Sample records for cox-2 selective inhibitor

  1. Risk of Cardiovascular Events Associated With Selective COX2 Inhibitors

    Microsoft Academic Search

    Debabrata Mukherjee; Steven E. Nissen; Eric J. Topol

    2005-01-01

    Atherosclerosis is a process with inflammatory features and selective cy- clooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic ef- fects by virtue of inhibiting inflammation. However, by decreasing vasodi- latory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular ef- fects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients

  2. Original article Potent, orally available, selective COX-2 inhibitors based

    E-print Network

    Hammock, Bruce D.

    Original article Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300

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

    Microsoft Academic Search

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

    2007-01-01

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

  4. Selective COX2 Inhibitors and Risk of Myocardial Infarction

    Microsoft Academic Search

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

    2005-01-01

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

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

    Microsoft Academic Search

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

    2000-01-01

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

  6. COX2: Where are we in 2003? - Be strong and resolute: continue to use COX2 selective inhibitors at recommended dosages in appropriate patients

    Microsoft Academic Search

    Marc C Hochberg

    2003-01-01

    Cyclooxygenase (COX)-2 selective inhibitors have been shown to have comparable efficacy to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Large outcome studies have shown that patients with OA and RA not taking low-dose aspirin have fewer symptomatic and complicated upper GI events when treated with COX-2 selective inhibitors than with

  7. Novel selective Cox-2 inhibitors induce apoptosis in Caco-2 colorectal carcinoma cell line.

    PubMed

    Entezari Heravi, Reza; Hadizadeh, Farzin; Sankian, Mojtaba; Tavakol Afshari, Jalil; Taghdisi, Seyed Mohammad; Jafarian, Hanieh; Behravan, Javad

    2011-11-20

    The cyclooxygenase-2 (COX-2) inhibitors including celecoxib inhibit cell growth and induce apoptosis in cancer cells. As COX-2 is over expressed in solid tumors such as colorectal cancer, it can be a suitable target for cancer treatment studies. In this study we designed and synthesized 4,5-bisaryl imidazolyl imidazoles as novel COX-2 inhibitors and evaluated their apoptosis inducing activities. The ability of our synthetic compounds to inhibit ovine COX-1 and COX-2 was determined using a colorimetric method. The effects of these COX-2 inhibitors and celecoxib on the proliferation of Caco-2 cells were evaluated by MTT assay. Cell apoptosis was determined by flow cytometry and DNA fragmentation assay. cDNA microarray technique was used to evaluate the effects of these synthetic compounds on 112 genes involved in apoptosis pathways. The expression of five apoptosis-related genes Bak-1, Bcl-x, BIRC (Survivin), TNFSF10 and CASP3 were evaluated by quantitative real-time PCR. Among our synthetic compounds (3a-c), 4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl derivative (compound 3c) exhibited the highest COX-1/COX-2 selectivity index (SI=262.9) and lowest growth inhibitory concentration (IC(50)=21.20?M). In addition, compounds 3a-c could up-regulate pro-apoptotic genes and down-regulate anti-apoptotic genes. So, these synthetic compounds seem to be inducers of apoptosis in Caco-2 cell line. This study indicates that 4,5-bisaryl imidazolyl imidazole is a suitable scaffold to design COX-2 inhibitors and 4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl derivative exhibited highly COX-2 inhibitory potency and selectivity even more than celecoxib. It seems that it could induce apoptosis in Caco-2 colorectal carcinoma cell line. PMID:21939759

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

    PubMed Central

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

    2013-01-01

    Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses. PMID:24098505

  9. Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner.

    PubMed

    Kim, So Ra; Park, Jung Hae; Lee, Mi Eun; Park, Jeong Soo; Park, Sang Chul; Han, Jeong A

    2008-12-01

    It has been recently proposed that pro-inflammatory genes such as cyclooxygenase-2 (COX-2) play a key role in the aging process. However, it remains unclear whether the pro-inflammatory activity of COX-2 is involved in the aging process and whether COX-2 inhibitors prevent aging. We therefore examined the effect of COX-2 inhibitors on aging in the cellular senescence model of human dermal fibroblasts (HDFs). While the catalytic activity of COX-2 was observed to increase in the senescence process, we found that among three selective COX-2 inhibitors studied, only NS-398 inhibited the senescence whereas celecoxib and nimesulide accelerated the senescence. Non-selective COX inhibitors including aspirin, ibuprofen and flurbiprofen accelerated the senescence. The senescence-regulating effect of selective COX-2 inhibitors had no correlation with cellular reactive oxygen species levels, NF-kappaB activities or protein levels of p53 and p21. We instead found that selective COX-2 inhibitors regulate caveolin-1 expression at transcriptional levels, which was closely associated with the inhibitors' effect on the senescence. Collectively, these results suggest that COX-2 catalytic activity does not mediate HDF senescence and that selective COX-2 inhibitors modulate HDF senescence by a catalytic activity-independent mechanism. PMID:18848576

  10. JTE-522, a selective COX2 inhibitor, inhibits growth of pulmonary metastases of colorectal cancer in rats

    Microsoft Academic Search

    Hirotoshi Kobayashi; Hiroyuki Uetake; Tetsuro Higuchi; Masayuki Enomoto; Kenichi Sugihara

    2005-01-01

    BACKGROUND: Epidemiological studies have shown that individuals who regularly consume NSAIDs have lower rates of mortality associated with colorectal cancer. Because COX-2 inhibitors prevent tumor growth through some mechanisms, we assessed the effect of JTE-522, a selective COX-2 inhibitor, on pulmonary metastases of colon cancer in a rat model. METHODS: A suspension of 5 × 106 RCN-9 (rat colon cancer

