related diseases. In senescent macrophages, elevated prostaglandin E2 (PGE2) production contributes to the suppression of T cell function with aging, which increases the susceptibility to infections. However, the regulation of these inflammatory cytokines and PGE2 with aging still remains unclear. We have verified that cyclooxygenase (COX)-2 expression and PGE2 production are higher in LPS-stimulated macrophages from old mice than that from young mice. Downregulation of RXR?, a nuclear receptor that can suppress NF-?B activity, mediates the elevation of COX2 expression and PGE2 production in senescent macrophages. We also have found less induction of ABCA1 and ABCG1 by RXR? agonist in senescent macrophages, which partially accounts for high risk of atherosclerosis in aged population. Systemic treatment with RXR? antagonist HX531 in young mice increases COX2, TNF-?, and IL-6 expression in splenocytes. Our study not only has outlined a mechanism of elevated NF-?B activity and PGE2 production in senescent macrophages, but also provides RXR? as a potential therapeutic target for treating the age-related diseases.

Chen, Huimin, E-mail: huiminchen.jq@gmail.com [Department of Geratology, Liaoning Jinqiu Hospital, Shenyang 110015 (China)] [Department of Geratology, Liaoning Jinqiu Hospital, Shenyang 110015 (China); Ma, Feng [Institute of Immunology, Zhejiang University of Medicine, Hangzhou 310058 (China)] [Institute of Immunology, Zhejiang University of Medicine, Hangzhou 310058 (China); Hu, Xiaona; Jin, Ting; Xiong, Chuhui [Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001 (China)] [Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001 (China); Teng, Xiaochun, E-mail: tengxiaochun@126.com [Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001 (China)] [Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001 (China)

2013-10-11

195

COX2 is necessary for venous ligation-mediated bone adaptation in mice  

Microsoft Academic Search

In osteoblasts, cyclooxygenase 2 (COX-2) is the major isozyme responsible for production of prostaglandins. Prostaglandins are local mediators of bone resorption and formation and are known to be involved in bone's adaptive response to fluid shear stress (FSS). We have previously described a model of trabecular bone loss in hindlimb-suspended mice and rats and demonstrated partial protection from osteopenia by

H. Y. Stevens; D. R. Meays; J. Yeh; L. M. Bjursten; J. A. Frangos

2006-01-01

196

Association between COX-2 rs 6681231 Genotype and Interleukin-6 in Periodontal Connective Tissue. A Pilot Study  

PubMed Central

Objectives The aim of this pilot study was to investigate associations between IL-6 and COX-2 expression in gingival biopsies and both clinical diagnosis and genotypes in the IL-6 and COX-2 genes. Design A case-control study included 41 gingival biopsies obtained from Caucasian patients grouped according to clinical diagnosis of gingival health (n?=?10), gingivitis (n?=?15) or chronic periodontitis (n?=?16). Immunohistochemistry analyses were performed to determine COX-2 expression in lamina propria, IL-6 expression in lamina propria and gingival epithelium and level of inflammatory cell infiltrate. Individual DNA was extracted and genotyped by real-time PCR for IL6 SNPs rs 2069827 and rs 2069825 and for COX-2 rs 6681231. Results The percentage of cellular COX-2 expression was associated with the extent of periodontal disease (Arbes index p?=?0.026) and inflammatory infiltrate (p<0.0001). No association was observed between IL6 haplotypes and cells positive to IL-6 or COX-2 in gingival tissues. The COX-2 rs 6681231 was associated with cells positive to IL-6 in the connective tissue (p?=?0.032). Conclusions COX-2 expression in gingival tissues may be a marker of periodontal disease severity. COX-2 rs 6681231 may be associated with IL-6 local production in gingival tissues. PMID:24551049

Mesa, Francisco; O'Valle, Francisco; Rizzo, Manfredi; Cappello, Francesco; Donos, Nikos; Parkar, Mohamed; Chaudhary, Navidah; Carini, Francesco; Munoz, Ricardo; Nibali, Luigi

2014-01-01

197

Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism  

PubMed Central

The intestinal epithelium is sensitive to radiation injury. Damage to the intestinal epithelium is dose limiting in radiation therapy of abdominal cancers. There is a need for agents that can be given before radiation therapy to protect the intestinal epithelium. C57BL6 mice were subjected to 12 Gy of total body radiation. Some mice received intraperitoneal hyaluronic acid (HA) before radiation. Mice were killed 6 h after radiation to assess radiation-induced apoptosis in the intestine; other mice were killed at 84 h to assess crypt survival. Total body radiation (12 Gy) resulted in increased expression of HA synthases and HA in the intestine and increased plasma HA (5-fold). Intraperitoneal injection of HA (30 mg/kg) before radiation resulted in a 1.8-fold increase in intestinal crypt survival and a decrease in radiation-induced apoptosis. The radioprotective effects of HA were not seen in Toll-like receptor 4 (TLR4)- or cyclooxygenase-2 (COX-2)-deficient mice. Intraperitoneal injection of HA induced a 1.5-fold increase in intestinal COX-2 expression, a 1.5-fold increase in intestinal PGE2, and the migration of COX-2-expressing mesenchymal stem cells from the lamina propria in the villi to the lamina propria near the crypt. We conclude that 1) radiation induces increased HA expression through inducing HA synthases, 2) intraperitoneal HA given before radiation reduces radiation-induced apoptosis and increases crypt survival, and 3) these radioprotective effects are mediated through TLR4, COX-2, and the migration of COX-2-expressing mesenchymal stem cells. PMID:22038822

Riehl, Terrence E.; Foster, Lynne

2012-01-01

198

tNOX, an alternative target to COX2 to explain the anticancer activities of non-steroidal anti-inflammatory drugs (NSAIDS)  

Microsoft Academic Search

Our work has identified a cancer-specific, cell surface and growth-related quinol oxidase with both NADH oxidase and protein\\u000a disulfide-thiol interchange activities, a member of the ECTO-NOX protein family designated tNOX. We provide evidence for tNOX\\u000a as an alternative drug target to COX-2 to explain the anticancer activity of COX inhibitors. Non-steroidal anti-inflammatory\\u000a drugs (NSAIDS), piroxicam, aspirin, ibuprofen, naproxen and celecoxib

D. James Morré; Dorothy M. Morre

2006-01-01

199

Discovery of Selective Inhibitors of the Clostridium difficile Dehydroquinate Dehydratase  

PubMed Central

A vibrant and healthy gut flora is essential for preventing the proliferation of Clostridium difficile, a pathogenic bacterium that causes severe gastrointestinal symptoms. In fact, most C. difficile infections (CDIs) occur after broad-spectrum antibiotic treatment, which, by eradicating the commensal gut bacteria, allows its spores to proliferate. Hence, a C. difficile specific antibiotic that spares the gut flora would be highly beneficial in treating CDI. Towards this goal, we set out to discover small molecule inhibitors of the C. difficile enzyme dehydroquinate dehydratase (DHQD). DHQD is the 3rd of seven enzymes that compose the shikimate pathway, a metabolic pathway absent in humans, and is present in bacteria as two phylogenetically and mechanistically distinct types. Using a high-throughput screen we identified three compounds that inhibited the type I C. difficile DHQD but not the type II DHQD from Bacteroides thetaiotaomicron, a highly represented commensal gut bacterial species. Kinetic analysis revealed that the compounds inhibit the C. difficile enzyme with Ki values ranging from 10 to 20 µM. Unexpectedly, kinetic and biophysical studies demonstrate that inhibitors also exhibit selectivity between type I DHQDs, inhibiting the C. difficile but not the highly homologous Salmonella enterica DHQD. Therefore, the three identified compounds seem to be promising lead compounds for the development of C. difficile specific antibiotics. PMID:24586713

Anderson, Wayne F.; Caffrey, Michael; Lavie, Arnon

2014-01-01

200

Fondaparinux: a new synthetic and selective inhibitor of Factor Xa.  

PubMed

Fondaparinux (Arixtra) is the first synthetic selective Factor Xa inhibitor. Its efficacy and safety in the prevention of venous thromboembolism (VTE) was first studied in patients undergoing major orthopedic surgery, a setting in the highest risk category for postoperative thrombotic complications. Low-molecular-weight heparins are frequently used in this setting, but the rates of VTE still range between 15% and 33%. In large clinical trials, fondaparinux started 6 hours postoperatively was significantly more effective than enoxaparin in preventing VTE in patients undergoing total hip replacement, total knee replacement or hip fracture surgery. The benefit of extended fondaparinux prophylaxis after hip fracture surgery was also investigated. Other trials have demonstrated that fondaparinux is efficacious in the prevention of VTE in other patient populations at risk of thrombosis and in the treatment of symptomatic VTE. PMID:15171960

Bauer, Kenneth A

2004-03-01

201

Triptolide inhibits COX-2 expression by regulating mRNA stability in TNF-{alpha}-treated A549 cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Triptolide inhibited COX-2 expression and the half-life of COX-2 mRNA is decreased. Black-Right-Pointing-Pointer The HuR protein shuttling from nucleus to cytoplasm is inhibited by triptolide. Black-Right-Pointing-Pointer Triptolide inhibited 3 Prime -UTR fluorescence reporter gene activity. Black-Right-Pointing-Pointer COX-2 mRNA binding to HuR is decreased by triptolide in pull-down experiments. -- Abstract: Cyclooxygenase-2 (COX-2) over-expression is frequently associated with human non-small-cell lung cancer (NSCLC) and involved in tumor proliferation, invasion, angiogenesis and resistance to apoptosis. In the present study, the effects of triptolide on COX-2 expression in A549 cells were investigated and triptolide was found to inhibit TNF-{alpha}-induced COX-2 expression. In our further studies, it was found that triptolide decreased the half-life of COX-2 mRNA dramatically and that it inhibited 3 Prime -untranslated region (3 Prime -UTR) fluorescence reporter gene activity. Meanwhile, triptolide inhibited the HuR shuttling from nucleus to cytoplasm. After triptolide treatment, decreased COX-2 mRNA in pull-down experiments with anti-HuR antibodies was observed, indicating that the decreased cytoplasmic HuR is responsible for the decreased COX-2 mRNA. Taken together, our results provided evidence for the first time that triptolide inhibited COX-2 expression by COX-2 mRNA stability modulation and post-transcriptional regulation. These results provide a novel mechanism of action for triptolide which may be important in the treatment of lung cancer.

Sun, Lixin; Zhang, Shuang; Jiang, Zhenzhou; Huang, Xin; Wang, Tao; Huang, Xiao; Li, Han [Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009 (China)] [Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009 (China); Zhang, Luyong, E-mail: lyzhang@cpu.edu.cn [Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009 (China)] [Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009 (China)

2011-12-09

202

Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Human colonic cancer associated fibroblasts are major sources of COX-2 and PGE{sub 2}. Black-Right-Pointing-Pointer The fibroblasts interact with human colonic epithelial cancer cells. Black-Right-Pointing-Pointer Activation of COX-2 signaling in the fibroblasts affects behavior of the epithelia. Black-Right-Pointing-Pointer Protein Kinase C controls the activation of COX-2 signaling. -- Abstract: COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.

Zhu, Yingting, E-mail: yitizhu@yahoo.com [Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724 (United States) [Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724 (United States); Tissue Tech Inc., Miami, FL 33173 (United States); Zhu, Min; Lance, Peter [Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724 (United States)] [Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724 (United States)

2012-08-31

203

Selective HDAC1/HDAC2 Inhibitors Induce Neuroblastoma Differentiation  

PubMed Central

Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective Class I histone deacetylase (HDAC) inhibitor (HDAC1>2>3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation. PMID:23706636

Frumm, Stacey M.; Fan, Zi Peng; Ross, Kenneth N.; Duvall, Jeremy R.; Gupta, Supriya; VerPlank, Lynn; Suh, Byung-Chul; Holson, Edward; Wagner, Florence F.; Smith, William B.; Paranal, Ronald M.; Bassil, Christopher F.; Qi, Jun; Roti, Giovanni; Kung, Andrew L.; Bradner, James E.; Tolliday, Nicola; Stegmaier, Kimberly

2013-01-01

204

Novel Allelic Variants in the Canine Cyclooxgenase-2 (Cox-2) Promoter Are Associated with Renal Dysplasia in Dogs  

PubMed Central

Renal dysplasia (RD) in dogs is a complex disease with a highly variable phenotype and mode of inheritance that does not follow a simple Mendelian pattern. Cox-2 (Cyclooxgenase-2) deficient mice have renal abnormalities and a pathology that has striking similarities to RD in dogs suggesting to us that mutations in the Cox-2 gene could be the cause of RD in dogs. Our data supports this hypothesis. Sequencing of the canine Cox-2 gene was done from clinically affected and normal dogs. Although no changes were detected in the Cox-2 coding region, small insertions and deletions of GC boxes just upstream of the ATG translation start site were found. These sequences are putative SP1 transcription factor binding sites that may represent important cis-acting DNA regulatory elements that govern the expression of Cox-2. A pedigree study of a family of Lhasa apsos revealed an important statistical correlation of these mutant alleles with the disease. We examined an additional 22 clinical cases from various breeds. Regardless of the breed or severity of disease, all of these had one or two copies of the Cox-2 allelic variants. We suggest that the unusual inheritance pattern of RD is due to these alleles, either by changing the pattern of expression of Cox-2 or making Cox-2 levels susceptible to influences of other genes or environmental factors that play an unknown but important role in the development of RD in dogs. PMID:21346820

Whiteley, Mary H.; Bell, Jerold S.; Rothman, Debby A.

2011-01-01

205

Relative contribution of acetylated cyclooxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin  

Microsoft Academic Search

In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)-2. The acetylated COX-2 remains active, and upon cell activation, initiates the generation of 15R-HETE, a lipid substrate for 5-lipoxygenase (LOX) leading to the formation of 15-epi-LXA4 (also termed \\

Stefano Fiorucci; Eleonora Distrutti; Octavio Menezes de Lima; Mario Romano; Andrea Mencarelli; Miriam Barbanti; Ernesto Palazzini; Antonio Morelli; John L. Wallace

2003-01-01

206

Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity  

Microsoft Academic Search

Small-molecule protein kinase inhibitors are widely used to elucidate cellular signaling pathways and are promising therapeutic agents. Owing to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments that use these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we

Theonie Anastassiadis; Sean W Deacon; Karthik Devarajan; Haiching Ma; Jeffrey R Peterson

2011-01-01

207

Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase.  

PubMed Central

Human mitochondrial aldehyde dehydrogenase (ALDH-I) is potently, reversibly, and selectively inhibited by an isoflavone isolated from Radix puerariae and identified as daidzin, the 7-glucoside of 4',7-dihydroxyisoflavone. Kinetic analysis with formaldehyde as substrate reveals that daidzin inhibits ALDH-I competitively with respect to formaldehyde with a Ki of 40 nM, and uncompetitively with respect to the coenzyme NAD+. The human cytosolic aldehyde dehydrogenase isozyme (ALDH-II) is nearly 3 orders of magnitude less sensitive to daidzin inhibition. Daidzin does not inhibit human class I, II, or III alcohol dehydrogenases, nor does it have any significant effect on biological systems that are known to be affected by other isoflavones. Among more than 40 structurally related compounds surveyed, 12 inhibit ALDH-I, but only prunetin and 5-hydroxydaidzin (genistin) combine high selectivity and potency, although they are 7- to 15-fold less potent than daidzin. Structure-function relationships have established a basis for the design and synthesis of additional ALDH inhibitors that could both be yet more potent and specific. PMID:8433985

Keung, W M; Vallee, B L

1993-01-01

208

Selectively Targeting Prostate Cancer with Antiandrogen Equipped Histone Deacetylase Inhibitors  

PubMed Central

Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with non-steroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone dependent (AR+) LNCaP and to a lesser extent against hormone independent (AR?) DU145 prostate cancer, while having greatly reduced toxicity in non-cancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type selective responses. PMID:24004176

Gryder, Berkley E.; Akbashev, Michelle J.; Rood, Michael K.; Raftery, Eric D.; Meyers, Warren M.; Dillard, Paulette; Khan, Shafiq; Oyelere, Adegboyega K.

2013-01-01

209

L-ascorbic acid represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.  

PubMed

There is increasing evidence that L-ascorbic acid (LAA) is selectively toxic to some types of cancer cells at pharmacological concentrations, functioning as a pro-oxidant rather than as an anti-oxidant. However, the molecular mechanisms by which LAA initiates cellular signaling leading to cell death are still unclear. In an effort to gain insight into these mechanisms, the effects of LAA on eukaryotic transcription nuclear factor NF-kappaB and cyclooxygenase-2 (COX-2) expression were investigated. In the present study, LAA suppressed DNA binding activity of NF-kappaB, composed of a p65/p50 heterodimer, through inhibition of degradation of inhibitory kappaB-alpha (IkappaB-alpha) and prevention of nuclear translocation of p65. The inhibitory effect of LAA on NF-kappaB activity was dependent upon glutathione levels in HL-60 cells, as well as generation of H2O2 but not superoxide anion. LAA also downregulated the expression of COX-2, which has a NF-kappaB binding site on its promoter, through repressing NF-kappaB DNA binding activity. Moreover, cotreatment of 1 microM arsenic trioxide (As2O3) with various concentrations of LAA enhanced an LAA-induced repression of NF-kappaB activity and COX-2 expression. In conclusion, our data suggest that LAA exerts its anti-tumor activity through downregulation of NF-kappaB activity and COX-2 expression, and these inhibitory effects can be enhanced by co-treatment with As2O3. PMID:15368354

Han, Seong-Su; Kim, Kihyun; Hahm, Eun-Ryeong; Lee, Sook J; Surh, Young-Joon; Park, Hye K; Kim, Won S; Jung, Chul W; Lee, Mark H; Park, Keunchil; Yang, Jung-Hyun; Yoon, Sung-Soo; Riordan, Neil H; Riordan, Hugh D; Kimler, Bruce F; Park, Chan H; Lee, Je-Ho; Park, Seyeon

2004-10-01

210

Enhanced contractility of rat aorta in DOCA-salt hypertension involves COX2 activation  

Microsoft Academic Search

Responsiveness to many contractile agonists increase in deoxycorticosterone acetate (DOCA)-salt induced hypertension We tested the hypothesis that enhanced contractility of rat aorta to norepinephrine (NE) in DOCA-salt hypertension is causally related to increased expression and activity of COX-2. Thoracic aortic rings were obtained from uninephrectomized rats fed for 3 weeks on either normal (control), or 8% sodium+potassium (experimental) diets. The

Ayotunde S. Adeagbo; Xiaodong Zhang; Yang Wang; Mabayoje A. Oriowo

2001-01-01

211

Coordinated Upregulation of COX2 and NF-?B Is a Steady Feature of Laryngeal Carcinogenesis  

Microsoft Academic Search

Background\\/Aims: Laryngeal cancer is the endpoint of a multistage process involving hyperplastic and dysplastic lesions, not adequately defined in their molecular aspect. Our objective was to evaluate the expression of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) and the chief transcription factor nuclear factor-?B (NF-?B) in laryngeal carcinomas and their precursors, as well as to explore any association between the two molecules.