  11. Novel selective Cox2 inhibitors induce apoptosis in Caco-2 colorectal carcinoma cell line

    Microsoft Academic Search

    Reza Entezari Heravi; Farzin Hadizadeh; Mojtaba Sankian; Jalil Tavakol Afshari; Seyed Mohammad Taghdisi; Hanieh Jafarian; Javad Behravan

    2011-01-01

    The cyclooxygenase-2 (COX-2) inhibitors including celecoxib inhibit cell growth and induce apoptosis in cancer cells. As COX-2 is over expressed in solid tumors such as colorectal cancer, it can be a suitable target for cancer treatment studies. In this study we designed and synthesized 4,5-bisaryl imidazolyl imidazoles as novel COX-2 inhibitors and evaluated their apoptosis inducing activities. The ability of

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

    Microsoft Academic Search

    A. Zarghi; S. Arfaei; R. Ghodsi

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

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

    Microsoft Academic Search

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

    2008-01-01

    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

  14. COX2 Inhibitors And Cardiovascular Risk

    Microsoft Academic Search

    Daniel J. Salzberg; Matthew R. Weir

    The development of drugs that selectively inhibit cyclooxygenase-2 (COX-2) demonstrates translational research from bench\\u000a to bedside based on underlying knowledge of micro-cellular structure and function. However, theoretical concerns about potentially\\u000a pro-thrombotic effects of selective COX-2 inhibitors coupled with observations of increased cardiovascular risk have produced\\u000a significant consternation and lead to the withdrawal of two of these agents from the market.

  15. Drug analogs of COX-2 selective inhibitors lumiracoxib and valdecoxib derived from in silico search and optimization.

    PubMed

    Bartzatt, Ronald

    2014-03-01

    The medicinal activity of COX-2 inhibitors are sufficiently beneficial to urge the search for new drug designs. This study presents 16 analogs of lumiracoxib and 10 analogs to valdecoxib having properties suitable as COX-2 inhibitors. For lumiracoxib analogs the mean Log P, polar surface area, and formula weight are 3.00, 70.46 A(2), and 276.60, respectively. For valdecoxib analogs the mean Log P, polar surface area, and formula weight are 3.65, 68.46 A(2), and 322.32, respectively. Grubb's test analysis of seven properties for seven known COX-2 selective inhibitors and those of 26 analog compounds indicated no outliers. The unpaired t-test compared Log P and polar surface area of seven known COX-2 inhibitors to all 26 analogs and found no difference. All 26 analogs showed no violation of the Rule of 5, this being an indicator of favorable bioavailability. Hierarchical cluster analysis by single linkage indicated lumiracoxib is most similar to analogs 2, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, and 17. Valdecoxib has highest similarity to analogs 8, 19, 21, 22, 23, 26, 27, and 28. Multiple regression analysis successfully produced equations for prediction of similar compounds to lumiracoxib and valdecoxib. Path analysis indicated that number of atoms, oxygen & nitrogen atoms, and Log P are the greatest determinants for formula weight for known COX-2 inhibitors. Criteria for molecular properties is established for identifying COX-2 inhibitors. These 26 analogs show much potential for active COX-2 inhibition. PMID:23984829

  16. Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

    PubMed Central

    Mahdi, Chanif; Nurdiana, Nurdiana; Kikuchi, Takheshi; Fatchiyah, Fatchiyah

    2014-01-01

    To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX), the three-dimensional (3D) structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117) was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2. PMID:25484897

  17. Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor.

    PubMed

    Raharjo, Sentot Joko; Mahdi, Chanif; Nurdiana, Nurdiana; Kikuchi, Takheshi; Fatchiyah, Fatchiyah

    2014-01-01

    To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX), the three-dimensional (3D) structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117) was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2. PMID:25484897

  18. NSAID-induced enteropathy: are the currently available selective COX-2 inhibitors all the same?

    PubMed

    Fornai, Matteo; Antonioli, Luca; Colucci, Rocchina; Pellegrini, Carolina; Giustarini, Giulio; Testai, Lara; Martelli, Alma; Matarangasi, Antuela; Natale, Gianfranco; Calderone, Vincenzo; Tuccori, Marco; Scarpignato, Carmelo; Blandizzi, Corrado

    2014-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E2 (PGE2) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy. PMID:24135073

  19. Selective COX2 inhibitor versus nonselective COX1 and COX2 inhibitor in the prevention of heterotopic ossification after total hip arthroplasty: a meta-analysis of randomised trials

    Microsoft Academic Search

    Deting Xue; Qiang Zheng; Hang Li; Shengjun Qian; Bo Zhang; Zhijun Pan

    2011-01-01

    Whether selective cyclo-oxygenase-2 (COX-2) inhibitors are equally effective compared to nonselective NSAIDs for the prevention\\u000a of heterotopic ossification (HO) after total hip arthroplasty (THA) is still unclear. We carried out a comprehensive search\\u000a strategy, in which only randomised controlled trials were included. Two reviewers independently assessed methodological quality\\u000a and extracted outcome data. Analyses were performed using Stata version 10.0. Four

  20. Selective COX-2 inhibitor versus nonselective COX-1 and COX-2 inhibitor in the prevention of heterotopic ossification after total hip arthroplasty: a meta-analysis of randomised trials.

    PubMed

    Xue, Deting; Zheng, Qiang; Li, Hang; Qian, Shengjun; Zhang, Bo; Pan, Zhijun

    2011-01-01

    Whether selective cyclo-oxygenase-2 (COX-2) inhibitors are equally effective compared to nonselective NSAIDs for the prevention of heterotopic ossification (HO) after total hip arthroplasty (THA) is still unclear. We carried out a comprehensive search strategy, in which only randomised controlled trials were included. Two reviewers independently assessed methodological quality and extracted outcome data. Analyses were performed using Stata version 10.0. Four eligible randomised controlled trials totalling 808 patients were included. Meta-analysis results showed that no statistically significant difference was found in overall incidence of HO (RR 1.08; 95% CI 0.71-1.64), incidence of moderate severe HO (Brooker II and III) (RR 0.83; 95% CI 0.48-1.42) and any grade of Brooker classification between two groups. In summary, the selective COX-2 inhibitors are equally effective as nonselective NSAIDs for the prevention of HO after THA. Considering the gastrointestinal side effects of nonselective NSAIDs, we recommend selective COX-2 inhibitors for the prevention of HO after THA. However, future well-designed, randomised controlled trials are still needed to further confirm our results. PMID:19830425

  1. 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

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

    2009-01-01

    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

  2. Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX2) inhibitors: replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere

    Microsoft Academic Search

    P. N. Praveen Rao; Edward E. Knaus

    2003-01-01

    A group of celecoxib analogues in which the para-SO2NH2 substituent on the N1-phenyl ring was replaced by a para-sulfonylazido (SO2N3) 4, or a meta-SO2N38, substituent were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonyl azide (4) with a para-SO2N3 substituent was a selective COX-1 inhibitor. In contrast, 3-[5-(4-methylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonyl azide (8a)

  3. Therapy switching and associated costs in elderly patients receiving COX2 selective inhibitors or non-selective non-steroidal anti-inflammatory drugs in Quebec, Canada

    Microsoft Academic Search

    E. Rahme; Y. Toubouti; E. Hunsche

    2006-01-01

    Objectives. Lack of efficacy or tolerability of some non-steroidal anti-inflammatory drugs (NSAIDs) may lead to switching between non-selective NSAIDs (nsNSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs), potentially increasing treatment costs due to additional physician visits and wastage of medication. This study assessed drug switching and associated costs among elderly chronic NSAID users. Methods. Data for patients who filled their first

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

    PubMed

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

    2013-01-01

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

  5. Dual, but not selective, COX-1 and COX-2 inhibitors, attenuate acetic acid-evoked bladder irritation in the anaesthetised female cat.

    PubMed

    Wibberley, Alexandra; McCafferty, Gerald P; Evans, Christopher; Edwards, Richard M; Hieble, J Paul

    2006-05-01

    Non-selective cyclooxygenase (COX) inhibitors exert effects on lower urinary tract function in several species. The exact contributions of COX-1 and COX-2 isozymes have not been studied much. The present studies investigated the effects of non- and selective COX inhibitors on bladder irritation in the cat.Chloralose-anaesthetised female cats were catheterised through the bladder dome for cystometric evaluation of bladder responses to intravesical infusion of saline or acetic acid. Bladder capacity, voiding efficiency, threshold pressure, and reflex-evoked bladder contraction amplitude and duration were measured. The cat COX selectivity of the doses of inhibitors examined was determined using an in vitro whole-blood assay and analysis of plasma levels. Pretreatment with indomethacin or ketoprofen (non-selective COX inhibitors; 0.3 mg kg(-1) i.v.) inhibited acetic acid-evoked irritation (characterised by a decrease in bladder capacity in vehicle pretreated animals). FR-122047 (selective COX-1 inhibitor), NS-398 and nimesulide (selective COX-2 inhibitors; 1 and 3 mg kg(-1) i.v.) had no effects on bladder irritation. Analysis of plasma levels of the doses examined and determination of COX-1 and COX-2 inhibition in cat whole blood confirmed the reported selectivity of these compounds in this species. The present studies suggest that dual COX inhibition is required to attenuate acetic acid-evoked bladder irritation in the cat. PMID:16547526

  6. A selective COX?2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis

    PubMed Central

    Reding, T; Bimmler, D; Perren, A; Sun, L?K; Fortunato, F; Storni, F; Graf, R

    2006-01-01

    Introduction Therapeutic strategies to treat chronic pancreatitis (CP) are very limited. Other chronic inflammatory diseases can be successfully suppressed by selective cyclooxygenase 2 (COX?2) inhibitors. As COX?2 is elevated in CP, we attempted to inhibit COX?2 activity in an animal model of CP (WBN/Kob rat). We then analysed the effect of COX?2 inhibition on macrophages, important mediators of chronic inflammation. Methods Male WBN/Kob rats were continuously fed the COX?2 inhibitor rofecoxib, starting at the age of seven weeks. Animals were sacrificed 2, 5, 9, 17, 29, 41, and 47?weeks later. In some animals, treatment was discontinued after 17?weeks, and animals were observed for another 24?weeks. Results Compared with the spontaneous development of inflammatory injury and fibrosis in WBN/Kob control rats, animals treated with rofecoxib exhibited a significant reduction and delay (p<0.0001) in inflammation. Collagen and transforming growth factor ? synthesis were significantly reduced. Similarly, prostaglandin E2 levels were markedly lower, indicating strong inhibition of COX?2 activity (p<0.003). If treatment was discontinued at 24?weeks of age, all parameters of inflammation strongly increased comparable with that in untreated rats. The correlation of initial infiltration with subsequent fibrosis led us to determine the effect of rofecoxib on macrophage migration. In chemotaxis experiments, macrophages became insensitive to the chemoattractant fMLP in the presence of rofecoxib. Conclusion In the WBN/Kob rat, chronic inflammatory changes and subsequent fibrosis can be inhibited by rofecoxib. Initial events include infiltration of macrophages. Cell culture experiments indicate that migration of macrophages is COX?2 dependent. PMID:16322109

  7. Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors.