Konstantinos Kourelis; Georgia Sotiropoulou-Bonikou; Gerasimos Vandoros; Maria Repanti; Ioannis Varakis; Panagiotis Goumas

2007-01-01

212

Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria.  

PubMed Central

OBJECTIVE: To establish specific criteria by which selective serotonin reuptake inhibitor (SSRI) discontinuation syndrome may be identified. DATA SOURCES: MEDLINE and PSYCHLIT databases were searched for case reports published from 1986 to 1997 inclusive, and references of relevant articles were also searched. STUDY SELECTION: Forty-six case reports of symptoms following the discontinuation of fluoxetine, fluvoxamine, paroxetine or sertraline were selected. Three studies of SSRI discontinuation were also reviewed. DATA EXTRACTION: Demographic and treatment information, as well as the timing, duration, number, nature and frequency of dicontinuation symptoms. DATA SYNTHESIS: Paroxetine was most frequently implicated. The drug had been tapered in half of the cases. In some cases, symptom onset began during taper, whereas, in most cases, symptoms began within 1 to 3 days of drug discontinuation. Fifty-three different symptoms were reported, with dizziness being the most common. Other common symptoms were nausea or emesis, fatigue, headache, gait instability and insomnia. Shock-like sensations, paresthesia and visual disturbances were the most rare. Without intervention, symptoms persisted for more than a week in half of the cases. In cases in which the SSRI was restarted, symptoms resolved within 72 hours. In some cases, withdrawal symptoms recurred when the same SSRI was again discontinued. CONCLUSIONS: Findings were used to construct diagnostic criteria for the SSRI discontinuation syndrome. These criteria are 2 or more of the following symptoms developing within 1 to 7 days of discontinuation or reduction in dosage of an SSRI after at least 1 month's use, when these symptoms cause clinically significant distress or impairment and are not due to a general medical condition or recurrence of a mental disorder: dizziness, light-headedness, vertigo or feeling faint; shock-like sensations or paresthesia; anxiety; diarrhea; fatigue; gait instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances. PMID:10863885

Black, K; Shea, C; Dursun, S; Kutcher, S

2000-01-01

213

Gastric adenomas: relationship between clinicopathological findings, Helicobacter pylori infection, APC mutations and COX-2 expression.  

PubMed

Gastric adenomas are rare neoplastic growths characterized by localized polypoid proliferations of dysplastic epithelium that tend to progress to infiltrating adenocarcinoma. Therefore, the identification of molecular markers that could reliably recognize adenomas at risk of progression is advocated in the clinical management. In this study we investigated, in a series of gastric adenoma specimens from an area at high risk of gastric cancer, the relationship between clinicopathological characteristics of adenoma and Helicobacter pylori infection, APC mutational status, and COX-2 and the down-stream enzyme mPGES1 expression. Helicobacter pylori infection, detected in 24%, and 33% by histology and PCR analyses, respectively, did not show any relationship with growth pattern, localization, size, dysplasia grade and presence of synchronous cancer. Pathogenetic mutations of MCR region (codons 1269-1589) of the APC gene were detected only in one case corresponding to a single, small size, low grade, H. pylori-negative adenoma. The expression of COX-2 largely matched that of mPGES(1). Both were overexpressed in 79% of cases showing a relationship with high-grade dysplasia, size >10 mm and presence of a synchronous carcinoma. In conclusion, COX-2 may play a key role in the development and progression of gastric adenoma and could be an attractive target in the management of gastric adenoma at major risk of cancer development. PMID:16760271

Rocco, A; Caruso, R; Toracchio, S; Rigoli, L; Verginelli, F; Catalano, T; Neri, M; Curia, M C; Ottini, L; Agnese, V; Bazan, V; Russo, A; Pantuso, G; Colucci, G; Mariani-Costantini, R; Nardone, G

2006-06-01

214

Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity  

PubMed Central

Ultraviolet (UV) radiation is the primary environmental risk factor in the development of nonmelanoma skin cancer, and UVB in particular promotes tumor growth through various signaling pathways. Kaempferol, a flavonoid with anti-inflammatory and anti-oxidative properties, has been studied as a chemopreventive agent; however, little is known regarding its effects on UVB-induced photo-carcinogenesis. Here, we examined the effect of kaempferol on UVB-induced skin inflammation. We found that kaempferol suppressed UVB-induced cyclooxygenase-2 (COX-2) protein expression in mouse skin epidermal JB6 P+ cells and attenuated the UVB-induced transcriptional activities of cox-2 and activator protein-1 (AP-1). Kaempferol attenuated the UVB-induced phosphorylation of several mitogen-activated protein kinases (MAPKs), including ERKs, p38, and JNKs, but had no effect on the phosphorylation of the upstream MAPK regulator Src. However, in vitro and ex vivo kinase assays demonstrated that kaempferol suppressed Src kinase activity. Furthermore, in vivo data from mouse skin support the idea that kaempferol suppresses UVB-induced COX-2 expression by blocking Src kinase activity. A pull-down assay revealed that kaempferol competes with ATP for direct binding to Src. Docking data suggest that kaempferol docks easily into the ATP-binding site of Src, which is located between the N and C lobes of the kinase domain. Taken together, these results suggest that kaempferol is a potent chemopreventive agent against skin cancer through its inhibitory interaction with Src. PMID:20599768

Lee, Kyung Mi; Lee, Ki Won; Jung, Sung Keun; Lee, Eun Jung; Heo, Yong-Seok; Bode, Ann M.; Lubet, Ronald A.; Lee, Hyong Joo; Dong, Zigang

2010-01-01

215

Synthesis and COX-2 inhibitory properties of N-phenyl- and N-benzyl-substituted amides of 2-(4-methylsulfonylphenyl)cyclopent-1-ene-1-carboxylic acid and of their pyrazole, thiophene and isoxazole analogs.  

PubMed

Some N-phenyl- (7a-10a) and N-benzyl-substituted (7b-10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7-10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds (7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 microM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a-9a present steric hindrances which may prevent a good interaction with COX-2 active site. PMID:14751313

Rapposelli, Simona; Lapucci, Annalina; Minutolo, Filippo; Orlandini, Elisabetta; Ortore, Gabriella; Pinza, Mario; Balsamo, Aldo

2004-01-01

216

Selective inhibitors of terminal deoxyribonucleotidyltransferase (TdT): Baicalin and genistin  

Microsoft Academic Search

Studies of mammalian terminal deoxyribonucleotidyltransferase (TdT) are facilitated by use of inhibitors that selectively knock down the activity of the enzyme. We have screened for selective inhibitors of TdT and identified a natural compound with this property in the Japanese vegetable, Arctium lappa. The compound has little effect on the activities of mammalian DNA polymerases, such as ?, ?, ?

Yukinobu Uchiyama; Junko Tagami; Shinji Kamisuki; Nobuyuki Kasai; Masahiko Oshige; Hiroyuki Chiku; Siroh Ibe; Osamu Koiwai; Fumio Sugawara; Kengo Sakaguchi

2005-01-01

217

Selective serotonin reuptake inhibitor drug interactions in patients receiving statins.  

PubMed

Elderly patients commonly receive statin drugs for the primary or secondary prevention of cardiovascular and cerebrovascular events. Elderly patients also commonly receive antidepressant drugs, usually selective serotonin reuptake inhibitors (SSRIs), for the treatment of depression, anxiety, or other conditions. SSRIs are associated with many pharmacokinetic drug interactions related to the inhibition of the cytochrome P450 (CYP) metabolic pathways. There is concern that drugs that inhibit statin metabolism can trigger statin adverse effects, especially myopathy (which can be potentially serious, if rhabdomyolysis occurs). However, a detailed literature review of statin metabolism and of SSRI effects on CYP enzymes suggests that escitalopram, citalopram, and paroxetine are almost certain to be safe with all statins, and rosuvastatin, pitavastatin, and pravastatin are almost certain to be safe with all SSRIs. Even though other SSRI-statin combinations may theoretically be associated with risks, the magnitude of the pharmacokinetic interaction is likely to be below the threshold for clinical significance. Risk, if at all, lies in combining fluvoxamine with atorvastatin, simvastatin, or lovastatin, and even this risk can be minimized by using lower statin doses and monitoring the patient. PMID:24602259

Andrade, Chittaranjan

2014-02-01

218

Selective serotonin reuptake inhibitors for premature ejaculation: review of erectile and ejaculatory side effects.  

PubMed

Premature ejaculation is one of the most prevalent sexual disorders affecting men today. The lack of approved therapies has resulted in the prescription of many 'off-label' treatments to manage the condition. Selective serotonin reuptake inhibitors have an interesting side effect of prolonging ejaculatory latency. Consequently, these agents are often considered a first line treatment for patients suffering from premature ejaculation. Erectile dysfunction is another common side effect reported by men treated with selective serotonin reuptake inhibitors. Nitric oxide is the primary mediator of erectile function. Preclinical studies have provided evidence that selective serotonin reuptake inhibitors decrease nitric oxide bioavailability. This invited mini-review aims to examine the physiology of the erectile and ejaculatory responses, discuss the indicated and 'off-label' clinical utility of selective serotonin reuptake inhibitors, and to summarize evidence from basic science and clinical studies pertaining to mechanisms of how selective serotonin reuptake inhibitor therapy modifies ejaculatory and erectile function. PMID:24446888

Lasker, George F; Halis, Fikret; Gokce, Ahmet

2014-01-01

219

The Spatiotemporal Role of COX-2 in Osteogenic and Chondrogenic Differentiation of Periosteum-Derived Mesenchymal Progenitors in Fracture Repair  

PubMed Central

Periosteum provides a major source of mesenchymal progenitor cells for bone fracture repair. Combining cell-specific targeted Cox-2 gene deletion approaches with in vitro analyses of the differentiation of periosteum-derived mesenchymal progenitor cells (PDMPCs), here we demonstrate a spatial and temporal role for Cox-2 function in the modulation of osteogenic and chondrogenic differentiation of periosteal progenitors in fracture repair. Prx1Cre-targeted Cox-2 gene deletion in mesenchyme resulted in marked reduction of intramembraneous and endochondral bone repair, leading to accumulation of poorly differentiated mesenchyme and immature cartilage in periosteal callus. In contrast, Col2Cre-targeted Cox-2 gene deletion in cartilage resulted in a deficiency primarily in cartilage conversion into bone. Further cell culture analyses using Cox-2 deficient PDMPCs demonstrated reduced osteogenic differentiation in monolayer cultures, blocked chondrocyte differentiation and hypertrophy in high density micromass cultures. Gene expression microarray analyses demonstrated downregulation of a key set of genes associated with bone/cartilage formation and remodeling, namely Sox9, Runx2, Osx, MMP9, VDR and RANKL. Pathway analyses demonstrated dysregulation of the HIF-1, PI3K-AKT and Wnt pathways in Cox-2 deficient cells. Collectively, our data highlight a crucial role for Cox-2 from cells of mesenchymal lineages in modulating key pathways that control periosteal progenitor cell growth, differentiation, and angiogenesis in fracture repair. PMID:24988184

Huang, Chunlan; Xue, Ming; Chen, Hongli; Jiao, Jing; Herschman, Harvey R.; O'Keefe, Regis J.; Zhang, Xinping

2014-01-01

220

Development of Potent and Selective Inhibitors of Aldo-Keto Reductase 1C3 (type 5 17?-Hydroxysteroid Dehydrogenase) Based on N-Phenyl-Aminobenzoates and Their Structure Activity Relationships  

PubMed Central

Aldo-keto reductase 1C3 (AKR1C3; type 5 17?-hydroxysteroid dehydrogenase) is overexpressed in castrate resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5?-dihydrotestosterone. Selective AKR1C3 inhibitors are required since compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5?-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular are potent but non-selective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid as lead compound, five classes of structural analogs were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads towards new therapeutics for CRPC. PMID:22263837

Adeniji, Adegoke O.; Twenter, Barry M.; Byrns, Michael C.; Jin, Yi; Chen, Mo; Winkler, Jeffrey D.; Penning, Trevor M.

2012-01-01

221

Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation  

NASA Technical Reports Server (NTRS)

Epidermal expression of the two isoforms of the prostaglandin H-generating cyclooxygenase (COX-1 and COX-2) was evaluated both by immunohistochemistry performed on human and mouse skin biopsy sections and by Western blotting of protein extracts from cultured human neonatal foreskin keratinocytes. In normal human skin, COX-1 immunostaining is observed throughout the epidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilar keratinocytes. Basal cell carcinomas express little if any COX-1 or COX-2 immunostaining whereas both isozymes are strongly expressed in squamous cell carcinomas deriving from a more differentiated layer of the epidermis. In human keratinocyte cultures, raising the extracellular calcium concentration, a recognized stimulus for keratinocyte differentiation, leads to an increased expression of both COX-2 protein and mRNA; expression of COX-1 protein, however, shows no significant alteration in response to calcium. Because of a recent report that failed to show COX-2 in normal mouse epidermis, we also looked for COX-1 and COX-2 immunostaining in sections of normal and acetone-treated mouse skin. In agreement with a previous report, some COX-1, but no COX-2, immunostaining is seen in normal murine epidermis. However, following acetone treatment, there is a marked increase in COX-1 expression as well as the appearance of significant COX-2 immunostaining in the basal layer. These data suggest that in human epidermis as well as in human keratinocyte cultures, the expression of COX-2 occurs as a part of normal keratinocyte differentiation whereas in murine epidermis, its constitutive expression is absent, but inducible as previously published.

Leong, J.; Hughes-Fulford, M.; Rakhlin, N.; Habib, A.; Maclouf, J.; Goldyne, M. E.

1996-01-01

222

Cyclooxygenase-2 (COX-2) Mediates Arsenite Inhibition of UVB-Induced Cellular Apoptosis in Mouse Epidermal Cl41 Cells  

PubMed Central

Inorganic arsenic is an environmental human carcinogen, and has been shown to act as a co-carcinogen with solar ultraviolet (UV) radiation in mouse skin tumor induction even at low concentrations. However, the precise mechanism of its co-carcinogenic action is largely unknown. Apoptosis plays an essential role as a protective mechanism against neoplastic development in the organism by eliminating genetically damaged cells. Thus, suppression of apoptosis is thought to contribute to carcinogenesis. It is known that cyclooxygenase-2 (COX-2) can promote carcinogenesis by inhibiting cell apoptosis under stress conditions; and our current studies investigated the potential contribution of COX-2 to the inhibitory effect of arsenite in UV-induced cell apoptosis in mouse epidermal Cl41 cells. We found that treatment of cells with low concentration (5 ?M) arsenite attenuated cellular apoptosis upon UVB radiation accompanied with a co-inductive effect on COX-2 expression and nuclear factor-?B (NF?B) transactivation. Our results also showed that the COX-2 induction by arsenite and UVB depended on an NF?B pathway because COX-2 co-induction could be attenuated in either p65-deficient or p50-deficient cells. Moreover, UVB-induced cell apoptosis could be dramatically reduced by the introduction of exogenous COX-2 expression, whereas the inhibitory effect of arsenite on UVB-induced cell apoptosis could be impaired in COX-2 knockdown Cl41 cells. Our results indicated that COX-2 mediated the anti-apoptotic effect of arsenite in UVB radiation through an NF?B-dependent pathway. Given the importance of apoptosis evasion during carcinogenesis, we anticipated that COX-2 induction might be at least partially responsible for the co-carcinogenic effect of arsenite on UVB-induced skin carcinogenesis. PMID:22463588

Zuo, Z.; Ouyang, W.; Li, J.; Costa, M.; Huang, C.

2013-01-01

223

Aspects of corrosion inhibitor selection at elevated temperatures  

SciTech Connect

Corrosion inhibitors were evaluated in a flow loop apparatus, for a subsea production flowline application in a major gas condensate project. The design temperature for the prediction was 115 C, with a considerable CO{sub 2} presence. Acceptable corrosion inhibitors were identified in this examination. However, the evaluation demonstrated that the presently available green inhibitors were not suitable. The corrosion performance was strongly dependent on temperature, especially above around 90 C. Most inhibitors performed well (less than 0.025 mm/y or 1 mpy) in the static environment, but exhibited poorer performance in the flowing (4 m/s) condition. Elevated temperature performance was associated with separation of the hydrocarbon and aqueous phases. This study was influenced by the general lack of corrosion inhibitor partitioning data available in the industry.

Kolts, J.; Jooaten, M.W.; Humble, P.G. [Conoco, Inc., Ponca City, OK (United States); Clapham, J. [Britannia Project, London (United Kingdom)

1998-12-31

224

Discovery of triazines as selective PDE4B versus PDE4D inhibitors.  

PubMed

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors. PMID:24998378

Hagen, Timothy J; Mo, Xuesheng; Burgin, Alex B; Fox, David; Zhang, Zheng; Gurney, Mark E

2014-08-15

225

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M  

SciTech Connect

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.

Zhou, Wenjun; Ercan, Dalia; Chen, Liang; Yun, Cai-Hong; Li, Danan; Capelletti, Marzia; Cortot, Alexis B.; Chirieac, Lucian; Iacob, Roxana E.; Padera, Robert; Engen, John R.; Wong, Kwok-Kin; Eck, Michael J.; Gray, Nathanael S.; Jänne, Pasi A.; (BWH); (NEU); (DFCI)

2010-01-12

226

KRAS, EGFR, PDGFR-?, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE)  

PubMed Central

Background CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid. Methods We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-? and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets. Results Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-? gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene. Conclusions All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-? gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016 PMID:24934485

2014-01-01

227

Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm  

PubMed Central

We investigated the prostaglandin (PG)E2 pathway in human abdominal aortic aneurysm (AAA) and its relationship with hypervascularization. We analyzed samples from patients undergoing AAA repair in comparison with those from healthy multiorgan donors. Patients were stratified according to maximum aortic diameter: low diameter (LD) (<55 mm), moderate diameter (MD) (55–69.9 mm), and high diameter (HD) (?70 mm). AAA was characterized by abundant microvessels in the media and adventitia with perivascular infiltration of CD45-positive cells. Like endothelial cell markers, cyclooxygenase (COX)-2 and the microsomal isoform of prostaglandin E synthase (mPGES-1) transcripts were increased in AAA (4.4- and 1.4-fold, respectively). Both enzymes were localized in vascular cells and leukocytes, with maximal expression in the LD group, whereas leukocyte markers display a maximum in the MD group, suggesting that the upregulation of COX-2/mPGES-1 precedes maximal leukocyte infiltration. Plasma and in vitro tissue secreted levels of PGE2 metabolites were higher in AAA than in controls (plasma-controls, 19.9 ± 2.2; plasma-AAA, 38.8 ± 5.5 pg/ml; secretion-normal aorta, 16.5 ± 6.4; secretion-AAA, 72.9 ± 6.4 pg/mg; mean ± SEM). E-prostanoid receptor (EP)-2 and EP-4 were overexpressed in AAA, EP-4 being the only EP substantially expressed and colocalized with mPGES-1 in the microvasculature. Additionally, EP-4 mediated PGE2-induced angiogenesis in vitro. We provide new data concerning mPGES-1 expression in human AAA. Our findings suggest the potential relevance of the COX-2/mPGES-1/EP-4 axis in the AAA-associated hypervascularization. PMID:24133193

Camacho, Mercedes; Dilmé, Jaume; Solà-Villà, David; Rodríguez, Cristina; Bellmunt, Sergi; Siguero, Laura; Alcolea, Sonia; Romero, José-María; Escudero, José-Román; Martínez-González, José; Vila, Luis

2013-01-01

228

Novel nonnucleoside inhibitors that select nucleoside inhibitor resistance mutations in human immunodeficiency virus type 1 reverse transcriptase.  