    PubMed

    Ali, Ahmed M; Saber, Gamal E; Mahfouz, Nadia M; El-Gendy, Mahmoud A; Radwan, Awwad A; Hamid, Mohamed A El

    2007-10-01

    In our effort for synthesis of selective COX2 inhibitors, certain new 2,4-thiazolidinedione derivatives were synthesized. It necessitates preparation of potassium salt of 2,4-thiazolidinedione 2, which condensed with intermediate 4a. The resulting 3-[2-(4-methylphenyl)-2-oxo-l-phenylethyl]-2,4-thiazolidinedione 8 was condensed with appropriate aldehyde to afford compounds 10a, 10i-l, 10o and 10p. Compounds (9a-l, 10a-n, 10p, 11 and 12) were obtained through the preparation of 5-arylmethylidene-2,4-thiazolidinediones 6a-p and reaction of its potassium salt 7a-p with compounds 4a, 4b, and 5. Some compounds displayed significant analgesic activity as compared to reference standards. The anti-inflammatory activity of the synthesized compounds revealed that intermediate 8 and compounds 9c, 10c and 10d showed good results. Compound 10c produced no significant mucosal injury. HipHop methodology of Catalyst program was used to build up hypothetical model of selective COX2 inhibitors followed by fitting the synthesized compounds to this model. Compounds 10c and 10d were suspected to be promising selective COX2 inhibitors. Also, compounds (6c, 8, 9a,c,d,k, 10a,c,d,k, 11 and 12) were docked into COX1 and COX2 X-ray structures, using DOCK6 program. Docking results suggested that several of these derivatives are active COX inhibitors with a significant preference for COX2. PMID:18038897

  8. Synthesis, Anti-Inflammatory and Anti- Nociceptive Activities and Cytotoxic Effect of Novel Thiazolidin-4-ones Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors

    PubMed Central

    Moallem, Seyed Adel; Imenshahidi, Mohsen; Shahini, Narges; Javan, Ahmad Reza; Karimi, Mohsen; Alibolandi, Mona; Ghandadi, Morteza; Etemad, Leila; Motamedshariaty, Vahidehsadat; Hosseini, Toktam; Hadizadeh, Farzin

    2013-01-01

    Objective(s): Nowadays, COX-2 inhibitors such as valdecoxib are removed from the market because of their cardiovascular toxicity and their potential to increase the risk of strokes. In response to this, medicinal chemists have attempted to synthesize new classes of COX-2 Inhibitors. Materials and Methods: In this study, three novel analogues of thiazolidin-4-ones derivatives 2a-c were synthesized. The ability of these compounds to inhibit ovine COX-1 and COX-2 (0.2- 0.8 µM) was determined using a colorimetric method. The cytotoxic effect of the synthesized compounds (25-100 M) was also investigated by measuring their cytotoxicity against Caco-2 and MCF-7 cell lines using MTT assay. Cell apoptosis was determined by ?ow cytometry. Writhing test (7.5-75 mg/kg) was used to examine the antinociceptive effects in mice. The effect of the analogues against acute inflammation (7.5-75 mg/kg) was also studied using xylene-induced ear edema test in mice. Results: The synthesized compounds showed a weak capacity to inhibit the proliferation of Caco-2 and MCF-7 cell lines. The COX-2 inhibition potency and selectivity index for test compounds 2a–b were as follows; celecoxib > 2b > 2a. On the other hand, all three analogues exhibited strong antinociceptive activity against acetic acid-induced writhing. The anti-inflammatory and antinociceptive effects of the analogues were markedly more than positive control, celecoxib. Conclusion: This study demonstrates that the antinociceptive and anti-inflammatory activity profiles exhibited by the novel synthesized compounds are independent from their COX-2 inhibitory potencies. The found antinociceptive and anti-inflammatory effects can be caused by interaction with other target; independent from COX-2. Accordingly, the compounds 2a-c could serve as lead compounds to develop novel anti-inflammation and antinociceptive drugs. PMID:24570829

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

    SciTech Connect

    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

    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.

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

    PubMed

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

    2012-04-01

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

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

    PubMed Central

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

    2011-01-01

    The significance of inflammation in KSHV biology and tumorigenesis prompted us to examine the role of COX-2 in primary effusion lymphoma (PEL), an aggressive AIDS-linked KSHV-associated non-Hodgkin's lymphoma (NHL) using nimesulide, a well-known COX-2 specific NSAID. We demonstrate that (1) nimesulide is efficacious in inducing proliferation arrest in PEL (KSHV+/EBV-; BCBL-1 and BC-3, KSHV+/EBV+; JSC-1), EBV-infected (KSHV-/EBV+; Raji) and non-infected (KSHV-/EBV-; Akata, Loukes, Ramos, BJAB) high malignancy human Burkitt's lymphoma (BL) as well as KSHV-/EBV+ lymphoblastoid (LCL) cell lines; (2) nimesulide is selectively toxic to KSHV infected endothelial cells (TIVE-LTC) compared to TIVE and primary endothelial cells (HMVEC-d); (3) nimesulide reduced KSHV latent gene expression, disrupted p53-LANA-1 protein complexes, and activated the p53/p21 tumor-suppressor pathway; (4) COX-2 inhibition down-regulated cell survival kinases (p-Akt and p-GSK-3?), an angiogenic factor (VEGF-C), PEL defining genes (syndecan-1, aquaporin-3, and vitamin-D3 receptor) and cell cycle proteins such as cyclins E/A and cdc25C; (5) nimesulide induced sustained cell death and G1 arrest in BCBL-1 cells; (6) nimesulide substantially reduced the colony forming capacity of BCBL-1 cells. Overall, our studies provide a comprehensive molecular framework linking COX-2 with PEL pathogenesis and identify the chemotherapeutic potential of nimesulide in treating PEL. PMID:21980345

  12. Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats.

    PubMed

    Citraro, Rita; Leo, Antonio; Marra, Rosario; De Sarro, Giovambattista; Russo, Emilio

    2015-04-01

    Different data suggest the involvement of specific inflammatory pathways in the pathogenesis of epilepsy. Cyclooxygenase (COX), which catalyses the production of pro-inflammatory prostaglandins, may play a significant role in seizure-induced neuroinflammation and neuronal hyperexcitability. COX-2 is constitutively expressed in the brain and also increased during/after seizures. COX-2 inhibitors may thus attenuate inflammation associated with brain disorders. We studied whether early long-term treatment (17 consecutive weeks starting from 45 days postnatal age) with the non-steroidal anti-inflammatory drug etoricoxib (10 mg/kg/day per os), a selective COX-2 inhibitor, was able to prevent/reduce the development of absence seizures in WAG/Rij rats, a recognized animal model of absence epilepsy and epileptogenesis. Drug effects on the incidence, duration and properties of absence seizure spike-wave discharges (SWDs) were measured both 1 and 5 months after treatment withdrawal; furthermore, the acute effects of etoricoxib on SWDs in 6-month-old WAG/Rij rats were measured. Early long-term treatment (ELTT) with etoricoxib led to an ?40% long-lasting (5 months) reduction in the development of spontaneous absence seizures in adult WAG/Rij rats thus exhibiting antiepileptogenic effects. Acutely administered etoricoxib (10 and 20mg/kg i.p.) also had anti-absence properties, significantly reducing the number and duration of SWDs by ?50%. These results confirm the antiepileptogenic effects of COX-2 inhibitors and suggest the possible role of COX-2, prostaglandin synthesis and consequent neuroinflammation in the epileptogenic process underlying the development of absence seizures in WAG/Rij rats. PMID:25701797

  13. Efficacy and tolerability of lumiracoxib, a highly selective cyclo-oxygenase-2 (COX2) inhibitor, in the management of pain and osteoarthritis

    PubMed Central

    Geusens, Piet; Lems, Willem

    2008-01-01

    Lumiracoxib is a COX2 inhibitor that is highly selective, is more effective than placebo on pain in osteoarthritis (OA), with similar analgesic and anti-inflammatory effects as non-selective NSAIDs and the selective COX2 inhibitor celecoxib, has a lower incidence of upper gastrointestinal (GI) side effects in patients not taking aspirin, and a similar incidence of cardiovascular (CV) side effects compared to naproxen or ibuprofen. In the context of earlier guidelines and taking into account the GI and CV safety results of the TARGET study, lumiracoxib had secured European Medicines Agency (EMEA) approval with as indication symptomatic treatment of OA as well as short-term management of acute pain associated with primary dysmenorrhea and following orthopedic or dental surgery. In the complex clinical context of efficiency and safety of selective and non-selective COX inhibitors, its prescription and use should be based on the risk and safety profile of the patient. In addition, there is further need for long-term GI and CV safety studies and general post-marketing safety on its use in daily practice. Meanwhile, at the time of submission of this manuscript, the EMEA has withdrawn lumiracoxib throughout Europe because of the risk of serious side effects affecting the liver. PMID:18728796

  14. Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors

    Microsoft Academic Search

    Ahmed M. Ali; Gamal E. Saber; Nadia M. Mahfouz; Mahmoud A. El-Gendy; Awwad A. Radwan; Mohamed A. E. Hamid

    2007-01-01

    In our effort for synthesis of selective COX2 inhibitors, certain new 2,4-thiazolidinedione derivatives were synthesized.\\u000a It necessitates preparation of potassium salt of 2,4-thiazolidinedione 2, which condensed with intermediate 4a. The resulting\\u000a 3-[2-(4-methylphenyl)-2-oxo-1-phenylethyl]-2,4-thiazolidinedione 8 was condensed with appropriate aldehyde to afford compounds\\u000a 10a, 10i-l, 10o and 10p. Compounds (9a-l, 10a-n, 10p, 11 and 12) were obtained through the preparation of 5-arylmethylidene-2,4-thiazolidinediones

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

    Microsoft Academic Search

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

    2007-01-01

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

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

    PubMed

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

    2004-06-01

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

  17. Esculentic acid, a novel and selective COX-2 inhibitor with anti-inflammatory effect in vivo and in vitro.

    PubMed

    Niu, Xiaofeng; Mu, Qingli; Li, Weifeng; Yao, Huan; Li, Huani; Huang, Huimin

    2014-10-01

    Esculentic acid (EA), a pentacyclic triterpenoids compound extracted from the Chinese herb Phytolacca esculenta, has long been used in traditional Chinese medicine for the treatment of rheumatoid arthritis, edema, hepatitis and bronchitis disease. The present study aimed to investigate the anti-inflammatory effect of EA in vivo and in vitro and the effect of EA on cyclooxygenase (COX) protein expression. To gain insight into the anti-inflammatory effect of EA both in vivo and in vitro and its effect on COX-2 expression, we used animal inflammatory models and lipopolysaccharide (LPS)-induced mouse peritoneal macrophages to examine the anti-inflammatory action of EA. Our findings demonstrated that EA possessed potent anti-inflammatory activity both in vivo and in vitro, while the anti-inflammation action in vitro may be attributed to the inhibition of the level of TNF-? and IL-6 pro-inflammatory cytokines and PGE2 inflammatory mediator in macrophages. Meanwhile, the production of PGE2 was possibly associated with COX-2 protein expression which was similar to that of NSAIDS. The study extends our understanding of the anti-inflammatory effect of EA both in vivo and in vitro and provides clarification of the molecular mechanisms underlying the effect of EA on PGE2 production, extending a novel aspect to the pharmacological activity of EA. PMID:24991788