PubMed

Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies. PMID:16870771

Zhang, Zhijun; Walker, Michelle; Xu, Wen; Shim, Jae Hoon; Girardet, Jean-Luc; Hamatake, Robert K; Hong, Zhi

2006-08-01

229

Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity  

PubMed Central

Small-molecule protein kinase inhibitors are central tools for elucidating cellular signaling pathways and are promising therapeutic agents. Due to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments utilizing these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we profiled the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases using a functional assay. Quantitative analysis revealed complex and often unexpected kinase-inhibitor interactions, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can be used to identify multi-targeted inhibitors of specific, diverse kinases. The results have significant implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments that use them. PMID:22037377

Anastassiadis, Theonie; Deacon, Sean W.; Devarajan, Karthik; Ma, Haiching; Peterson, Jeffrey R.

2011-01-01

230

Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence  

Microsoft Academic Search

1 Selective inhibitors of cyclo-oxygenase-2 have been shown to be eÄective anti-inflammatory drugs with reduced gastrointestinal toxicity relative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, we examined the possibility that selective COX-2 inhibition, by blocking prostacyclin synthesis, would increase blood pressure and cause leukocyte adherence and platelet aggregation. 2 Normal rats and rats with hypertension induced by

Marcelo N. Muscara; Nathalie Vergnolle; Fina Lovren; Christopher R. Triggle; Susan N. Elliott; Samuel Asfaha; John L. Wallace

2000-01-01

231

Synthesis of some novel potent and selective catechol O-methyltransferase inhibitors.  

PubMed

A series of disubstituted catechol derivatives was synthesized and tested as potential COMT inhibitors. The most active compounds were more than 1000 times more potent (IC50 = 3-6 nM) in vitro than the known COMT inhibitor, 3',4'-dihydroxy-2-methylpropiophenone (U 0521, IC50 = 6000 nM). The new compounds were also highly selective COMT inhibitors with no activity against other essential enzymes involved in the synthesis and metabolism of catecholamines. PMID:2704029

Bäckström, R; Honkanen, E; Pippuri, A; Kairisalo, P; Pystynen, J; Heinola, K; Nissinen, E; Linden, I B; Männistö, P T; Kaakkola, S

1989-04-01

232

Identification of a potent and selective non-basic cathepsin K inhibitor.  

PubMed

Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors. PMID:16413777

Li, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald B; Léger, Serge; Massé, Frédéric; McGrath, Mary E; McKay, Daniel J; Percival, M David; Riendeau, Denis; Rodan, Sevgi B; Thérien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W Cameron

2006-04-01

233

Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy  

PubMed Central

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays. PMID:24900590

2013-01-01

234

Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47(phox) pathway.  

PubMed

Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation and decreased reactive oxygen species (ROS) generation and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-Jun and c-Fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPK phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases. PMID:24967690

Tsai, Ming-Horng; Lin, Zih-Chan; Liang, Chan-Jung; Yen, Feng-Lin; Chiang, Yao-Chang; Lee, Chiang-Wen

2014-09-01

235

Quantitative Assessment of the Association of COX-2 (Cyclooxygenase-2) Immunoexpression with Prognosis in Human Osteosarcoma: A Meta-Analysis  

PubMed Central

Background Numerous studies examining the relationship between Cyclooxygenase-2 (COX-2) immunoexpression and clinical outcome in osteosarcoma patients have yielded inconclusive results. Methods We accordingly conducted a meta-analysis of 9 studies (442 patients) that evaluated the correlation between COX-2 immunoexpression and clinical prognosis (death). Pooled odds ratios (OR) and risk ratios (RR) with 95% confidence intervals (95% CI) were calculated using the random-effects or fixed-effects model. Results Meta–analysis showed no significant association between COX-2 positivity and age, gender, tumor location, histology, stage, metastasis or 90% necrosis. Conversely, COX-2 immunoexpression was associated with overall survival rate (RR=2.12; 95% CI: 1.10–3.74; P=0.009) and disease-free survival rate (RR=1.63; 95% CI: 1.17–2.28; P=0.004) at 2 years. Sensitivity analysis performed by omitting low quality studies showed that the pooled results were stable. Conclusions COX-2 positivity was associated with a lower 2-year overall survival rate and disease-free survival rate. COX-2 expression change is an independent prognostic factor in patients with osteosarcoma. PMID:24358237

Xiao, Zengming; Wu, Hao; Wu, Yang

2013-01-01

236

Biochemical And Structural Evaluation of Highly Selective 2-Arylbenzoxazole-Based Transthyretin Amyloidogenesis Inhibitors  

SciTech Connect

To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding. High resolution crystal structures (1.3-1.5 A) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to characterize their binding orientation. Collectively, the results demonstrate that thyroid hormone-like substitution patterns on one aryl ring lead to potent and highly selective TTR amyloidogenesis inhibitors that lack undesirable thyroid hormone receptor or COX-1 binding.

Johnson, S.M.; Connelly, S.; Wilson, I.A.; Kelly, J.W.

2009-05-18

237

Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): Pyridodiazepine amines  

Microsoft Academic Search

An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E–I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface.

Bolin Geng; Gregory Basarab; Janelle Comita-Prevoir; Madhusudhan Gowravaram; Pamela Hill; Andrew Kiely; James Loch; Lawrence MacPherson; Marshall Morningstar; George Mullen; Ekundayo Osimboni; Alexander Satz; Charles Eyermann; Tomas Lundqvist

2009-01-01

238

Structure based design of a series of potent and selective non peptidic PTP-1B inhibitors.  

PubMed

A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase. PMID:15013020

Lau, Cheuk K; Bayly, Christopher I; Gauthier, Jacques Yves; Li, Chun Sing; Therien, Michel; Asante-Appiah, Ernest; Cromlish, Wanda; Boie, Yves; Forghani, Farnaz; Desmarais, Sylvie; Wang, Qingping; Skorey, Kathryn; Waddleton, Deena; Payette, Paul; Ramachandran, Chidambaram; Kennedy, Brian P; Scapin, Giovana

2004-02-23

239

Structure based design of a series of potent and selective non peptidic PTP1B inhibitors  

Microsoft Academic Search

A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase.

Cheuk K. Lau; Christopher I. Bayly; Jacques Yves Gauthier; Chun Sing Li; Michel Therien; Ernest Asante-Appiah; Wanda Cromlish; Yves Boie; Farnaz Forghani; Sylvie Desmarais; Qingping Wang; Kathryn Skorey; Deena Waddleton; Paul Payette; Chidambaram Ramachandran; Brian P. Kennedy; Giovana Scapin

2004-01-01

240

Selectivity of Nonsteroidal Antiinflammatory Drugs as Inhibitors of Constitutive and Inducible Cyclooxygenase  

Microsoft Academic Search

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)

Jane A. Mitchell; Pravit Akarasereenont; Christoph Thiemermann; Roderick J. Flower; John R. Vane

1993-01-01

241

Progress in the development of selective inhibitors of aurora kinases.  

PubMed

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family. PMID:16101420

Mortlock, Andrew A; Keen, Nicholas J; Jung, Frederic H; Heron, Nicola M; Foote, Kevin M; Wilkinson, Robert W; Green, Stephen

2005-01-01

242

Progress in the development of selective inhibitors of Aurora kinases.  

PubMed

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family. PMID:15853647

Mortlock, Andrew; Keen, Nicholas J; Jung, Frederic H; Heron, Nicola M; Foote, Kevin M; Wilkinson, Robert; Green, Stephen

2005-01-01

243

The selectivity of protein kinase inhibitors: a further update  

PubMed Central

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)–raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes. PMID:17850214

Bain, Jenny; Plater, Lorna; Elliott, Matt; Shpiro, Natalia; Hastie, C. James; Mclauchlan, Hilary; Klevernic, Iva; Arthur, J. Simon C.; Alessi, Dario R.; Cohen, Philip

2007-01-01

244

Expression of integrin ?3?1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer  

PubMed Central

Background Expression of integrin ?3?1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin ?3?1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin ?3?1 and COX2 by testing for their correlated expression among various forms of human breast cancer. Methods Immunohistochemistry was performed to assess co-expression of ?3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n?=?59 samples) or obtained from Albany Medical Center archives (n?=?68 samples). Immunostaining intensity for the integrin ?3 subunit or COX2 was scored, and Spearman’s rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria. Results Although expression of integrin ?3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between ?3 and COX2 in both tissue microarrays (rs?=?0.49, p?COX2 and ?3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin ?3?1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of ?3?1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target ?3?1, and that ?3 expression might serve as an independent prognostic biomarker. PMID:24950714

2014-01-01

245

Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C(2)C(12) myotubes.  

PubMed

In skeletal muscle, saturated free fatty acids (FFAs) act as proinflammatory stimuli, and cyclooxygenase-2 (COX-2) is a pro/anti-inflammatory enzyme induced at sites of inflammation, which contributes to prostaglandin production. However, little is known about the regulation of COX-2 expression and its responses to FFAs in skeletal muscle. Herein, we examined the effects of saturated and unsaturated FFAs, including a recently identified lipokine (lipid hormone derived from adipocytes), palmitoleate, on COX-2 expression in C(2)C(12) myotubes as a skeletal muscle model. Exposure of myotubes to saturated FFAs [palmitate (16:0) and stearate (18:0)], but not to unsaturated FFAs [palmitoleate (16:1), oleate (18:1), and linoleate (18:2)], led to a slow-onset induction of COX-2 expression and subsequent prostaglandin E(2) production via mechanisms involving the p38 MAPK and NF-kappaB but not the PKC signaling cascades. Pharmacological modulation of mitochondrial oxidative function failed to interfere with COX-2 expression, suggesting the mitochondrial overload/excessive beta-oxidation contribution to this event to be minimal. On the contrary, unsaturated FFAs appeared to effectively antagonize palmitate-induced COX-2 expression with markedly different potencies (linoleate > oleate > palmitoleate), being highly associated with the suppressive profile of each unsaturated FFA toward palmitate-evoked intracellular signals, including p38, JNK, ERK1/2 MAPKs, and PKCtheta, as well as IkappaB degradation. In addition, our data suggest little involvement of PPAR in the protective actions of unsaturated FFAs against palmitate-induced COX-2 expression. No direct contribution of the increased COX-2 activity in generating palmitate-induced insulin resistance was detected, at least in terms of insulin-responsive Akt phosphorylation and GLUT4 translocation. Taken together, our data provide a novel insight into the molecular mechanisms responsible for the FFA-induced COX-2 expression in skeletal muscle and raise the possibility that, in skeletal myocytes, COX-2 and its product prostaglandins may play an important role in the complex inflammation responses caused by elevated FFAs, for example, in the diabetic state. PMID:19755671

Kadotani, Akito; Tsuchiya, Yo; Hatakeyama, Hiroyasu; Katagiri, Hideki; Kanzaki, Makoto

2009-12-01

246

Molecular dynamics simulations for selection of kinetic hydrate inhibitors  

Microsoft Academic Search

Natural gas hydrates are ice-like structures composed of water and gas molecules that have long been a problem in petroleum industry. Heavy cost of alcohol and glycol injection has spurred an interest in called ‘kinetic inhibitors’ able to slow down the hydrate formation rather than prevent it. Since it is not possible to compare directly the macroscopic effects of different

Bjørn Kvamme; Tatyana Kuznetsova; Kjetil Aasoldsen

2005-01-01

247

Effects of selected enzyme inhibitors on blood and eggshell parameters in the laying hen  

E-print Network

EFFECTS OF SELECTED ENZYME INHIBITORS ON BLOOD AND EGGSHELL PARAMETERS IN THE LAYING HEN A Thesis by JODY RENEE LONG Submitted to the Graduate College of Texas ASM University in partial fullfilment of the requirement for the degree... of MASTER OF SCIENCE December 1987 Major Subject: Poultry Science EFFECTS OF SELECTED ENZYME INHIBITORS ON BLOOD AND EGGSHELL PARANETERS IN THE LAYING HEN A Thesis by JODY RENEE LONG Approved as to style and content by: T. . Odom (Chairman...

Long, Jody Renee

2012-06-07

248

Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys  

Microsoft Academic Search

Modification of the behavioral effects of cocaine by the selective serotonin (5-HT) uptake inhibitors citalopram and fluoxetine and the selective dopamine (DA) uptake inhibitor GBR 12909 was investigated in squirrel monkeys trained under a fixed-interval schedule of reinforcement or a two-lever cocaine-discrimination procedure. Under the fixed-interval schedule cocaine (0.03–1.78 mg\\/kg) produced dose-related increases in response rate, reaching an average maximum

R. D. Spealman

1993-01-01

249

Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability  

Microsoft Academic Search

OBJECTIVE--To examine the evidence for using selective serotonin reuptake inhibitors instead of tricyclic antidepressants in the first line treatment of depression. DESIGN--Meta-analysis of 63 randomised controlled trials comparing the efficacy and acceptability of selective serotonin reuptake inhibitors with those of tricyclic and related antidepressants. MAIN OUTCOME MEASURES--Improvement in mean scores on Hamilton depression rating scale for 53 randomised controlled trials.

F Song; N Freemantle; T. A Sheldon; A House; P Watson; A Long; J Mason

1993-01-01

250

Selection and analysis of HIV1 integrase strand transfer inhibitor resistant mutant viruses  

Microsoft Academic Search

This report describes methods for the selection and analysis of antiretroviral resistance to HIV integrase strand transfer inhibitors (InSTIs) in cell culture. The method involves the serial passage of HIV-1 in the presence of increasing concentrations of test inhibitors, followed by the cloning and sequencing of the integrase coding region from the selected viruses. The identified mutations are subsequently re-engineered

Marc Witmer; Robert Danovich

2009-01-01

251

Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity.  

PubMed Central

The binding of two 5-substituted-1,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (P1-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-155 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzyme/inhibitor complexes, the S1' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity. PMID:9792098

Finzel, B. C.; Baldwin, E. T.; Bryant, G. L.; Hess, G. F.; Wilks, J. W.; Trepod, C. M.; Mott, J. E.; Marshall, V. P.; Petzold, G. L.; Poorman, R. A.; O'Sullivan, T. J.; Schostarez, H. J.; Mitchell, M. A.

1998-01-01

252

Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants: a meta-analysis.  

PubMed Central

OBJECTIVE--To assess treatment discontinuation rates with selective serotonin reuptake inhibitors compared with tricyclic antidepressants. DESIGN--Meta-analysis of 62 randomised controlled trials. SUBJECTS--6029 patients with major unipolar depression. MAIN OUTCOME MEASURES--Pooled risk ratios for drop out rates with respect to all cases of discontinuation and those due to side effects and treatment failure. RESULTS--The total discontinuation rate was 10% lower with selective serotonin reuptake inhibitors than with tricyclic antidepressants (risk ratio 0.90; 95% confidence interval 0.84 to 0.97) and the drop out rate due to side effects was 25% lower (risk ratio 0.75; 0.66 to 0.84). There was no significant difference between drug classes in the drop out rates for treatment failure. The risk ratios for drop out did not differ significantly between individual selective serotonin reuptake inhibitors. CONCLUSIONS--Selective serotonin reuptake inhibitors are better tolerated than tricyclic antidepressants as measured by total numbers of drop outs. The definite advantage to selective serotonin reuptake inhibitors is explained by fewer drop outs due to side effects. The overall difference, however, is comparatively small and may not be clinically relevant. Analyses of cost effectiveness should not overestimate the advantage to selective serotonin reuptake inhibitors. PMID:7613276

Anderson, I. M.; Tomenson, B. M.

1995-01-01

253

Identification of Selective and Potent Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase  

PubMed Central

Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-d-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets. PMID:23594271

Poplawski, Sarah E.; Lai, Jack H.; Li, Youhua; Jin, Zhiping; Liu, Yuxin; Wu, Wengen; Wu, Yong; Zhou, Yuhong; Sudmeier, James L.; Sanford, David G.; Bachovchin, William W.

2014-01-01

254

Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development  

PubMed Central

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development. PMID:24900593

2013-01-01

255

Development of highly selective casein kinase 1?/1? (CK1?/?) inhibitors with potent antiproliferative properties.  

PubMed

The development of a series of potent and highly selective casein kinase 1?/? (CK1?/?) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC?? ? 50 nM versus CK1?. The two lead compounds have ?100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines. PMID:23787102

Bibian, Mathieu; Rahaim, Ronald J; Choi, Jun Yong; Noguchi, Yoshihiko; Schürer, Stephan; Chen, Weimin; Nakanishi, Shima; Licht, Konstantin; Rosenberg, Laura H; Li, Lin; Feng, Yangbo; Cameron, Michael D; Duckett, Derek R; Cleveland, John L; Roush, William R

2013-08-01

256

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer.  

PubMed

SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. Cancer Res; 74(20); 5925-33. ©2014 AACR. PMID:25320180

Ming, Mei; Han, Weinong; Zhao, Baozhong; Sundaresan, Nagalingam R; Deng, Chu-Xia; Gupta, Mahesh P; He, Yu-Ying

2014-10-15

257

Selection of corrosion inhibitors for use in sour media  

SciTech Connect

Extended Hueckel molecular orbital (EHMO) calculations were performed on some substituted aliphatic amines and some substituted pyridine derivatives that are used as corrosion inhibitors in sour media. Correlations of corrosion rates with the charge on the nitrogen atom (Z[sub n]), energy of the highest occupied molecular orbital (E[sub HOMO]), energy gap between the lowest unoccupied molecular orbital (E[sub LUMO]) and E[sub HOMO], ionization potential, and Hammett's [sigma] parameter were made.