  18. Exploiting cyclooxygenase-(in)dependent properties of COX-2 inhibitors for malignant glioma therapy.

    PubMed

    Schönthal, Axel H

    2010-07-01

    Cyclooxygenase 2 (COX-2) is frequently found up-regulated during pathological conditions and in cancer, where it is thought to support carcinogenesis and tumor angiogenesis. The development of newer-generation non-steroidal anti-inflammatory drugs (NSAIDs) able to more selectively inhibit cyclooxygenase 2 (COX-2) raised expectations that these agents might be beneficial for cancer prevention and therapy. However, while chemopreventive effects of some selective COX-2 inhibitors have been established, it has remained unpersuasive whether these new NSAIDs, such as celecoxib, rofecoxib or etoricoxib, are able to exert cancer therapeutic effects, i.e., whether they would be beneficial for the treatment of advanced cancers that are already grown and established. This issue was further complicated by findings that celecoxib was able to exert pronounced pro-apoptotic effects in vitro and in vivo in the absence of any apparent involvement of COX-2. In fact, newly synthesized close structural analogs of the celecoxib molecule revealed that it was possible to separate COX-2 inhibitory function from the ability to trigger apoptosis; for example, the analog 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet exerts increased cytotoxic potency. This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib. PMID:20879982

  19. Heme oxygenase/carbon monoxide-biliverdin pathway may be involved in the antinociceptive activity of etoricoxib, a selective COX-2 inhibitor.

    PubMed

    Grangeiro, Niedja M G; Aguiar, Jordana A; Chaves, Hellíada V; Silva, Antonio A R; Lima, Vilma; Benevides, Norma M B; Brito, Gerly A C; da Graça, José R V; Bezerra, Mirna M

    2011-01-01

    The aim of this study was to assess the interaction between the heme oxygenase-1/ biliverdin/carbon monoxide (HO-1/BVD/CO) and cyclooxygenase-2 (COX-2) pathways in the writhing test. Mice were pretreated with 0.1, 1 or 10 mg/kg, ip etoricoxib, a selective COX-2 inhibitor, or with one of the following HO-1/BVD/CO pathway modulators: 1, 3 or 9 mg/kg, sc ZnPP IX, a specific HO-1 inhibitor, 0.3, 1 or 3 mg/kg, sc hemin, a substrate of the HO-1/BVD/CO pathway; or 0.00025, 0.025 or 2.5 ?mol/kg, sc DMDC, a CO donor. Mice pretreated with etoricoxib or one of the HO-1/BVD/CO pathway modulators received an injection of acetic acid (ip) after 30 and 60 min, respectively. Next, the number of writhes was quantified between 0 and 30 min after stimulus injection. In another series of experiments, ineffective doses of etoricoxib were co-administered with hemin or DMDC and an effective dose of etoricoxib with ZnPP IX, followed by an acetic acid injection. Four hours after the acetic acid injection, levels of bilirubin, which is a product of BVD conversion by the BVD reductase enzyme, in the peritoneal lavage were determined. Hemin or DMDC reduced (p<0.05) the number of writhes, but ZnPP IX potentiated (p<0.05) the effect of acetic acid by increasing (p < 0.05) the number of writhes. The co-administration of etoricoxib with hemin or DMDC reduced (p<0.05) the number of writhes. However, the analgesic effect of etoricoxib was not observed in the presence of ZnPP IX. Pretreatment with ZnPP IX reduced bilirubin levels, but etoricoxib pretreatment significantly increased the bilirubin concentration in peritoneal exudates. The data obtained from these experiments showed that the HO-1/BVD/CO pathway was activated in the acetic acid-induced abdominal writhing model. The analgesic effect of etoricoxib was at least partially dependent on the participation of the HO-1/BVD/CO pathway. PMID:21441618

  20. Cardiovascular and gastrointestinal effects of COX2 inhibitors and NSAIDs: achieving a balance

    Microsoft Academic Search

    Jeffrey S Borer; Lee S Simon

    2005-01-01

    Conventional 'nonselective' nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation; however, the potential gastrointestinal risks associated with their use can be a cause for concern. In response to the adverse effects that can accompany nonselective NSAID use, selective cyclo-oxygenase (COX)-2 inhibitors were developed to target the COX-2 isoenzyme, thus providing anti-inflammatory and analgesic benefits

  1. Comparative QSAR modeling of COX2 inhibitor 1,2-diarylimidazoles using Estate and physicochemical parameters

    Microsoft Academic Search

    Santanu Chakraborty; Chandana Sengupta; Kunal Roy

    Considering importance of developing selective COX-2 inhibitors, COX-2 binding affinity data of 4-(2-aryl-1- imidazolyl)-phenyl methyl sulfones and sulfonamides (n = 83) have been modeled using electrotopological state (E-state) index as electronic parameter, hydrophobic substituent constant (?) and molar refractivity (MR) of aryl ring substituents as lipophilic and steric parameters, respectively. Additionally, suitable dummy parameters have been used for the development

  2. Virtual Screening for Finding Novel COX-2 Inhibitors as Antitumor Agents

    PubMed Central

    Badieyan, Zohreh S; Moallem, Seyed Adel; Mehri, Soghra; Shahsavand, Shabnam; Hadizadeh, Farzin

    2012-01-01

    The cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid resulting in the release of metabolites that induce pain and inflammatory responses. Recent studies have shown that strong COX-2 expression is highly correlated with increased tumor risk. Therefore, the development of potent COX-2 inhibitors to relieve pain and treat cancers requires further investigation. We used virtual screening to find three COX-2 inhibitors (Phar-95239, T0511-4424 and Zu- 4280011) from a huge zinc database containing 2000000 compounds. The effects of the compounds on COX-2 were compared to those on COX-1 using a colorimetric COX (ovine) screening assay kit. The selectivity index, the ratio of IC50 for COX-1 inhibition to that of COX-2, calculated were MTT assay was used to evaluate the cytotoxic activity of the compounds using different dilutions. The IC50 values were calculated. Based on the results of the MTT assay, the IC50 values for compounds Phar-95239, T0511-4424 and Zu-4280011 were 178.52, 143 and 97.61 µM, respectively, and the selectivity indices of the compounds were 11.36, 12.20 and 20.03, respectively. These results indicated a relationship between the selectivity index and anticancer activity. Zu-4280011 displayed the highest selectivity index and the best results in the MTT assay among selected componds. PMID:23115597

  3. Virtual Screening for Finding Novel COX-2 Inhibitors as Antitumor Agents.

    PubMed

    Badieyan, Zohreh S; Moallem, Seyed Adel; Mehri, Soghra; Shahsavand, Shabnam; Hadizadeh, Farzin

    2012-01-01

    The cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid resulting in the release of metabolites that induce pain and inflammatory responses. Recent studies have shown that strong COX-2 expression is highly correlated with increased tumor risk. Therefore, the development of potent COX-2 inhibitors to relieve pain and treat cancers requires further investigation. We used virtual screening to find three COX-2 inhibitors (Phar-95239, T0511-4424 and Zu- 4280011) from a huge zinc database containing 2000000 compounds. The effects of the compounds on COX-2 were compared to those on COX-1 using a colorimetric COX (ovine) screening assay kit. The selectivity index, the ratio of IC(50) for COX-1 inhibition to that of COX-2, calculated were MTT assay was used to evaluate the cytotoxic activity of the compounds using different dilutions. The IC(50) values were calculated. Based on the results of the MTT assay, the IC(50) values for compounds Phar-95239, T0511-4424 and Zu-4280011 were 178.52, 143 and 97.61 µM, respectively, and the selectivity indices of the compounds were 11.36, 12.20 and 20.03, respectively. These results indicated a relationship between the selectivity index and anticancer activity. Zu-4280011 displayed the highest selectivity index and the best results in the MTT assay among selected componds. PMID:23115597

  4. Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: anti-inflammatory and analgesic activities.

    PubMed

    Alanazi, Amer M; El-Azab, Adel S; Al-Suwaidan, Ibrahim A; ElTahir, Kamal Eldin H; Asiri, Yousif A; Abdel-Aziz, Naglaa I; Abdel-Aziz, Alaa A-M

    2015-03-01

    A group of 30 cyclic imides (1-10a-c) was designed for evaluation as a selective COX-2 inhibitor and investigated in vivo for anti-inflammatory and analgesic activities. Compounds 6a, 6b, 7a and 7b exhibit optimal COX-2 inhibitory potency (IC50 = 0.18, 0.24, 0.28 and 0.36 ?M; respectively) and selectivity index (SI) range of 363-668. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 6a as a highly potent (IC50 = 0.18 ?M), and an extremely selective [COX-2 (SI) = 668] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50 = 54.0 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). Molecular Docking study of the synthesized compound 6a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. Docking study showed that the methoxy moeities of 6a inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such groups underwent an H-bonding interaction with His(90) (3.02 ?), Arg(513) (1.94, 2.83 ?), and Gln(192) (3.25 ?). PMID:25549551

  5. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization.

    PubMed

    Meng, Zhen; Gan, Ye-Hua

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. PMID:25770423

  6. Cyclooxygenase2 (COX2) immunoreactivity in human endometrial carcinoma and precursor lesions: the potential use of COX2 inhibitors in cancer chemoprevention and therapy

    Microsoft Academic Search

    A. Nasir; D. Boulware; H. E. Kaiser; J. M. Lancaster; D. Coppola; P. V. Smith; A. Hakam; S. E. Siegel; B. Bodey

    The design of new antineoplastic agents that can halt the progression of human malignancies with minimal systemic damage has been emerging in recent years, with COX-2 as a major tar- get molecule. With an aim to demonstrate the expression and role of COX-2, the principal puta- tive target of COX-2 inhibitor therapy, in endometrial adenocarcinoma (EACA) and precursor lesions, atypical

  7. CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models.

    PubMed

    Kim, Sun-Hee; Margalit, Ofer; Katoh, Hiroshi; Wang, Dingzhi; Wu, Hong; Xia, Dianren; Holla, Vijaykumar R; Yang, Peiying; DuBois, Raymond N

    2014-12-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors (COXIBs) can reduce the risk of developing colorectal cancer (CRC) and are being considered for use as adjuvant therapy for treatment of CRC patients. However, long-term use of most NSAIDs, except aspirin, increases cardiovascular risk, hampering use of these drugs in CRC prevention and possibly for treatment. CG100649 is a new member of the COXIB family, which is proposed to inhibit both COX-2 and carbonic anhydrase-I/-II (CA-I/-II) activity. Using mouse models, we show here that CG100649 inhibits premalignant and malignant colorectal lesions in mouse models, partly through inhibiting tumor cell proliferation. These pre-clinical findings suggest a need for further exploration of CG100649 for CRC prevention and treatment. The long-term safety profile of CG100649, particularly regarding its effect on cardiovascular risk, is yet to be determined. PMID:25085205