Sastri, V.S. (CANMET, Ottawa, Ontario (Canada). Metals Technology Labs.); Perumareddi, J.R. (Florida Atlantic Univ., Boca Raton, FL (United States). Dept. of Chemistry)

1994-06-01

258

Structural Basis for Binding and Selectivity of Antimalarial and Anticancer Ethylenediamine Inhibitors to Protein Farnesyltransferase  

SciTech Connect

Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.

Hast, Michael A.; Fletcher, Steven; Cummings, Christopher G.; Pusateri, Erin E.; Blaskovich, Michelle A.; Rivas, Kasey; Gelb, Michael H.; Voorhis, Wesley C.Van; Sebti, Said M.; Hamilton, Andrew D.; Beese, Lorena S. ((Yale)); ((USF)); ((UWASH)); ((Duke))

2009-03-20

259

Peptide-Based Selective Inhibitors of Matrix Metalloproteinase-Mediated Activities  

PubMed Central

The matrix metalloproteinases (MMPs) exhibit a broad array of activities, some catalytic and some non-catalytic in nature. An overall lack of selectivity has rendered small molecule, active site targeted MMP inhibitors problematic in execution. Inhibitors that favor few or individual members of the MMP family often take advantage of interactions outside the enzyme active site. We presently focus on peptide-based MMP inhibitors and probes that do not incorporate conventional Zn2+ binding groups. In some cases, these inhibitors and probes function by binding only secondary binding sites (exosites), while others bind both exosites and the active site. A myriad of MMP mediated-activities beyond selective catalysis can be inhibited by peptides, particularly cell adhesion, proliferation, motility, and invasion. Selective MMP binding peptides comprise highly customizable, unique imaging agents. Areas of needed improvement for MMP targeting peptides include binding affinity and stability. PMID:23201642

Ndinguri, Margaret W.; Bhowmick, Manishabrata; Tokmina-Roszyk, Dorota; Robichaud, Trista K.; Fields, Gregg B.

2013-01-01

260

Expression of COX2 and p53 in Rat Esophageal Cancer Induced by Reflux of Duodenal Contents  

PubMed Central

Aim. Reflux of duodenal contents can induce mucosal injury, stimulate cell proliferation, and promote tumorigenesis. We examined the expression of COX2 and p53 in rat esophageal lesions induced by duodenal content reflux. Methods. Thirty 8-week-old male Wistar rats were exposed to duodenal content esophageal reflux. All animals underwent an esophagoduodenal anastomosis (EDA) with total gastrectomy in order to produce chronic esophagitis. Ten rats were the sham. Control. They were sacrificed at the 40th week. Their esophagi were examined for HE, COX2, p53, and proliferating cell nuclear antigen (PCNA). Results. After 40 weeks of reflux, dysplasia, squamous cell carcinoma (SCC), and adenocarcinoma (ADC) were found. PCNA labeling index was higher in dysplastic and cancer tissue than that in normal. Overexpression of COX2 was shown in ADC and SCC. Wild-type p53 accumulation was found in ADC, and not in SCC. Conclusion. Reflux of duodenal contents into the esophagus led to ADC and SCC in rats. COX2 may play an important role in esophageal cancer by duodenal content reflux. Our present results suggest an association between wild-type p53 accumulation and COX2 expression in ADC, with no such relation seen in SCC. PMID:22272378

Hashimoto, Naoki

2012-01-01

261

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease  

PubMed Central

Introduction Inhibition of gamma-secretase presents a direct target for lowering A? production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. Methods In vitro assays monitoring inhibitor potencies at APP ?-site cleavage (equivalent to A?40), and Notch ?-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A? production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A? was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A? reduction vs. Notch signaling endpoints in periphery. Results The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A? production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A? in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A? was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. Conclusions The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD. PMID:21190552

2010-01-01

262

Effects of Novel Isoform-Selective Phosphoinositide 3-Kinase Inhibitors on Natural Killer Cell Function  

PubMed Central

Phosphoinositide 3-kinases (PI3Ks) are promising targets for therapeutic development in cancer. The class I PI3K isoform p110? has received considerable attention in oncology because the gene encoding p110? (PIK3CA) is frequently mutated in human cancer. However, little is known about the function of p110? in lymphocyte populations that modulate tumorigenesis. We used recently developed investigational inhibitors to compare the function of p110? and other isoforms in natural killer (NK) cells, a key cell type for immunosurveillance and tumor immunotherapy. Inhibitors of all class I isoforms (pan-PI3K) significantly impaired NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity against tumor cells, whereas p110?-selective inhibitors had no effect. In NK cells stimulated through NKG2D, p110? inhibition modestly reduced PI3K signaling output as measured by AKT phosphorylation. Production of IFN-? and NK cell-derived chemokines was blocked by a pan-PI3K inhibitor and partially reduced by a p110?inhibitor, with lesser effects of p110? inhibitors. Oral administration of mice with MLN1117, a p110? inhibitor in oncology clinical trials, had negligible effects on NK subset maturation or terminal subset commitment. Collectively, these results support the targeting of PIK3CA mutant tumors with selective p110? inhibitors to preserve NK cell function. PMID:24915189

Yea, Sung Su; So, Lomon; Mallya, Sharmila; Lee, Jongdae; Rajasekaran, Kamalakannan; Malarkannan, Subramaniam; Fruman, David A.

2014-01-01

263

Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors  

PubMed Central

Hyperactivation of the calcium-dependent cysteine protease, calpain-1 (Cal1), is implicated as a primary or secondary pathological event in a wide range of illnesses, and in neurodegenerative states, including Alzheimer’s disease (AD). E-64 is an epoxide-containing natural product identified as a potent non-selective, calpain inhibitor, with demonstrated efficacy in animal models of AD. Using E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogs were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1cat), demonstrated using LC-MS/MS. Refinement yielded 2nd generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetic studies comparing full length Cal1 with the general cysteine protease, papain. PMID:23834438

Schiefer, Isaac T.; Tapadar, Subhasish; Litosh, Vladislav; Siklos, Marton; Scism, Rob; Wijewickrama, Gihani T.; Chandrasena, Esala P.; Sinha, Vaishali; Tavassoli, Ehsan; Brunsteiner, Michael; Fa?, Mauro; Arancio, Ottavio; Petukhov, Pavel; Thatcher, Gregory R. J.

2014-01-01

264

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design  

E-print Network

Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde- 3-phosphate, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various

Gelb, Michael

265

Celastrol, an inhibitor of heat shock protein 90? potently suppresses the expression of matrix metalloproteinases, inducible nitric oxide synthase and cyclooxygenase-2 in primary human osteoarthritic chondrocytes.  

PubMed

Overexpression of matrix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have long been suggested to play crucial roles in the progression of osteoarthritis. Studies have showed that selective MMPs, iNOS and COX-2 inhibitors possess great potential as chondroprotective agents for osteoarthritis. Therefore, there have been intensive efforts to develop novel natural compounds that target MMPs, iNOS and COX-2 activation. As interleukin-1? (IL-1?) is one of the key proinflammatory cytokines contributing to the progression in osteoarthritis, we investigated the effect of celastrol, a triterpenoid compound extracted from the Chinese herb Tript erygium wilfordii Hook F, in neutralizing the inflammatory effects of IL-1? on MMPs, iNOS and COX-2 expression as well as nitric oxide (NO) and prostaglandin E2 (PGE2) production. Protein expression was detected by Western blotting or by enzyme-linked immunosorbent assay (ELISA); messenger RNA (mRNA) expression was examined by real-time reverse transcription-polymerase chain reaction analysis and the involvement of signal pathway was assessed by transient transfection and luciferase activity assay. We found that treatment of primary human osteoarthritic chondrocytes with various concentrations of celastrol resulted in striking decrease in the expression of MMP-1, MMP-3, MMP-13, iNOS-2 and COX-2. In addition, celastrol treatment of cells also inhibited the activation of nuclear factor-kappa B (NF-kappaB). Taken together, we provide evidence that celastrol can protect human chondrocytes by downregulating the expression of MMPs, iNOS and COX-2. We suggest that celastrol could be a useful agent for prevention and treatment of osteoarthritis. PMID:23396231

Ding, Qian-Hai; Cheng, Ye; Chen, Wei-Ping; Zhong, Hui-Ming; Wang, Xiang-Hua

2013-05-15

266

Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors  

PubMed Central

Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell survival. SphK phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has been implicated in cancer growth and survival. SphK exists as two different isotypes, namely SphK1 and SphK2, which play different roles inside the cell. In this report, we describe SphK inhibitors based on the immunomodulatory drug, FTY720, which is phosphorylated by SphK2 to generate a S1P mimic. Structural modification of FTY720 provided a template for synthesizing new inhibitors. A diversity-oriented synthesis generated a library of SphK inhibitors with a novel scaffold and headgroup. We have discovered subtype selective inhibitors with Ki’s in the low micromolar range. This is the first report describing quaternary ammonium salts as SphK inhibitors. PMID:22137932

Raje, Mithun R.; Knott, Kenneth; Kharel, Yugesh; Bissel, Philippe; Lynch, Kevin R.; Santos, Webster L.

2013-01-01

267

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold  

PubMed Central

Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>103) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory. PMID:24900696

2013-01-01

268

Sulfated Pentagalloylglucoside is a Potent, Allosteric, and Selective Inhibitor of Factor XIa  

PubMed Central

Inhibition of factor XIa (FXIa) is a novel paradigm for developing anticoagulants without major bleeding consequences. We present the discovery of sulfated pentagalloylglucoside (6) as a highly selective inhibitor of human FXIa. Biochemical screening of a focused library led to the identification of 6, a sulfated aromatic mimetic of heparin. Inhibitor 6 displayed a potency of 551 nM against FXIa, which was at least 200-fold more selective than other relevant enzymes. It also prevented activation of factor IX and prolonged human plasma and whole blood clotting. Inhibitor 6 reduced VMAX of FXIa hydrolysis of chromogenic substrate without affecting the KM suggesting an allosteric mechanism. Competitive studies showed that 6 bound in the heparin-binding site of FXIa. No allosteric small molecule has been discovered to date that exhibits equivalent potency against FXIa. Inhibitor 6 is expected to open up a major route to allosteric FXIa anticoagulants with clinical relevance. PMID:23316863

Al-Horani, Rami A.; Ponnusamy, Pooja; Mehta, Akul Y.; Gailani, David; Desai, Umesh R.

2013-01-01

269

Discovery of Potent and Selective Inhibitors of Trypanosoma brucei Ornithine Decarboxylase*  

PubMed Central

Human African trypanosomiasis, caused by the eukaryotic parasite Trypanosoma brucei, is a serious health problem in much of central Africa. The only validated molecular target for treatment of human African trypanosomiasis is ornithine decarboxylase (ODC), which catalyzes the first step in polyamine metabolism. Here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of ODC. This screen identified four novel families of ODC inhibitors, including the first inhibitors selective for the parasitic enzyme. These compounds display unique binding modes, suggesting the presence of allosteric regulatory sites on the enzyme. Docking of a subset of these inhibitors, coupled with mutagenesis, also supports the existence of these allosteric sites. PMID:20220141

Smithson, David C.; Lee, Jeongmi; Shelat, Anang A.; Phillips, Margaret A.; Guy, R. Kiplin

2010-01-01

270

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors  

PubMed Central

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity. PMID:22373386

2011-01-01

271

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors.  

PubMed

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity. PMID:22373386

Kato, Noriyasu; Oka, Mitsuru; Murase, Takayo; Yoshida, Masahiro; Sakairi, Masao; Yakufu, Mirensha; Yamashita, Satoko; Yasuda, Yoshika; Yoshikawa, Aya; Hayashi, Yuji; Shirai, Masahiro; Mizuno, Yukie; Takeuchi, Mitsuaki; Makino, Mitsuhiro; Takeda, Motohiro; Kakigami, Takuji

2011-01-01

272

Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): pyridodiazepine amines.  

PubMed

An SAR study of an HTS screening hit generated a series of pyridodiazepine amines as potent inhibitors of Helicobacter pylori glutamate racemase (MurI) showing highly selective anti-H. pylori activity, marked improved solubility, and reduced plasma protein binding. X-ray co-crystal E-I structures were obtained. These uncompetitive inhibitors bind at the MurI dimer interface. PMID:19097892

Geng, Bolin; Basarab, Gregory; Comita-Prevoir, Janelle; Gowravaram, Madhusudhan; Hill, Pamela; Kiely, Andrew; Loch, James; MacPherson, Lawrence; Morningstar, Marshall; Mullen, George; Osimboni, Ekundayo; Satz, Alexander; Eyermann, Charles; Lundqvist, Tomas

2009-02-01

273

Structure-based design of potent and selective leishmania N-myristoyltransferase inhibitors.  

PubMed

Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme. PMID:25238611

Hutton, Jennie A; Goncalves, Victor; Brannigan, James A; Paape, Daniel; Wright, Megan H; Waugh, Thomas M; Roberts, Shirley M; Bell, Andrew S; Wilkinson, Anthony J; Smith, Deborah F; Leatherbarrow, Robin J; Tate, Edward W

2014-10-23

274

Structure-Based Design of Potent and Selective LeishmaniaN-Myristoyltransferase Inhibitors  

PubMed Central

Inhibitors of LeishmaniaN-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme. PMID:25238611

2014-01-01

275

Structural origins of AGC protein kinase inhibitor selectivities: PKA as a drug discovery tool.  

PubMed

The era of structure-based protein kinase inhibitor design began in the early 1990s with the determination of crystal structures of protein kinase A (PKA, or cyclic AMP-dependent kinase). Although many other protein kinases have since been extensively characterized, PKA remains a prototype for studies of protein kinase active conformations. It serves well as a model for the structural properties of AGC subfamily protein kinases, clarifying inhibitor selectivity profiles. Its reliable expression, constitutive activity, simple domain structure, and reproducible crystallizability have also made it a useful surrogate for the discovery of inhibitors of both established and emerging AGC kinase targets. PMID:23092797

Åberg, Espen; Lund, Bjarte; Pflug, Alexander; Gani, Osman A B S M; Rothweiler, Ulli; de Oliveira, Taianà M; Engh, Richard A

2012-10-01

276

Discovery of novel second mitochondria-derived activator of caspase mimetics as selective inhibitor of apoptosis protein inhibitors.  

PubMed

Inhibitor of apoptosis (IAP) proteins are widely considered as promising cancer drug targets, especially for drug-resistant tumors. Mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (SMAC) is a rational strategy to design potential IAP inhibitors. In this report, we used the bioactive conformation of AVPI tetrapeptide in the N terminus of SMAC as a template and performed a shape-based virtual screening against a drug-like compound library to identify novel IAP inhibitors. Top hits were subsequently docked to available IAP crystal structures as a secondary screening followed by validation using in vitro biologic assays. Four novel hit compounds were identified to potently inhibit cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines. The best compound, UC-112 [5-((benzyloxy)methyl)-7-(pyrrolidin-1-ylmethyl)quinolin-8-ol], has IC50 values ranging from 0.7 to 3.4 µM. UC-112 also potently inhibits the growth of P-glycoprotein (P-gp)-overexpressed multidrug-resistant cancer cells, strongly activates caspase-3/7 and caspase-9 activities, and selectively downregulates survivin level at a concentration as low as 1 µM. Coincubation of UC-112 with a known proteasome inhibitor Z-Leu-Leu-Leu-CHO (MG-132) rescued survivin inhibition, consistent with the anticipated mechanism of action for UC-112. As a single agent, UC-112 strongly inhibits tumor growth and reduces both X chromosome-linked IAP and survivin levels in an A375 human melanoma xenograft model in vivo. Overall, our study identified novel scaffolds, especially UC-112, as new platforms on which potent and selective IAP antagonists can be developed. PMID:24623800

Wang, Jin; Li, Wei

2014-05-01

277

Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1  

PubMed Central

A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-XL, and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-XL, and Bcl-w and a set of inhibitors with varied selectivity to Bcl-2, Bcl-XL, and Bcl-w protein have been identified. Molecular modeling of the interaction of the BHI-1 based analogs with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-XL, and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for anti-apoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-XL, and Bcl-w by targeting the nonconserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling aided rational development of BHI-1 based selective inhibitor for anti-apoptotic Bcl-2 proteins is underway. PMID:17227711

Xing, Chengguo; Wang, Liangyou; Tang, XiaoHu; Sham, Yuk Y

2007-01-01

278

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

PubMed Central

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 the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. Results The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. Conclusion The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor. PMID:15987447

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

2005-01-01

279

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors.  

PubMed

Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a-2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-?-diketones (5a-5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H2S gas in the presence of triethylamine. All the synthesized compounds (2a-2i and 3a-3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3-4h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data. PMID:23769654

Chandna, Nisha; Kumar, Satish; Kaushik, Pawan; Kaushik, Dhirender; Roy, Somendu K; Gupta, Girish K; Jachak, Sanjay M; Kapoor, Jitander K; Sharma, Pawan K

2013-08-01

280

[Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis].  

PubMed

The medical treatment of endometriosis needs to be optimized. Therapeutic management strategies of endometriosis-associated pain or recurrent disease is primarily aimed at downregulating the ovarian function or at antagonizing the effect of estrogen in ectopic endometrial implants. In this context, basic research is delivering powerful tools for the possible development of new, specific treatment modalities. Recently, aromatase overexpression has been detected in endometriotic tissue. Aromatase (p450arom) is responsible for conversion of C19 androgens to estrogen in several human tissues. Aromatase activity gives rise to local estrogen biosynthesis, which, in turn, stimulates prostaglandin E(2) production by upregulation of cyclooxygenase-2 (COX-2), thus establishing a positive feedback cycle. Another abnormality in endometriosis, i. e. the deficiency in 17 beta-hydroxysteroiddehydrogenase type-II (17 beta-HSD-Type-II) expression, impairs the inactivation of estradiol to estrone. In contrast to the eutopic endometrium, these molecular aberrations collectively favour accumulation of increasing amounts of local estradiol and prostaglandin E(2) in endometriosis. In several human cell lines, prostaglandin and estrogen concentrations are associated with proliferation, migration, angiogenesis, apoptosis resistance, and even invasiveness. Consequently, aromatase and COX-2 are promising new therapeutic targets. In summary, specific aromatase inhibitors (such as Letrozole, Anastrozol or Exemestan) or selective COX-2 inhibitors (e.g. Celecoxib, Rofecoxib) are of great interest to be studied in clinical trials in premenopausal woman with endometriosis to extend the spectrum of currently available treatment options. PMID:14505258

Ebert, A D; Bartley, J; David, M; Schweppe, K-W

2003-01-01

281

Conformationally-Restricted Dipeptide Amides as Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors  

PubMed Central

Four new conformationally-restricted analogues of the potent and selective neuronal nitric oxide synthase inhibitor, L-nitroargininyl-L-2,4-diaminobutyramide (1), have been synthesized. N?-Methyl and N?-benzyl derivatives (3 and 4, respectively) of 4N-(L-ArgNO2)-trans-4-amino-L-prolineamide (2) are also selective inhibitors, but the potency and selectivity of 3 are weak. Analogue 4 has only one-third the potency and one-half to one-third the selectivity of 2 against iNOS and eNOS, respectively. 3-N-(L-ArgNO2)-trans-3-amino-L-prolineamide (6) is as potent an inhibitor of nNOS as is 2; selectivity for nNOS over iNOS is half of that for 2 but the selectivity for nNOS over eNOS is almost double that for 2. The corresponding cis-isomer (5) is a weak inhibitor of nNOS. These results are supported by computer modeling. PMID:17034131

Ji, Haitao; Gomez-Vidal, Jose A.; Martasek, Pavel; Roman, Linda J.; Silverman, Richard B.

2008-01-01

282

Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor  

Microsoft Academic Search

Background: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression.Methods: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake

Erik H. F. Wong; Mark S. Sonders; Susan G. Amara; Paula M. Tinholt; Montford F. P. Piercey; William P. Hoffmann; Deborah K. Hyslop; Stanley Franklin; Roger D. Porsolt; Alberto Bonsignori; Nicola Carfagna; Robert A. McArthur

2000-01-01

283

Luteolin, a bioflavonoid inhibits azoxymethane-induced colon carcinogenesis: Involvement of iNOS and COX-2  

PubMed Central

Colon cancer (CRC) is a serious health problem through worldwide. Development of novel drug without side effect for this cancer was crucial. Luteolin (LUT), a bioflavonoid has many beneficial effects such as antioxidant, anti-inflammatory, anti-proliferative properties. Azoxymethane (AOM), a derivative of 1, 2-Dimethyl hydrazine (DMH) was used for the induction of CRC in Balb/C mice. CRC was induced by intraperitoneal injection of AOM to mice at the dose of 15 mg/body kg weight for 3 weeks. Mouse was treated with LUT at the dose of 1.2 mg/body kg weight orally until end of the experiment. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygense (COX)-2 were analyzed by RT-PCR and immunohistochemistry. The expressions of iNOS and COX-2 were increased in the case of AOM induction. Administration of LUT effectively reduced the expressions of iNOS and COX-2. The present study revealed that, LUT suppresses both iNOS and COX-2 expressions and act as an anti-inflammatory role against CRC. PMID:24991108

Pandurangan, Ashok Kumar; Kumar, Suresh Ananda Sadagopan; Dharmalingam, Prakash; Ganapasam, Sudhandiran

2014-01-01

284

Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO  

ERIC Educational Resources Information Center

It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we…

Albrecht, Doris

2007-01-01

285

Lead induces COX-2 expression in glial cells in a NFAT-dependent, AP-1/NF?B-independent manner.  

PubMed

Epidemiologic studies have provided solid evidence for the neurotoxic effect of lead for decades of years. In view of the fact that children are more vulnerable to the neurotoxicity of lead, lead exposure has been an urgent public health concern. The modes of action of lead neurotoxic effects include disturbance of neurotransmitter storage and release, damage of mitochondria, as well as induction of apoptosis in neurons, cerebrovascular endothelial cells, astroglia and oligodendroglia. Our studies here, from a novel point of view, demonstrates that lead specifically caused induction of COX-2, a well known inflammatory mediator in neurons and glia cells. Furthermore, we revealed that COX-2 was induced by lead in a transcription-dependent manner, which relayed on transcription factor NFAT, rather than AP-1 and NF?B, in glial cells. Considering the important functions of COX-2 in mediation of inflammation reaction and oxidative stress, our studies here provide a mechanistic insight into the understanding of lead-associated inflammatory neurotoxicity effect via activation of pro-inflammatory NFAT3/COX-2 axis. PMID:25193092

Wei, Jinlong; Du, Kejun; Cai, Qinzhen; Ma, Lisha; Jiao, Zhenzhen; Tan, Jinrong; Xu, Zhou; Li, Jingxia; Luo, Wenjin; Chen, Jingyuan; Gao, Jimin; Zhang, Dongyun; Huang, Chuanshu

2014-11-01

286

Preventive inositol hexaphosphate extracted from rice bran inhibits colorectal cancer through involvement of Wnt/?-catenin and COX-2 pathways.  

PubMed

Nutritional or dietary factors have drawn attention due to their potential as an effective chemopreventive agent, which is considered a more rational strategy in cancer treatment. This study was designed to evaluate the effect of IP? extracted from rice bran on azoxymethane- (AOM-) induced colorectal cancer (CRC) in rats. Initially, male Sprague Dawley rats were divided into 5 groups, with 6 rats in each group. The rats received two intraperitoneal (i.p.) injections of AOM in saline (15 mg/kg body weight) over a 2-week period to induce CRC. IP? was given in three concentrations, 0.2% (w/v), 0.5% (w/v), and 1.0% (w/v), via drinking water for 16 weeks. The deregulation of the Wnt/?-catenin signaling pathway and the expression of cyclooxygenase (COX)-2 have been implicated in colorectal tumorigenesis. ?-Catenin and COX-2 expressions were analysed using the quantitative RT-PCR and Western blotting. Herein, we reported that the administration of IP? markedly suppressed the incidence of tumors when compared to the control. Interestingly, the administration of IP? had also markedly decreased ?-catenin and COX-2 in colon tumors. Thus, the downregulation of ?-catenin and COX-2 could play a role in inhibiting the CRC development induced by IP? and thereby act as a potent anticancer agent. PMID:24260743

Shafie, Nurul Husna; Mohd Esa, Norhaizan; Ithnin, Hairuszah; Md Akim, Abdah; Saad, Norazalina; Pandurangan, Ashok Kumar

2013-01-01

287

Preventive Inositol Hexaphosphate Extracted from Rice Bran Inhibits Colorectal Cancer through Involvement of Wnt/?-Catenin and COX-2 Pathways  

PubMed Central

Nutritional or dietary factors have drawn attention due to their potential as an effective chemopreventive agent, which is considered a more rational strategy in cancer treatment. This study was designed to evaluate the effect of IP6 extracted from rice bran on azoxymethane- (AOM-) induced colorectal cancer (CRC) in rats. Initially, male Sprague Dawley rats were divided into 5 groups, with 6 rats in each group. The rats received two intraperitoneal (i.p.) injections of AOM in saline (15?mg/kg body weight) over a 2-week period to induce CRC. IP6 was given in three concentrations, 0.2% (w/v), 0.5% (w/v), and 1.0% (w/v), via drinking water for 16 weeks. The deregulation of the Wnt/?-catenin signaling pathway and the expression of cyclooxygenase (COX)-2 have been implicated in colorectal tumorigenesis. ?-Catenin and COX-2 expressions were analysed using the quantitative RT-PCR and Western blotting. Herein, we reported that the administration of IP6 markedly suppressed the incidence of tumors when compared to the control. Interestingly, the administration of IP6 had also markedly decreased ?-catenin and COX-2 in colon tumors. Thus, the downregulation of ?-catenin and COX-2 could play a role in inhibiting the CRC development induced by IP6 and thereby act as a potent anticancer agent. PMID:24260743

Mohd Esa, Norhaizan; Ithnin, Hairuszah; Md Akim, Abdah; Pandurangan, Ashok Kumar

2013-01-01

288

Research on a correlation between Cox2 protein expression and the resistance of radiation therapy in esophageal squamous cell carcinoma  

Microsoft Academic Search

Objective To study a correlation between the resistance of radiation therapy in esophageal squamous cell carcinoma and Cox-2 protein expression for cancer organization before radiation therapy. Methods 76 cases were treated by pathology and confirmed the diagnosis of patients with esophageal squamous cell carcinoma, and all by radical radiation therapy for 6MV X-ray, illuminated the dose of 60 Gy. According

Hui Wu; Qing-xia Fan

2011-01-01

289

Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1.  

PubMed

We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS) of a small molecule library led to the identification of benzoisothiazolones as potent and selective inhibitors of PHOSPHO1. Critical structural requirements for activity were determined, and the compounds were subsequently derivatized and measured for in vitro activity and ADME parameters including metabolic stability and permeability. On the basis of its overall profile the benzoisothiazolone analogue 2q was selected as MLPCN probe ML086. PMID:25124115

Bravo, Yalda; Teriete, Peter; Dhanya, Raveendra-Panickar; Dahl, Russell; Lee, Pooi San; Kiffer-Moreira, Tina; Ganji, Santhi Reddy; Sergienko, Eduard; Smith, Layton H; Farquharson, Colin; Millán, José Luis; Cosford, Nicholas D P

2014-09-01

290

The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity  

SciTech Connect

Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5{prime}-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10{sup 3} selectivity for the parasite enzyme over human IMPDH2.

MacPherson, Iain S.; Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Riera, Thomas V.; D’ Aquino, J. Alejandro; Zhang, Minjia; Cuny, Gregory D.; Hedstrom, Lizbeth (BWH); (Brandeis)

2010-03-29

291

The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor.  

PubMed

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases. PMID:24900191

Ducharme, Yves; Blouin, Marc; Brideau, Christine; Châteauneuf, Anne; Gareau, Yves; Grimm, Erich L; Juteau, Hélène; Laliberté, Sébastien; MacKay, Bruce; Massé, Frédéric; Ouellet, Marc; Salem, Myriam; Styhler, Angela; Friesen, Richard W

2010-07-01

292

The Discovery of Setileuton, a Potent and Selective 5-Lipoxygenase Inhibitor  

PubMed Central

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases. PMID:24900191

2010-01-01

293

Structure-guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase  

PubMed Central

Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of l-arginine to l-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs. PMID:23451760

Huang, He; Li, Huiying; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.

2013-01-01

294

Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach.  

PubMed

Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of ?-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration. PMID:25275824

Cui, Huaqing; Kamal, Zeeshan; Ai, Teng; Xu, Yanli; More, Swati S; Wilson, Daniel J; Chen, Liqiang

2014-10-23

295

Identification of Potent and Selective Diphenylpropanamide ROR? Inhibitors  

PubMed Central

Retinoic acid-related orphan receptor ROR?t plays a pivotal role in the differentiation of TH17 cells. Antagonizing ROR?t transcriptional activity is a potential means to treat TH17-related autoimmune diseases. Herein, we describe the identification of a series of diphenylpropanamides as novel and selective ROR? antagonists. Diphenylpropanamide 4n inhibited the transcriptional activity of ROR?t, but not ROR?, in cells. In addition, it suppressed human TH17 cell differentiation at submicromolar concentrations. PMID:24040486

2012-01-01

296

Design of potent and selective human cathepsin K inhibitors that span the active site  

PubMed Central

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention. PMID:9405598

Thompson, Scott K.; Halbert, Stacie M.; Bossard, Mary J.; Tomaszek, Thaddeus A.; Levy, Mark A.; Zhao, Baoguang; Smith, Ward W.; Abdel-Meguid, Sherin S.; Janson, Cheryl A.; D'Alessio, Karla J.; McQueney, Michael S.; Amegadzie, Bernard Y.; Hanning, Charles R.; DesJarlais, Renee L.; Briand, Jacques; Sarkar, Susanta K.; Huddleston, Michael J.; Ijames, Carl F.; Carr, Steven A.; Garnes, Keith T.; Shu, Art; Heys, J. Richard; Bradbeer, Jeremy; Zembryki, Denise; Lee-Rykaczewski, Liz; James, Ian E.; Lark, Michael W.; Drake, Fred H.; Gowen, Maxine; Gleason, John G.; Veber, Daniel F.

1997-01-01

297

The Attenuation of Pain Behavior and Serum COX-2 Concentration by Curcumin in a Rat Model of Neuropathic Pain  

PubMed Central

Background Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. There is a lack of effective treatment for neuropathic pain, which may possibly be related to poor understanding of pathological mechanisms at the molecular level. Curcumin, a therapeutic herbal extract, has shown to be effectively capable of reducing chronic pain induced by peripheral administration of inflammatory agents such as formalin. In this study, we aimed to show the effect of curcumin on pain behavior and serum COX-2 level in a Chronic Constriction Injury (CCI) model of neuropathic pain. Methods Wistar male rats (150-200 g, n = 8) were divided into three groups: CCI vehicle-treated, sham-operated, and CCI drug-treated group. Curcumin (12.5, 25, 50 mg/kg, IP) was injected 24 h before surgery and continued daily for 7 days post-surgery. Behavioral tests were performed once before and following the days 1, 3, 5, 7 after surgery. The serum COX-2 level was measured on day 7 after the surgery. Results Curcumin (50 mg/kg) decreased mechanical and cold allodynia (P < 0.001) and produced a decline in serum COX-2 level (P < 0.001). Conclusions A considerable decline in pain behavior and serum COX-2 levels was seen in rat following administration of curcumin in CCI model of neuropathic pain. High concentration of Curcumin was able to reduce the chronic neuropathic pain induced by CCI model and the serum level of COX-2. PMID:25031810

Moini Zanjani, Taraneh; Ameli, Haleh; Labibi, Farzaneh; Sedaghat, Katayoun

2014-01-01

298

Associations between Cox-2 rs20417 and rs5275 polymorphisms and the risk of hepatocellular carcinoma: a meta analysis  

PubMed Central

Genetic polymorphisms of cyclooxygenase-2 (Cox-2) gene have been implicated in the susceptibility to hepatocellular carcinoma (HCC), but the findings from published studies are conflicting and inconclusive. To obtain a more precise estimate of the association of Cox-2 polymorphisms with HCC risk, we performed a meta-analysis of eight eligible case-control studies identified through an extensive online database search of PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang and Chinese Biomedicine Database; after exclusion, 2324 cases and 2604 controls were included. The pooled odds ratios with corresponding 95% confidence intervals were calculated to assess associations, using fixed- or random-effect models. In addition, subgroup analysis by ethnicity and sensitivity analysis were performed. Our results showed that the Cox-2 rs20417 (-765 G/C) polymorphism was not associated with HCC risk in the studied genetic contrast modes (C vs. G, GC vs. GG, and CC + GC vs. GG). No significant association was found with ethnic groups examined (P > 0.05). Similarly, no significant association of the Cox-2 rs5275 (+ 8473 T/C) polymorphism and HCC risk was found under any of the studied contrasts (C vs. T, TC vs. TT, CC vs. TT, CC + TC vs. TT, CC vs. TC + TT). The present meta-analysis, combining all currently available data, suggests no significant associations of either Cox-2 polymorphism with HCC risk. Further studies with a larger sample size are needed to determine the association in different ethnicities. PMID:25400773

Wu, Hexing; Wu, Xiangwei; Wan, Guoxing; Zhang, Shijie

2014-01-01

299

Isoform selectivity of adenylyl cyclase inhibitors: characterization of known and novel compounds.  

PubMed

Nine membrane-bound adenylyl cyclase (AC) isoforms catalyze the production of the second messenger cyclic AMP (cAMP) in response to various stimuli. Reduction of AC activity has well documented benefits, including benefits for heart disease and pain. These roles have inspired development of isoform-selective AC inhibitors, a lack of which currently limits exploration of functions and/or treatment of dysfunctions involving AC/cAMP signaling. However, inhibitors described as AC5- or AC1-selective have not been screened against the full panel of AC isoforms. We have measured pharmacological inhibitor profiles for all transmembrane AC isoforms. We found that 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22,536), 2-amino-7-(furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80), and adenine 9-?-d-arabinofuranoside (Ara-A), described as supposedly AC5-selective, do not discriminate between AC5 and AC6, whereas the putative AC1-selective inhibitor 5-[[2-(6-amino-9H-purin-9-yl)ethyl]amino]-1-pentanol (NB001) does not directly target AC1 to reduce cAMP levels. A structure-based virtual screen targeting the ATP binding site of AC was used to identify novel chemical structures that show some preference for AC1 or AC2. Mutation of the AC2 forskolin binding pocket does not interfere with inhibition by SQ22,536 or the novel AC2 inhibitor, suggesting binding to the catalytic site. Thus, we show that compounds lacking the adenine chemical signature and targeting the ATP binding site can potentially be used to develop AC isoform-specific inhibitors, and discuss the need to reinterpret literature using AC5/6-selective molecules SQ22,536, NKY80, and Ara-A. PMID:24006339

Brand, Cameron S; Hocker, Harrison J; Gorfe, Alemayehu A; Cavasotto, Claudio N; Dessauer, Carmen W

2013-11-01

300

Isoform Selectivity of Adenylyl Cyclase Inhibitors: Characterization of Known and Novel Compounds  

PubMed Central

Nine membrane-bound adenylyl cyclase (AC) isoforms catalyze the production of the second messenger cyclic AMP (cAMP) in response to various stimuli. Reduction of AC activity has well documented benefits, including benefits for heart disease and pain. These roles have inspired development of isoform-selective AC inhibitors, a lack of which currently limits exploration of functions and/or treatment of dysfunctions involving AC/cAMP signaling. However, inhibitors described as AC5- or AC1-selective have not been screened against the full panel of AC isoforms. We have measured pharmacological inhibitor profiles for all transmembrane AC isoforms. We found that 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22,536), 2-amino-7-(furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80), and adenine 9-?-d-arabinofuranoside (Ara-A), described as supposedly AC5-selective, do not discriminate between AC5 and AC6, whereas the putative AC1-selective inhibitor 5-?[[2-?(6-?amino-?9H-?purin-?9-?yl)?ethyl]?amino]?-?1-?pentanol (NB001) does not directly target AC1 to reduce cAMP levels. A structure-based virtual screen targeting the ATP binding site of AC was used to identify novel chemical structures that show some preference for AC1 or AC2. Mutation of the AC2 forskolin binding pocket does not interfere with inhibition by SQ22,536 or the novel AC2 inhibitor, suggesting binding to the catalytic site. Thus, we show that compounds lacking the adenine chemical signature and targeting the ATP binding site can potentially be used to develop AC isoform–specific inhibitors, and discuss the need to reinterpret literature using AC5/6-selective molecules SQ22,536, NKY80, and Ara-A. PMID:24006339

Brand, Cameron S.; Hocker, Harrison J.; Gorfe, Alemayehu A.; Cavasotto, Claudio N.

2013-01-01

301

Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase  

PubMed Central

In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) vs. (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors we have introduced a CF2 moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pKa NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished. PMID:20843082

Xue, Fengtian; Li, Huiying; Delker, Silvia L.; Fang, Jianguo; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.

2010-01-01

302

Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability.  

PubMed Central

OBJECTIVE--To examine the evidence for using selective serotonin reuptake inhibitors instead of tricyclic antidepressants in the first line treatment of depression. DESIGN--Meta-analysis of 63 randomised controlled trials comparing the efficacy and acceptability of selective serotonin reuptake inhibitors with those of tricyclic and related antidepressants. MAIN OUTCOME MEASURES--Improvement in mean scores on Hamilton depression rating scale for 53 randomised controlled trials. Pooled drop out rates from the 58 trials which reported drop out by treatment group. RESULTS--Among the 20 studies reporting standard deviation for the Hamilton score no difference was found in efficacy between serotonin reuptake inhibitors and tricyclic and related antidepressants (standardised mean difference 0.004, 95% confidence interval -0.096 to 0.105). The difference remained insignificant when the remaining 33 studies that used the 17 item and 21 item Hamilton score were included by ascribing weighted standard deviations. The odds ratio for drop out rate in patients receiving serotonin reuptake inhibitors compared with those receiving tricyclic antidepressants was 0.95 (0.86 to 1.07). Similar proportions in both groups cited lack of efficacy as the reason for dropping out but slightly more patients in the tricyclic group cited side effects (18.8% v 15.4% in serotonin reuptake group). CONCLUSIONS--Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit. PMID:8471919

Song, F; Freemantle, N; Sheldon, T A; House, A; Watson, P; Long, A; Mason, J

1993-01-01

303

Synthesis of 2,6-disubstituted benzylamine derivatives as reversible selective inhibitors of copper amine oxidases.  

PubMed

In order to obtain substrate-like inhibitors of copper amine oxidases (CAOs), a class of enzymes involved in important cellular processes as well as in crosslinking of elastin and collagen and removal of biogenic primary amines, we synthesized a set of benzylamine derivatives properly substituted at positions 2 and 6 and studied their biological activity towards some members of CAOs. With benzylamines 6, 7, 8 containing linear alkoxy groups we obtained reversible inhibitors of benzylamine oxidase (BAO), very active and selective toward diamine oxidase (DAO), lysyl oxidase (LO) and monoamine oxidase B (MAO B) characterized by a certain toxicity consequent to the crossing of the brain barrier. Poorly toxic, up to very active, reversible inhibitors of BAO, very selective toward DAO, LO and MAO B, were obtained with benzylamines 10, 11, 12 containing hydrophilic ?-hydroxyalkoxy groups. With benzylamines 13, 14, 15, containing linear alkyl groups endowed with steric, but not conjugative effects for the absence of properly positioned oxygen atoms, we synthesized moderately active inhibitors of BAO reversible and selective toward DAO, LO and MAO B. The cross examination of the entire biological data brought us to the conclusion that the bioactive synthesized compounds most likely exert their physiological role of reversible inhibitors in consequence of the formation of a plurality of hydrogen bonds or hydrophobic non-covalent interactions with proper sites in the protein. Accordingly, the reported inhibitors may be considered as a set of research tools for general biological studies and the formation of enzyme complexes useful for X-ray structure determinations aimed at the design of more sophisticated inhibitors to always better modulate the protein activity without important side effects. PMID:24529308

Lucchesini, Francesco; Pocci, Marco; Alfei, Silvana; Bertini, Vincenzo; Buffoni, Franca

2014-03-01

304

Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency.  

PubMed

Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size. PMID:24955776

Tzvetkov, Nikolay T; Hinz, Sonja; Küppers, Petra; Gastreich, Marcus; Müller, Christa E

2014-08-14

305

Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4  

PubMed Central

Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate ?-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD+ binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold. PMID:23762361

Haikarainen, Teemu; Venkannagari, Harikanth; Narwal, Mohit; Obaji, Ezeogo; Lee, Hao-Wei; Nkizinkiko, Yves; Lehtiö, Lari

2013-01-01

306

New potent and selective polyfluoroalkyl ketone inhibitors of GVIA calcium-independent phospholipase A2  

PubMed Central

Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2. PMID:23916152

Magrioti, Victoria; Nikolaou, Aikaterini; Smyrniotou, Annetta; Shah, Ishita; Constantinou-Kokotou, Violetta; Dennis, Edward A.; Kokotos, George

2013-01-01

307

6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site.  

PubMed

Histone acetyltransferases are important enzymes that regulate various cellular functions, such as epigenetic control of DNA transcription. Development of HAT inhibitors with high selectivity and potency will provide powerful mechanistic tools for the elucidation of the biological functions of HATs and may also have pharmacological value for potential new therapies. In this work, analogs of the known HAT inhibitor anacardic acid were synthesized and evaluated for inhibition of HAT activity. Biochemical assays revealed novel anacardic acid analogs that inhibited the human recombinant enzyme Tip60 selectively compared to PCAF and p300. Enzyme kinetics studies demonstrated that inhibition of Tip60 by one such novel anacardic acid derive, 20, was essentially competitive with Ac-CoA and non-competitive with the histone substrate. In addition, these HAT inhibitors effectively inhibited acetyltransferase activity of nuclear extracts on the histone H3 and H4 at micromolar concentrations. PMID:22100137

Ghizzoni, Massimo; Wu, Jiang; Gao, Tielong; Haisma, Hidde J; Dekker, Frank J; George Zheng, Y

2012-01-01

308

Short-term cardiovascular effects of selective phosphodiesterase 3 inhibitor olprinone versus non-selective phosphodiesterase inhibitor aminophylline in a meconium-induced acute lung injury.  

PubMed

Various anti-inflammatory drugs have been used for treatment of neonatal meconium aspiration syndrome (MAS). As their adverse effects are poorly described, this study compared effects of selective phosphodiesterase (PDE) 3 inhibitor olprinone and non-selective PDE inhibitor aminophylline on cardiovascular parameters in animal model of MAS. Oxygen-ventilated rabbits were intratracheally instilled 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were intravenously given olprinone (0.2 mg/kg) at a single dose at 0.5 h after meconium instillation, or aminophylline (2.0 mg/kg) at two doses at 0.5 and 2.5 h after meconium instillation, or were left without treatment. Cardiovascular changes were evaluated within 5 min of administration and 5 min after finishing the administration. Furthermore, respiratory and cardiovascular parameters were measured within 5 hours following treatment delivery. Oxidation markers (thiobarbituric acid-reactive substances (TBARS), and total antioxidant status) and markers of cardiovascular injury (aldosterone, gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)) were determined in the plasma. Meconium instillation induced acute lung injury associated with oxidative stress, elevated aldosterone, and slightly increased GGT and AST levels. Both aminophylline and olprinone improved lung functions and reduced oxidation stress. However, the PDE inhibitors acutely increased blood pressure and heart rate, whereas heart rate variability remained higher till the end of experiment and correlated well with markers of cardiovascular injury. Considering that systemic administration of olprinone and aminophylline was accompanied by acute cardiovascular changes in the meconium-instilled animals, use of PDE inhibitors in the newborns with MAS should be carefully monitored. PMID:24388890

Mokra, D; Tonhajzerova, I; Pistekova, H; Visnovcova, Z; Mokry, J; Drgova, A; Repcakova, M; Calkovska, A

2013-12-01

309

Suicidality, violence and mania caused by selective serotonin reuptake inhibitors (SSRIs): A review and analysis  

Microsoft Academic Search

Evidence from many sources confirms that selective serotonin reuptake inhibitors (SSRIs) commonly cause or ex- acerbate a wide range of abnormal mental and behavioral conditions. These adverse drug reactions include the following overlapping clinical phenomena: a stimulant profile that ranges from mild agitation to manic psychoses, agitated depression, obsessive preoccupations that are alien or uncharacteristic of the individual, and akathisia.

Peter R. Breggin

2004-01-01

310

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing  

PubMed Central

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice. PMID:22111927

2011-01-01

311

Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data  

Microsoft Academic Search

Summary Background Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs. Methods We did a meta-analysis of data from randomised controlled trials that evaluated an SSRI versus placebo in participants aged 5-18 years and

Craig J Whittington; Tim Kendall; Peter Fonagy; David Cottrell; Andrew Cotgrove; Ellen Boddington

2004-01-01

312

Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression  

ERIC Educational Resources Information Center

Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

2012-01-01

313

PDE4 inhibitors in COPD—a more selective approach to treatment  

Microsoft Academic Search

Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic

Antonio Maurizio Vignola

2004-01-01

314

Glycosidase inhibition by ring-modified castanospermine analogues: tackling enzyme selectivity by inhibitor tailoring.  

PubMed

Synthesis of a panel of iso(thio)urea-type ring-modified castanospermine analogues bearing a freely mutarotating pseudoanomeric hydroxyl group results in tight-binding beta-glucosidase inhibitors with unusual binding signatures; the presence of an N-octyl substituent imparts a remarkable anomeric selectivity, promoting strong binding of the appropriate beta-anomer by the beta-glucosidase. PMID:19532990

Aguilar-Moncayo, Matilde; Gloster, Tracey M; Turkenburg, Johan P; García-Moreno, M Isabel; Ortiz Mellet, Carmen; Davies, Gideon J; García Fernández, José M

2009-07-01

315

Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor  

PubMed Central

Structure–activity relationship analysis in a series of 3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)amides identified compound 13, a pan-Pim kinases inhibitor with excellent biochemical potency and kinase selectivity. Compound 13 exhibited in vitro synergy with chemotherapeutics and robust in vivo efficacy in two Pim kinases driven tumor models. PMID:24900437

2011-01-01

316

Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction in Adolescents: A Review.  

ERIC Educational Resources Information Center

Objective: To review the existing literature on selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction in adolescents. Method: A literature review of SSRI-induced adverse effects in adolescents focusing on sexual dysfunction was done. Nonsexual SSRI-induced adverse effects were compared in adult and pediatric populations.…

Scharko, Alexander M.

2004-01-01

317

Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review  

Microsoft Academic Search

The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology. As a result, the discovery of these agents marks a milestone in neuropsychopharmacology and rational drug design, and has launched a new era in psychotropic drug development. Prior to the SSRIs, all psychotropic medications were the result of chance observation. In an attempt to develop

Meera Vaswani; Farzana Kadar Linda; Subramanyam Ramesh

2003-01-01

318

Effect of Selective Serotonin Reuptake Inhibitors on the Risk of Fracture  

Microsoft Academic Search

Background: Depression and osteoporotic fractures are common ailments among elderly persons. Selective sero- tonin reuptake inhibitors (SSRIs) are frequently used in the treatment of depression in this population, and the as- sociation between daily SSRI use and fragility fractures is unclear. Our objective was to examine the effect of daily SSRI use on the risk of incident clinical fragility fracture.

J. Brent Richards; Alexandra Papaioannou; Jonathan D. Adachi; Lawrence Joseph; Heather E. Whitson; Jerilynn C. Prior; David Goltzman

2007-01-01

319

Design and synthesis of paracaseolide A analogues as selective protein tyrosine phosphatase 1B inhibitors.  

PubMed

A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects. PMID:24752625

Yin, Jian-Peng; Tang, Chun-Lan; Gao, Li-Xin; Ma, Wei-Ping; Li, Jing-Ya; Li, Ying; Li, Jia; Nan, Fa-Jun

2014-06-01

320

Should the Use of Selective Serotonin Reuptake Inhibitors in Child and Adolescent Depression Be Banned?  

Microsoft Academic Search

Background: European and US pharmaceutical agencies have recently warned against the use of selective serotonin reuptake inhibitors (SSRIs) in child and adolescent depression. This came as a surprise to many practitioners, who had made treatment decisions based on data from pharmaceutical trials using adult samples. Method: The author reviews the recent literature relevant to the use of SSRIs in youth

David Cohen

2007-01-01

321

Deprenyl administration in man: A selective monoamine oxidase B inhibitor without the ‘cheese effect’  

Microsoft Academic Search

After pretreatment with the selective monoamine oxidase B inhibitor, (-)-deprenyl, in doses sufficient for complete inhibition of the platelet enzyme, 4 normal and 6 parkinsonian volunteers (2 receiving levodopa and 2 levodopa plus carbidopa) suffered no adverse pressor reaction (‘cheese effect’) after challenge with oral tyramine in amounts considerably greater than those likely to be encountered in a normal diet.

J. D. Elsworth; Vivette Glover; G. P. Reynolds; M. Sandler; A. J. Lees; P. Phuapradit; K. M. Shaw; G. M. Stern; Parveen Kumar

1978-01-01

322

Use of Selective Serotonin Reuptake Inhibitors and the Risk of Breast Cancer  

Microsoft Academic Search

Selective serotonin reuptake inhibitors (SSRIs) were introduced in 1987 and, by 1997, were prescribed to 58% of Americans receiving outpatient treatment for depression. In 1992, a study reported that one of the SSRIs, fluox- etine, accelerated the growth of mammary tumors in rodents. By use of data from 1988 to 2002 from their hospital- based, case-control surveillance study, the authors

Patricia F. Coogan; Julie R. Palmer; Brian L. Strom; Lynn Rosenberg

323

In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder  

ERIC Educational Resources Information Center

We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status.…

Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor; Yudell, Michael; Mortensen, Erik L.; Newschaffer, Craig J.

2014-01-01

324

Highly potent and selective chiral inhibitors of PDE5: An illustration of Pfeiffer’s rule  

Microsoft Academic Search

A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer’s rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity

Mark E. Bunnage; John P. Mathias; Anthony Wood; Duncan Miller

2008-01-01

325

Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.  

PubMed

Topoisomerase IB (Top1) inhibitors, such as camptothecin (CPT), stabilize the Top1-DNA cleavage complex in a DNA sequence-dependent manner. The sequence selectivity of Top1 inhibitors is important for targeting specific genomic sequences of therapeutic value. However, the molecular mechanisms underlying this selectivity remain largely unknown. We performed molecular dynamics simulations to delineate structural, dynamic and energetic features that contribute to the differential sequence selectivity of the Top1 inhibitors. We found the sequence selectivity of CPT to be highly correlated with the drug binding energies, dynamic and structural properties of the linker domain. Chemical insights, gained by per-residue binding energy analysis revealed that the non-polar interaction between CPT and nucleotide at the +1 position of the cleavage site was the major (favorable) contributor to the total binding energy. Mechanistic insights gained by a potential of mean force analysis implicated that the drug dissociation step was associated with the sequence selectivity. Pharmaceutical insights gained by our molecular dynamics analyses explained why LMP-776, an indenoisoquinoline derivative under clinical development at the National Institutes of Health, displays different sequence selectivity when compared with camptothecin and its clinical derivatives. PMID:24021629

Siu, Fung-Ming; Pommier, Yves

2013-12-01

326

Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study  

PubMed Central

Topoisomerase IB (Top1) inhibitors, such as camptothecin (CPT), stabilize the Top1-DNA cleavage complex in a DNA sequence-dependent manner. The sequence selectivity of Top1 inhibitors is important for targeting specific genomic sequences of therapeutic value. However, the molecular mechanisms underlying this selectivity remain largely unknown. We performed molecular dynamics simulations to delineate structural, dynamic and energetic features that contribute to the differential sequence selectivity of the Top1 inhibitors. We found the sequence selectivity of CPT to be highly correlated with the drug binding energies, dynamic and structural properties of the linker domain. Chemical insights, gained by per-residue binding energy analysis revealed that the non-polar interaction between CPT and nucleotide at the +1 position of the cleavage site was the major (favorable) contributor to the total binding energy. Mechanistic insights gained by a potential of mean force analysis implicated that the drug dissociation step was associated with the sequence selectivity. Pharmaceutical insights gained by our molecular dynamics analyses explained why LMP-776, an indenoisoquinoline derivative under clinical development at the National Institutes of Health, displays different sequence selectivity when compared with camptothecin and its clinical derivatives. PMID:24021629

Siu, Fung-Ming; Pommier, Yves

2013-01-01

327

A SMALL MOLECULE SCREEN IDENTIFIES SELECTIVE INHIBITORS OF UREA TRANSPORTER UT-A  

PubMed Central

SUMMARY Urea transporter (UT) proteins, including UT-A in kidney tubule epithelia and UT-B in vasa recta microvessels, facilitate urinary concentrating function. A screen for UT-A inhibitors was developed in MDCK cells expressing UT-A1, water channel aquaporin-1, and YFP-H148Q/V163S. An inwardly directed urea gradient produces cell shrinking followed by UT-A1-dependent swelling, which was monitored by YFP-H148Q/V163S fluorescence. Screening of ~90,000 synthetic small molecules yielded four classes of UT-A1 inhibitors with low micromolar IC50 that fully and reversibly inhibited urea transport by a non-competitive mechanism. Structure-activity analysis of >400 analogs revealed UT-A1-selective and UT-A1/UT-B non-selective inhibitors. Docking computations based on homology models of UT-A1 suggested inhibitor binding sites. UT-A inhibitors may be useful as diuretics (‘urearetics’) with a novel mechanism of action that may be effective in fluid-retaining conditions in which conventional salt transport-blocking diuretics have limited efficacy. PMID:24055006

Esteva-Font, Cristina; Phuan, Puay-Wah; Anderson, Marc O.; Verkman, A.S.

2013-01-01

328

Kinetic basis for selective inhibition of cyclo-oxygenases.  

PubMed Central

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics on COX-1 (Ki=10-16 microM). An initial competitive interaction with COX-2 can also be discerned with celecoxib (Ki=11-15 microM), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (Kinact=0.03-0.5 s-1). Half-maximal inhibition (IC50) using end-point assays reflects the competitive component on COX-1 (IC50=4-19 microM) and the inactivation component on COX-2 (IC50=0.003-0.006 microM). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with this class is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-1 and COX-2 using IC50 ratios of questionable validity. PMID:10215599

Gierse, J K; Koboldt, C M; Walker, M C; Seibert, K; Isakson, P C

1999-01-01

329

6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance.  

PubMed

Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. PMID:20631063

Issaeva, Natalia; Thomas, Huw D; Djureinovic, Tatjana; Djurenovic, Tatjana; Jaspers, Janneke E; Stoimenov, Ivaylo; Kyle, Suzanne; Pedley, Nicholas; Gottipati, Ponnari; Zur, Rafal; Sleeth, Kate; Chatzakos, Vicky; Mulligan, Evan A; Lundin, Cecilia; Gubanova, Evgenia; Kersbergen, Ariena; Harris, Adrian L; Sharma, Ricky A; Rottenberg, Sven; Curtin, Nicola J; Helleday, Thomas

2010-08-01

330

Selection and characterization of HIV1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir  

Microsoft Academic Search

Tipranavir is a novel, non-peptidic protease inhibitor, which possesses broad antiviral activity against multiple protease inhibitor-resistant HIV-1. Resistance to this inhibitor however has not yet been well described. HIV was passaged for 9 months in culture in the presence of tipranavir to select HIV with a drug-resistant phenotype. Characterization of the selected variants revealed that the first mutations to be

Louise Doyon; Sonia Tremblay; Lise Bourgon; Elizabeth Wardrop; Michael G. Cordingley

2005-01-01

331

Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2.  

PubMed

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a moderately potent and poorly selective inhibitor of protein kinase CK2, one of the most pleiotropic serine/threonine protein kinases, implicated in neoplasia and in other global diseases. By virtual screening of the MMS (Molecular Modeling Section) database, we have now identified quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) as an inhibitor of CK2 that is more potent and selective than emodin. CK2 inhibition by quinalizarin is competitive with respect to ATP, with a Ki value of approx. 50 nM. Tested at 1 microM concentration on a panel of 75 protein kinases, quinalizarin drastically inhibits only CK2, with a promiscuity score (11.1), which is the lowest ever reported so far for a CK2 inhibitor. Especially remarkable is the ability of quinalizarin to discriminate between CK2 and a number of kinases, notably DYRK1a (dual-specificity tyrosine-phosphorylated and -regulated kinase), PIM (provirus integration site for Moloney murine leukaemia virus) 1, 2 and 3, HIPK2 (homeodomain-interacting protein kinase-2), MNK1 [MAPK (mitogen-activated protein kinase)-interacting kinase 1], ERK8 (extracellular-signal-regulated kinase 8) and PKD1 (protein kinase D 1), which conversely tend to be inhibited as drastically as CK2 by commercially available CK2 inhibitors. The determination of the crystal structure of a complex between quinalizarin and CK2alpha subunit highlights the relevance of polar interactions in stabilizing the binding, an unusual characteristic for a CK2 inhibitor, and disclose other structural features which may account for the narrow selectivity of this compound. Tested on Jurkat cells, quinalizarin proved able to inhibit endogenous CK2 and to induce apoptosis more efficiently than the commonly used CK2 inhibitors TBB (4,5,6,7-tetrabromo-1H-benzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole). PMID:19432557

Cozza, Giorgio; Mazzorana, Marco; Papinutto, Elena; Bain, Jenny; Elliott, Matthew; di Maira, Giovanni; Gianoncelli, Alessandra; Pagano, Mario A; Sarno, Stefania; Ruzzene, Maria; Battistutta, Roberto; Meggio, Flavio; Moro, Stefano; Zagotto, Giuseppe; Pinna, Lorenzo A

2009-08-01

332

The role of COX-2 and Nrf2/ARE in anti-inflammation and antioxidative stress: Aging and anti-aging.  

PubMed

Oxidative stress and inflammation are constant features of many chronic diseases and complications, and have been linked to carcinogenesis. Cyclooxygenase 2 (COX-2), a rate-limiting enzyme for the synthesis of prostaglandins, plays important roles in physiology and pathology, but has been a source of controversy within the scientific and clinical community. However, recent work has shown that nuclear factor erythroid-2-related factor-2 (Nrf2) confers protection against oxidative stress. Furthermore, COX-2-dependent electrophile oxo-derivative (EFOX) molecules have been shown to act as anti-inflammatory mediators via activation of the Nrf2-dependent antioxidant response element (ARE). These studies have provided more insight into COX-2-mediated events. The function of all tissues, especially epithelial and endothelial tissues, declines with age, leading to the production of reactive oxygen species (ROS). COX-2 expression increases with aging in most tissues, due in part to ROS, chemical reactions, physical shearing, and dietary molecules. Here we discuss new findings related to COX-2 inflammatory and anti-inflammatory responses. Taken together, we hypothesize that COX-2 levels increase during the aging process because increasing levels of ROSs necessitate the involvement of COX-2-dependent EFOXs for anti-inflammation and Nrf2/ARE signaling for antioxidation. We also propose that COX-2 may act as an intrinsic biological aging clock due to its role in balancing inflammatory and anti-inflammatory responses. PMID:21530094

Luo, Cheng; Urgard, Egon; Vooder, Tõnu; Metspalu, Andres

2011-08-01

333

Structural Characterization of Inhibitors with Selectivity against Members of a Homologous Enzyme Family  

SciTech Connect

The aspartate biosynthetic pathway provides essential metabolites for many important biological functions, including the production of four essential amino acids. As this critical pathway is only present in plants and microbes, any disruptions will be fatal to these organisms. An early pathway enzyme, L-aspartate-{beta}-semialdehyde dehydrogenase, produces a key intermediate at the first branch point of this pathway. Developing potent and selective inhibitors against several orthologs in the L-aspartate-{beta}-semialdehyde dehydrogenase family can serve as lead compounds for antibiotic development. Kinetic studies of two small molecule fragment libraries have identified inhibitors that show good selectivity against L-aspartate-{beta}-semialdehyde dehydrogenases from two different bacterial species, Streptococcus pneumoniae and Vibrio cholerae, despite the presence of an identical constellation of active site amino acids in this homologous enzyme family. Structural characterization of enzyme-inhibitor complexes have elucidated different modes of binding between these structurally related enzymes. This information provides the basis for a structure-guided approach to the development of more potent and more selective inhibitors.

Pavlovsky, Alexander G.; Liu, Xuying; Faehnle, Christopher R.; Potente, Nina; Viola, Ronald E. (Toledo)

2013-01-31

334

The Discovery of VX-745: A Novel and Selective p38? Kinase Inhibitor  

PubMed Central

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38? inhibitors is described. Application of structural information from enzyme–ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38? inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation. PMID:24900264

2011-01-01

335

Evolution of antiferromagnetic susceptibility under uniaxial pressure in Ba(Fe1-xCox)2As2  

NASA Astrophysics Data System (ADS)

Neutron diffraction measurements are presented measuring the responses of both magnetic and structural order parameters of parent and lightly Co-doped Ba(Fe1-xCox)2As2 under the application of uniaxial pressure. We find that the uniaxial pressure induces a thermal shift in the onset of antiferromagnetic order that grows as a percentage of TN as Co doping is increased and the superconducting phase is approached. Additionally, as uniaxial pressure is increased within parent and lightly doped Ba(Fe1-xCox)2As2 on the first-order side of the tricritical point, we observe a decoupling between the onsets of the orthorhombic structural distortion and antiferromagnetism. Our findings place needed constraints on models exploring the nematic susceptibility of the bilayer pnictides in the tetragonal, paramagnetic regime.

Dhital, Chetan; Hogan, Tom; Yamani, Z.; Birgeneau, Robert J.; Tian, W.; Matsuda, M.; Sefat, A. S.; Wang, Ziqiang; Wilson, Stephen D.

2014-06-01

336

Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer.  

PubMed

Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer. PMID:15561779

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

2004-11-01

337

Dynamic compression inhibits fibronectin fragment induced iNOS and COX2 expression in chondrocyte\\/agarose constructs  

Microsoft Academic Search

Mechanical loading and the fibronectin fragments (FN-fs) are known to stimulate the anabolic and catabolic processes in articular\\u000a cartilage, possible through pathways mediated by ·NO. This study examined the combined effects of dynamic compression and the NH2-hep I or COOH-hep II FN-fs on the expression levels of iNOS and COX-2 and production of ·NO and PGE2 release. Both types of

S. P. Raveenthiran; T. T. Chowdhury

2009-01-01

338

Moraxella catarrhalis induces ERK and NF B-dependent COX2 and prostaglandin E2 in lung epithelium  

Microsoft Academic Search

Moraxella catarrhalis is a major cause of infectious exacerbations of chronic obstructive lung disease. Cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E2 (PGE2), are considered to be important regulators of lung function. The present authors tested the hypothesis that M. catarrhalis induces COX-2-dependent PGE2 production in pulmonary epithelial cells. In the present study, the authors demonstrate that M. catarrhalis specifically induces

P. D. N'Guessan; B. Temmesfeld-Wollbruck; J. Zahlten; J. Eitel; S. Zabel; B. Schmeck; B. Opitz; S. Hippenstiel; N. Suttorp; H. Slevogt

2007-01-01

339

Diesel exhaust particles increase LPS-stimulated COX2 expression and PGE2 production in human monocytes  

Microsoft Academic Search

Little is known about health effects of ultrafine particles (UFP) found in ambient air, but much of their action may be on cells of the lung, including cells of the monocyte\\/macrophage lin- eage. We have analyzed the effects of diesel ex- haust particles (DEP; SRM1650a) on human monocytes in vitro. DEP, on their own, had little effect on cyclooxygenase (COX)-2

Thomas P. J. Hofer; Ellen Bitterle; Ingrid Beck-Speier; Konrad L. Maier; Marion Frankenberger; Joachim Heyder; Loms Ziegler-Heitbrock

2004-01-01

340

COX2, Inflammatory Secreted PLA2, and Cytoplasmic PLA2 Protein Expression in Small Bowel Adenocarcinomas Compared with Colorectal Adenocarcinomas  

Microsoft Academic Search

Cyclooxygenase-2 (COX-2), human synovial inflammatory secreted phospholipase A2 (sPLA2) and cytoplasmic phospholipase A2 (cPLA2) are involved in eicosanoid production and also seem to participate in colorectal tumorigenesis. As there are no data regarding these enzymes in human small bowel tumors, we wanted to determine whether they were involved in human small bowel tumorigenesis, and whether their expression was different in

Dominique Wendum; Magali Svrcek; Valérie Rigau; Pierre-Yves Boëlle; Nicole Sebbagh; Rolland Parc; Joëlle Masliah; Germain Trugnan; Jean-François Fléjou

2003-01-01

341

Modulation of COX2 and hTERT expression by photodynamic therapy in human colon cancer cells  

NASA Astrophysics Data System (ADS)

Photodynamic therapy (PDT) was employed as a cancer therapy with photosensitizer (PS)-loaded cancer cells, eradicated by the reactive oxygen species after light activation. Cyclo-oxygenase 2 (COX2) is an enzyme expressed in 80% of colon adenocarcinoma and is one of the targets for effective cancer treatment. There is also uprising evidence that the human telomerase reverse transcriptase (hTERT), a catalytic component of telomerase, is reported as a promising indicator for monitoring cancer treatment. In this study, NPe6 mediated PDT on COX2 induced apoptosis in HT-29 was investigated. The cell cycle changes was analysed by flow cytometry and the hTERT expression at pre and post PDT was evaluated at transcription level by Taqman real time PCR. NPe6-PDT in HT-29 cells demonstrated anti-proliferating effect in a drug and light dose dependent manner. LD50 was achieved at 16?g/mL and 2J/cm2 at 4 hour-post treatment with a significant down-regulation of COX2 expression at LD30 and LD50 by immunohistochemical staining (IHC) (p<0.05, One-Way ANOVA). Membrane blebbing was detected in over 60% of cells. 35.2% of treated cells arrested in S-phase at LD50 after 24 hours by flow cytometry. A 0.25- and 0.6-fold down-regulation of hTERT mRNA expression was achieved at LD30 and LD50 respectively by TaqMan real-time PCR. To summarize, NPe6 mediated PDT down-regulated COX2 expression and triggered cell apoptosis. The hTERT can serve as an indicative marker for monitoring NPe6-PDT cancer treatment efficacy.

Yow, Christine Li Miu N.; Chu, Ellie Shihng M.

2009-06-01

342

Hydroxytyrosol inhibits pro-inflammatory cytokines, iNOS, and COX2 expression in human monocytic cells  

Microsoft Academic Search

Hydroxytyrosol (HT), isolated from extra-virgin olive oil, possesses a marked antioxidant activity and is a good radical scavenger.\\u000a In this study, our aim was to examine the anti-inflammatory mechanism of HT through measuring the inducible nitric oxide synthase\\u000a (iNOS), cyclooxygenase-2 (COX-2) expression, TNF-? formation, and nitric oxide (NO) release in lipopolysaccharide (LPS)-induced\\u000a human monocytic (THP-1) cells. Results showed that HT

Xiaomei Zhang; Jun Cao; Laifu Zhong

2009-01-01

343

Distinct states of methionyl-tRNA synthetase indicates inhibitor binding by conformational selection  

PubMed Central

Summary To guide development of new drugs targeting methionyl-tRNA synthetase (MetRS) for treatment of human African trypanosomiasis, crystal structure determinations of Trypanosoma brucei MetRS in complex with its substrate methionine and its intermediate product methionyl-adenylate were followed by those of the enzyme in complex with high-affinity aminoquinolone inhibitors via soaking experiments. Drastic changes in conformation of one of the two enzymes in the asymmetric unit allowed these inhibitors to occupy an enlarged methionine pocket and a new so-called auxiliary pocket. Interestingly, a small low-affinity compound caused the same conformational changes, removed the methionine without occupying the methionine pocket, and occupied the previously not existing auxiliary pocket. Analysis of these structures indicates that the binding of the inhibitors is the result of conformational selection, not induced fit. PMID:22902861

Koh, Cho Yeow; Kim, Jessica E.; Shibata, Sayaka; Ranade, Ranae M.; Yu, Mingyan; Liu, Jiyun; Gillespie, J. Robert; Buckner, Frederick S.; Verlinde, Christophe L.M.J.; Fan, Erkang; Hol, Wim G.J.

2012-01-01

344

Selective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic Approaches†  

PubMed Central

Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N?-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. The results of initial binding and inhibition assays directed the production and analysis of a set of N-oxalyl-d-tyrosine derivatives to explore the extent of a subpocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compounds. PMID:20088513

2010-01-01

345

Ventricular hypertrophy blocked delayed anesthetic cardioprotection in rats by alteration of iNOS/COX-2 signaling.  

PubMed

The aim of the current study was to determine whether ventricular hypertrophy affects the delayed isoflurane preconditioning against myocardial ischemia-reperfusion (IR) injury. Transverse aortic constriction (TAC) was performed on male Sprague-Dawley rats to induce left ventricular (LV) hypertrophy, then sham-operated or hypertrophied rat hearts were subjected to isoflurane preconditioning (2.1% v/v, 1?h). 24?h after exposure, the hearts were isolated and perfused retrogradely by the Langendorff for 30?min (equilibration) followed by 40?min of ischemia and then 120?min of reperfusion. The hemodynamics, infarct size, apoptosis, nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2), Cleaved Caspase-3 and production of NO were determined. We found that the hemodynamic parameters were all markedly improved during the reperfusion period and the myocardial infarct size and apoptosis was significantly reduced by delayed isoflurane preconditioning in sham-operated rats. However, such cardiac improvement induced by delayed isoflurane preconditioning was not observed in hypertrophied hearts. The expression of iNOS, COX-2 and NO was markedly enhanced, whereas Cleaved Caspase-3 activity was inhibited by delayed isoflurane preconditioning in sham-operated rats, a phenomenon was not found in TAC-control groups pretreated with isoflurane. Our results demonstrated that ventricular hypertrophy abrogated isoflurane-induced delayed cardioprotection by alteration of iNOS/COX-2 pathway. PMID:25400168

Ma, Leilei; Kong, Feijuan; Ge, Hongwei; Liu, Jingquan; Gong, Fangxiao; Xu, Liang; Hu, Bangchuan; Sun, Renhua

2014-01-01

346

Arsenic reduces the antipyretic activity of paracetamol in rats: modulation of brain COX-2 activity and CB? receptor expression.  

PubMed

We examined whether subacute arsenic exposure can reduce paracetamol-mediated antipyretic activity by affecting COX pathway and cannabinoid CB1 receptor regulation. Rats were preexposed to elemental arsenic (4 ppm) as sodium arsenite through drinking water for 28 days. Next day pyrexia was induced with lipopolysaccharide and paracetamol's (200 mg/kg, oral) antipyretic activity was assessed. The activities of COX-1 and COX-2, the levels of PGE?, TNF-? and IL-1? and expression of CB? receptors were assessed in brain. Arsenic inhibited paracetamol-mediated antipyretic activity. COX-1 activity was not affected by any treatments. Paracetamol decreased COX-2 activity, levels of PGE?, TNF-? and IL-1? and caused up-regulation of CB1 receptors. Arsenic caused opposite effects on these parameters. In the arsenic-preexposed rats, paracetamol-mediated effects were attenuated, while CB? receptor up-regulation was reversed to down-regulation. Results suggest that elevated COX-2 activity and reduced CB? expression could be involved in the arsenic-mediated attenuation of the antipyretic activity of paracetamol. PMID:24448467

Vijayakaran, Karunakaran; Kannan, Kandasamy; Kesavan, Manickam; Suresh, Subramaniyam; Sankar, Palanisamy; Tandan, Surendra Kumar; Sarkar, Souvendra Nath

2014-01-01

347

COX-2-765G>C Polymorphism Increases the Risk of Cancer: A Meta-Analysis  

PubMed Central

Background Chronic inflammation has been regarded as an important mechanism in carcinogenesis. Inflammation-associated genetic variants have been highly associated with cancer risk. Polymorphisms in the gene cyclooxygenase-2 (COX-2), a pro-inflammation factor, have been suggested to alter the risk of multiple tumors, but the findings of various studies are not consistent. Methods A literature search through February 2013 was performed using PubMed, EMBASE, and CNKI databases. We used odds ratios (ORs) with confidence intervals (CIs) of 95% to assess the strength of the association between the COX-2-765G>C polymorphism and cancer risk in a random-effect model. We also assessed heterogeneity and publication bias. Results In total, 65 articles with 29,487 cancer cases and 39,212 non-cancer controls were included in this meta-analysis. The pooled OR (95% CIs) in the co-dominant model (GC vs. GG) was 1.11 (1.02–1.22), and in the dominant model ((CC+GC) vs. GG), the pooled OR was 1.12 (1.02–1.23). In the subgroup analysis, stratified by cancer type and race, significant associations were found between the-765 C allele and higher risk for gastric cancer, leukemia, pancreatic cancer, and cancer in the Asian population. Conclusion In summary, the COX-2-765 C allele was related to increased cancer susceptibility, especially gastric cancer and cancer in the Asian population. PMID:24023834

Zhang, Xiao-wei; Hua, Rui-xi; Guo, Wei-jian

2013-01-01

348

Osteocyte expression of caspase-3, COX-2, IL-6 and sclerostin are spatially and temporally associated following stress fracture initiation  

PubMed Central

Stress fractures (SFxs) are debilitating injuries and exact mechanisms that initiate their repair incompletely understood. We hypothesised that osteocyte apoptosis and expression of cytokines and proteins such as sclerostin, VEGF, TGF-?, COX-2 and IL-6 were early signalling events to facilitate the formation of periosteal woven bone and recruitment of osteoclast precursors to the site of remodelling. A SFx was created in the right ulna of mature female wistar rats using cyclic end loading. Rats were killed 1, 4 and 7 days after loading (n=5 per group). Standard histological staining was used to examine SFx morphology and immunohistochemistry to detect the localisation of these proteins and in situ hybridisation to detect mRNA along the SFx line or gene expression to quantify the target genes. Unloaded ulnae served as controls. The labelling index of caspase-3, COX-2 and IL-6 was significantly elevated in the region of SFxs at all time points compared with controls (P<0.001). In addition, the labelling index of sclerostin protein was significantly reduced in osteocytes adjacent to the SFx region when compared with controls at all three time points (P<0.001). Both VEGF and TGF-? expressions were only localised in the woven bone. These data reinforce the involvement of osteocyte apoptosis in the healing of fatigue damage in bone, and demonstrate that local regulation of sclerostin, COX-2 and IL-6 are important signalling events associated with new bone formation and SFx remodelling.

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

2014-01-01

349

Ventricular hypertrophy blocked delayed anesthetic cardioprotection in rats by alteration of iNOS/COX-2 signaling  

PubMed Central

The aim of the current study was to determine whether ventricular hypertrophy affects the delayed isoflurane preconditioning against myocardial ischemia-reperfusion (IR) injury. Transverse aortic constriction (TAC) was performed on male Sprague-Dawley rats to induce left ventricular (LV) hypertrophy, then sham-operated or hypertrophied rat hearts were subjected to isoflurane preconditioning (2.1% v/v, 1?h). 24?h after exposure, the hearts were isolated and perfused retrogradely by the Langendorff for 30?min (equilibration) followed by 40?min of ischemia and then 120?min of reperfusion. The hemodynamics, infarct size, apoptosis, nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2), Cleaved Caspase-3 and production of NO were determined. We found that the hemodynamic parameters were all markedly improved during the reperfusion period and the myocardial infarct size and apoptosis was significantly reduced by delayed isoflurane preconditioning in sham-operated rats. However, such cardiac improvement induced by delayed isoflurane preconditioning was not observed in hypertrophied hearts. The expression of iNOS, COX-2 and NO was markedly enhanced, whereas Cleaved Caspase-3 activity was inhibited by delayed isoflurane preconditioning in sham-operated rats, a phenomenon was not found in TAC-control groups pretreated with isoflurane. Our results demonstrated that ventricular hypertrophy abrogated isoflurane-induced delayed cardioprotection by alteration of iNOS/COX-2 pathway. PMID:25400168

Ma, Leilei; Kong, Feijuan; Ge, Hongwei; Liu, Jingquan; Gong, Fangxiao; Xu, Liang; Hu, Bangchuan; Sun, Renhua

2014-01-01

350

AMPK potentiates hypertonicity-induced apoptosis by suppressing NF?B/COX-2 in medullary interstitial cells.  

PubMed

Cells residing in the hypertonic, hypoxic renal medulla depend on dynamic adaptation mechanisms to respond to changes in energy supply and demand. The serine/threonine kinase 5'-AMP protein kinase (AMPK) is a sensor of cellular energy status, but whether it contributes to the survival of cells in the renal medulla is unknown. Here, hypertonic conditions induced a decrease in AMPK phosphorylation within 12 hours in renal medullary interstitial cells (RMIC), followed by a gradual return to baseline levels. Activation of AMPK markedly increased hypertonicity-induced apoptosis of RMICs and suppressed both hypertonicity-induced NF?B nuclear translocation and cyclooxygenase-2 (COX-2) activation; overexpression of COX-2 significantly attenuated these effects. AMPK activation also markedly reduced generation of reactive oxygen species and nuclear expression of tonicity-responsive enhancer-binding protein, which prevented upregulation of osmoprotective genes. In vivo, pharmacologic activation of AMPK led to massive apoptosis of RMICs and renal dysfunction in the setting of water deprivation in mice. Taken together, these results identify a critical role for AMPK in the maintenance of RMIC viability and suggest that AMPK modulates the NF?B-COX-2 survival pathway in the renal medulla. Furthermore, this study raises safety concerns for the development of AMPK activators as anti-diabetic drugs, especially for patients prone to dehydration. PMID:21903993

Han, Qifei; Zhang, Xiaoyan; Xue, Rui; Yang, Hang; Zhou, Yunfeng; Kong, Xiaomu; Zhao, Pan; Li, Jing; Yang, Jichun; Zhu, Yi; Guan, Youfei

2011-10-01

351

Chagasic antibodies induce cardiac COX-2/iNOS mRNA expression with PGE2/NO production.  

PubMed

We demonstrate that serum IgG in chagasic patients interacting with the second extracellular loop of human cardiac M(2) muscarinic acetylcholine receptors (M(2) mAChR) trigger the production of PGE(2) and NO, that in turn induces COX-2/iNOS mRNA expression. An association between serum anti-M(2) peptide IgG, anti-cardiac membrane IgG and PGE(2) levels (p<0.05) in chagasic dysautonomic patients was observed. Thus, we establish that serum anti-mAChR autoantibodies and PGE(2) might be considered as early markers of Chagas' associated dysautonomia. Affinity purified anti-M(2) peptide IgG from chagasic sera, while stimulating myocardial M(2) mAChR, it exerts an increase on PGE(2) generation and NOS activity, as well as COX-2/iNOS isoforms mRNA expression. The expression of these genes is related with phosphoinositides (PIs), cGMP accumulation and PKC activity. Inhibition of these enzymes shows that chagasic autoantibodies up-regulation of COX-2/iNOS mRNA level is under the control of endogenous iNO/cGMP signaling system. These results provide a novel insight into the role that cholinoceptor antibodies play in the development of myocardial inflammation. To our knowledge, there has been no previous report showing that an antibody interacting with heart mAChR can act as expression inducer of proinflammatory mediators. PMID:18579232

Ganzinelli, Sabrina; Borda, Enri; Joensen, Lilian; Sterin-Borda, Leonor

2009-05-15

352

Synthesis and Properties of a Selective Inhibitor of Homeodomain-Interacting Protein Kinase 2 (HIPK2)  

PubMed Central

Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival, whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. SB203580, a p38 MAP kinase inhibitor, has been used as a tool to inhibit HIPK2 in cells, but here we show that its efficacy as HIPK2 inhibitor is negligible (IC50>40 µM). In contrast by altering the scaffold of the promiscuous CK2 inhibitor TBI a new class of HIPK2 inhibitors has been generated. One of these, TBID, displays toward HIPK2 unprecedented efficacy (IC50?=?0.33 µM) and selectivity (Gini coefficient 0.592 out of a panel of 76 kinases). The two other members of the HIPK family, HIPK1 and HIPK3, are also inhibited by TBID albeit less efficiently than HIPK2. The mode of action of TBID is competitive with respect to ATP, consistent with modelling. We also provide evidence that TBID is cell permeable by showing that HIPK2 activity is reduced in cells treated with TBID, although with an IC50 two orders of magnitude higher (about 50 µM) than in vitro. PMID:24586573

Cozza, Giorgio; Zanin, Sofia; Determann, Renate; Ruzzene, Maria; Kunick, Conrad; Pinna, Lorenzo A.

2014-01-01

353

Discovery and Characterization of a Potent and Selective Inhibitor of Aedes aegypti Inward Rectifier Potassium Channels.  

PubMed

Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening 'hits', the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels can be developed using conventional drug discovery approaches. Furthermore, it reinforces the notion that the physical and chemical properties that determine a compound's bioavailability in vivo will be critical in determining the efficacy of Kir channel inhibitors as insecticides. PMID:25375326

Raphemot, Rene; Rouhier, Matthew F; Swale, Daniel R; Days, Emily; Weaver, C David; Lovell, Kimberly M; Konkel, Leah C; Engers, Darren W; Bollinger, Sean F; Hopkins, Corey; Piermarini, Peter M; Denton, Jerod S

2014-01-01

354

Discovery and Characterization of a Potent and Selective Inhibitor of Aedes aegypti Inward Rectifier Potassium Channels  

PubMed Central

Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors of Aedes aegypti Kir1 (AeKir1) channels heterologously expressed in HEK293 cells. Of 283 confirmed screening ‘hits’, the small-molecule inhibitor VU625 was selected for lead optimization and in vivo studies based on its potency and selectivity toward AeKir1, and tractability for medicinal chemistry. In patch clamp electrophysiology experiments of HEK293 cells, VU625 inhibits AeKir1 with an IC50 value of 96.8 nM, making VU625 the most potent inhibitor of AeKir1 described to date. Furthermore, electrophysiology experiments in Xenopus oocytes revealed that VU625 is a weak inhibitor of AeKir2B. Surprisingly, injection of VU625 failed to elicit significant effects on mosquito behavior, urine excretion, or survival. However, when co-injected with probenecid, VU625 inhibited the excretory capacity of mosquitoes and was toxic, suggesting that the compound is a substrate of organic anion and/or ATP-binding cassette (ABC) transporters. The dose-toxicity relationship of VU625 (when co-injected with probenecid) is biphasic, which is consistent with the molecule inhibiting both AeKir1 and AeKir2B with different potencies. This study demonstrates proof-of-concept that potent and highly selective inhibitors of mosquito Kir channels can be developed using conventional drug discovery approaches. Furthermore, it reinforces the notion that the physical and chemical properties that determine a compound's bioavailability in vivo will be critical in determining the efficacy of Kir channel inhibitors as insecticides. PMID:25375326

Raphemot, Rene; Rouhier, Matthew F.; Swale, Daniel R.; Days, Emily; Weaver, C. David; Lovell, Kimberly M.; Konkel, Leah C.; Engers, Darren W.; Bollinger, Sean F.; Hopkins, Corey; Piermarini, Peter M.; Denton, Jerod S.

2014-01-01

355

Selective Aurora kinase inhibitors identified using a Taxol-induced checkpoint sensitivity screen  

PubMed Central

The members of the Aurora kinase family play critical roles in the regulation of the cell cycle and mitotic spindle assembly and have been intensively investigated as potential targets for a new class of anti-cancer drugs. We describe a new highly potent and selective class of Aurora kinase inhibitors discovered using a phenotypic cellular screen. Optimized inhibitors display many of the hallmarks of Aurora inhibition including endoreduplication, polyploidy, and loss of cell viability in cancer cells. Structure-activity relationships with respect to kinome-wide selectivity and guided by an Aurora B co-crystal structure resulted in the identification of key selectivity determinants and discovery of a sub-series with selectivity towards Aurora A. A direct comparison of biochemical and cellular profile with respect to published Aurora inhibitors including VX-680, AZD1152, MLN8054, and a pyrimidine-based compound from Genentech demonstrates that compounds 1 and 3 will become valuable additional pharmacological probes of Aurora dependent functions. PMID:21992004

Kwiatkowski, Nicholas; Deng, Xianming; Wang, Jinhua; Tan, Li; Villa, Fabrizio; Santaguida, Stefano; Huang, Hsiao-Chun; Mitchison, Tim; Musacchio, Andrea; Gray, Nathanael

2011-01-01

356

Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects.  

PubMed

Epigenetic modifications represent a promising new approach to modulate cell functions as observed in autoimmune diseases. Emerging evidence suggests the utility of HDAC inhibitors in the treatment of chronic immune and inflammatory disorders. However, class and isoform selective inhibition of HDAC is currently favored as it limits the toxicity that has been observed with pan-HDAC inhibitors. HDAC6, a member of the HDAC family, whose major substrate is ?-tubulin, is being increasingly implicated in the pathogenesis of inflammatory disorders. The present study was carried out to study the potential anti-inflammatory and anti-rheumatic effects of HDAC6 selective inhibitor Tubastatin. Tubastatin, a potent human HDAC6 inhibitor with an IC50 of 11 nM showed significant inhibition of TNF-? and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM respectively. Additionally, Tubastatin inhibited nitric oxide (NO) secretion in murine Raw 264.7 macrophages dose dependently with an IC50 of 4.2 ?M and induced ?-tubulin hyperacetylation corresponding to HDAC6 inhibition in THP-1 cells without affecting the cell viability. Tubastatin showed significant inhibition of paw volume at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. The disease modifying activity of Tubastatin was also evident in collagen induced arthritis DBA1 mouse model at 30 mg/kg i.p. The significant attenuation of clinical scores (~70%) by Tubastatin was confirmed histopathologically and was found comparable to dexamethasone (~90% inhibition of clinical scores). Tubastatin showed significant inhibition of IL-6 in paw tissues of arthritic mice. The present work has demonstrated anti-inflammatory and antirheumatic effects of a selective HDAC6 inhibitor Tubastatin. PMID:23541634

Vishwakarma, Santosh; Iyer, Lakshmi R; Muley, Milind; Singh, Pankaj Kumar; Shastry, Arun; Saxena, Ambrish; Kulathingal, Jayanarayan; Vijaykanth, G; Raghul, J; Rajesh, Navin; Rathinasamy, Suresh; Kachhadia, Virendra; Kilambi, Narasimhan; Rajgopal, Sridharan; Balasubramanian, Gopalan; Narayanan, Shridhar

2013-05-01

357

A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.  

PubMed

The jumonji (JMJ) family of histone demethylases are Fe2+- and ?-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family. PMID:22842901

Kruidenier, Laurens; Chung, Chun-wa; Cheng, Zhongjun; Liddle, John; Che, KaHing; Joberty, Gerard; Bantscheff, Marcus; Bountra, Chas; Bridges, Angela; Diallo, Hawa; Eberhard, Dirk; Hutchinson, Sue; Jones, Emma; Katso, Roy; Leveridge, Melanie; Mander, Palwinder K; Mosley, Julie; Ramirez-Molina, Cesar; Rowland, Paul; Schofield, Christopher J; Sheppard, Robert J; Smith, Julia E; Swales, Catherine; Tanner, Robert; Thomas, Pamela; Tumber, Anthony; Drewes, Gerard; Oppermann, Udo; Patel, Dinshaw J; Lee, Kevin; Wilson, David M

2012-08-16

358

Multi-walled carbon nanotubes induce COX-2 and iNOS expression via MAP Kinase-dependent and -independent mechanisms in mouse RAW264.7 macrophages  

PubMed Central

Background Carbon nanotubes (CNTs) are engineered graphene cylinders with numerous applications in engineering, electronics and medicine. However, CNTs cause inflammation and fibrosis in the rodent lung, suggesting a potential human health risk. We hypothesized that multi-walled CNTs (MWCNTs) induce two key inflammatory enzymes in macrophages, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), through activation of extracellular signal-regulated kinases (ERK1,2). Methods RAW264.7 macrophages were exposed to MWCNTs or carbon black nanoparticles (CBNPs) over a range of doses and time course. Uptake and subcellular localization of MWCNTs was visualized by transmission electron microscopy (TEM). Protein levels of COX-2, iNOS, and ERK1,2 (total ERK and phosphorylated ERK) were measured by Western blot analysis. Prostaglandin-E2 (PGE2) and nitric oxide (NO) levels in cell supernatants were measured by ELISA and Greiss assay, respectively. Results MWCNTs, but not CBNPs, induced COX-2 and iNOS in a time- and dose-dependent manner. COX-2 and iNOS induction by MWCNTs correlated with increased PGE2 and NO production, respectively. MWCNTs caused ERK1,2 activation and inhibition of ERK1,2 (U0126) blocked MWCNT induction of COX-2 and PGE2 production, but did not reduce the induction of iNOS. Inhibition of iNOS (L-NAME) did not affect ERK1,2 activation, nor did L-NAME significantly decrease COX-2 induction by MWCNT. Nickel nanoparticles (NiNPs), which are present in MWCNTs as a residual catalyst, also induced COX-2 via ERK-1,2. However, a comparison of COX-2 induction by MWCNTs containing 4.5 and 1.8% Ni did not show a significant difference in ability to induce COX-2, indicating that characteristics of MWCNTs in addition to Ni content contribute to COX-2 induction. Conclusion This study identifies COX-2 and subsequent PGE2 production, along with iNOS induction and NO production, as inflammatory mediators involved in the macrophage response to MWCNTs. Furthermore, our work demonstrates that COX-2 induction by MWCNTs in RAW264.7 macrophages is ERK1,2-dependent, while iNOS induction by MWCNTs is ERK1,2-independent. Our data also suggest contributory physicochemical factors other than residual Ni catalyst play a role in COX-2 induction to MWCNT. PMID:22571318

2012-01-01

359

Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase  

PubMed Central

Microbes that have gained resistance against antibiotics pose a major emerging threat to human health. New targets must be identified that will guide the development of new classes of antibiotics. The selective inhibition of key microbial enzymes that are responsible for the biosynthesis of essential metabolites can be an effective way to counter this growing threat. Aspartate semialdehyde dehydrogenases (ASADHs) produce an early branch point metabolite in a microbial biosynthetic pathway for essential amino acids and for quorum sensing molecules. In this study, molecular modeling and docking studies were performed to achieve two key objectives that are important for the identification of new selective inhibitors of ASADH. First, virtual screening of a small library of compounds was used to identify new core structures that could serve as potential inhibitors of the ASADHs. Compounds have been identified from diverse chemical classes that are predicted to bind to ASADH with high affinity. Next, molecular docking studies were used to prioritize analogs within each class for synthesis and testing against representative bacterial forms of ASADH from Streptococcus pneumoniae and Vibrio cholerae. These studies have led to new micromolar inhibitors of ASADH, demonstrating the utility of this molecular modeling and docking approach for the identification of new classes of potential enzyme inhibitors. PMID:22464683

Luniwal, Amarjit; Wang, Lin; Pavlovsky, Alexander; Erhardt, Paul W.; Viola, Ronald E.

2013-01-01

360

Analysis by phage display selection and site-directed retromutagenesis of the Mustard Trypsin Inhibitor 2 reactive site.  

PubMed

The Mustard Trypsin Inhibitor (MSI) family is a small family of plant protease inhibitors so far only found in Brassicaceae. Using a phage display selection, MTI-2 (Mustard Trypsin Inhibitor 2) mutants were detected and analysed for their biochemical characteristics. Retromutants of the selected MTI-2 proteins were constructed and expressed in the Pichia pastoris system. The recombinant proteins were analysed by activity assays against bovine trypsin and Helicoverpa zea trypsin, and by circular dichroism. These analyses suggest a strict requirement for a specific proline residue adjacent to the inhibitor reactive site and give additional insights for future phage display application. PMID:20692717

Volpicella, Mariateresa; Leoni, Claudia; Arnesano, Fabio; Gallerani, Raffaele; Ceci, Luigi R

2010-11-15

361

Effects of nimesulide, a preferential cyclooxygenase-2 inhibitor, on carrageenan-induced pleurisy and stress-induced gastric lesions in rats  

Microsoft Academic Search

Intrapleural injection of carrageenan in rats increased prostaglandin E2 (PGE2) production and induced newly synthesized cyclooxygenase-2 (COX-2) in pleural exudate cells without affecting COX-1 levels. Nimesulide, a preferential inhibitor of COX-2, reduced pleural P