  8. Etoricoxib: new drug. Avoid using cox-2 inhibitors for pain.

    PubMed

    2007-12-01

    (1) Paracetamol is the first-choice analgesic for joint pain. Nonsteroidal antiinflammatory drugs (NSAIDs), especially ibuprofen, are second-line options. Cox-2 inhibitors are no more effective than traditional NSAIDs and have no tangible advantages in terms of gastrointestinal tolerability. In contrast, they expose patients to an increased risk of cardiovascular adverse effects. (2) Etoricoxib is marketed in some European countries to relieve symptoms of osteoarthritis, rheumatoid arthritis, and gout attacks. (3) Many clinical trials have tested etoricoxib in these indications, as well as in ankylosing spondylitis, low back pain, and various types of acute pain. Etoricoxib was no more effective than other NSAIDs such as ibuprofen, naproxen or diclofenac in these situations. (4) Comparative trials showed a higher overall mortality rate with etoricoxib than with naproxen. A combined analysis of long-term comparative trials including 5441 patients, mainly versus naproxen, showed that etoricoxib does not reduce the risk of perforation, ulcer or severe gastrointestinal haemorrhage. Similarly, it does not reduce the risk of mild gastrointestinal events in at-risk patients: those with a history of gastrointestinal disorders, aspirin use, etc. (5) Three trials including a total of 34 701 patients (MEDAL programme) compared cardiovascular thrombotic events associated with etoricoxib and diclofenac. Overall, the cardiovascular risks appear to be similar but the thrombotic risk may be slightly higher with diclofenac than with other conventional NSAIDs. (6) Etoricoxib provoked arterial hypertension, oedema and heart failure during clinical trials. Serious skin reactions were reported both during clinical trials and after marketing, but their precise incidence is not known. Etoricoxib is partly metabolised by the cytochrome P450 isoenzyme CYP 3A4 and increases the bioavailability of ethinylestradiol. (7) When a NSAID is considered, drugs with which we have the most experience should be chosen, such as ibuprofen, and used at the lowest acceptable dose regimen (daily dose and length of treatment). Etoricoxib should be avoided. PMID:18084859

  9. Impact of Medicaid Prior Authorization Requirement for COX-2 Inhibitor Drugs in Nebraska

    PubMed Central

    Siracuse, Mark V; Vuchetich, Phillip J

    2008-01-01

    Objective Determine the impact of a Prior Authorization Requirement (PAR) program on Medicaid pharmacy expenditures and utilization. Data Source Prescription claims for Nebraska Medicaid recipients who received a cyclooxygenase-2 (COX-2) inhibitor, a nonselective nonsteroidal antiinflammatory (NSAID) drug, or other pain relievers between July 2001 and June 2003. Study Design and Data Collection/Extraction This was a retrospective cross-sectional study with a 12-month pre-PAR implementation period and a 12-month post-PAR implementation period. Pharmacy transactions for COX-2 inhibitors, NSAIDs, other pain relievers, and gastroprotectants were identified by their National Drug Code (NDC) in a Microsoft SQL query. The PAR was designed to approve COX-2 inhibitor use only for recipients at high risk of GI side effects while restricting access to those patients at low to moderate risk of GI side effects. Principal Findings One year following implementation of the PAR, overall expenditures on COX-2 inhibitors for Nebraska Medicaid dropped 50 percent. The overall impact on pharmacy expenditures, including NSAIDs, pain relief medications, and gastroprotectants when necessary to relieve gastrointestinal (GI) side effects, for those recipients who switched from a COX-2 inhibitor to an NSAID or other pain relievers was a decline of approximately 35 percent. Conclusion and Implications for State Policy PAR for COX-2 inhibitors successfully reduced Medicaid prescription expenditures. Recipients at high risk for GI side effects appropriately received COX-2 inhibitors. Recipients at low to moderate risk for GI side effects who were switched to NSAIDs or other pain relievers had lower overall prescription expenditures. Further research is needed to determine the impact of PAR on overall health outcomes and costs. In this study, rather than take a “one size fits all” approach to prescription drug cost-saving strategies, Medicaid policy makers understood that patient variation required accurate identification of disease severity to determine when equally efficacious low-cost alternatives were appropriate. PMID:18199195

  10. A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomas.

    PubMed Central

    Portnow, Jana; Suleman, Samia; Grossman, Stuart A.; Eller, Susan; Carson, Kathryn

    2002-01-01

    Although dexamethasone is very effective for controlling peritumoral cerebral edema, it is associated with distressing side effects that decrease the quality of life for many patients. One potential mechanism to explain the ability of dexamethasone to repair blood-brain barrier dysfunction is through the inhibition of cyclooxygenase-2 (COX-2). The purpose of this study was to determine in a rat brain tumor model whether SC-236, a selective COX-2 inhibitor, is as effective as dexamethasone. Twenty-nine adult male Fischer 344 rats were implanted with intracerebral 9L gliosarcomas and divided into 3 treatment groups. One group (n = 9) served as controls, another (n = 9) was treated with dexamethasone (3 mg/kg p.o. daily), and a third group (n = 11) received SC-236 (3 mg/kg p.o. daily). A survival study was performed. The median survival in the control group was 16 days, compared with 23 days for the dexamethasone group and 23 days for the COX-2 inhibitor group. Kaplan-Meier analysis on pairwise group comparisons showed improved survival that was statistically significant for each treatment group compared with the control group (log-rank test P = 0.009 for dexamethasone to control and P = 0.005 for COX-2 to control), and no significant difference in survival for the COX-2 compared with dexamethasone (log-rank test P = 0.2). These results suggest that a selective COX-2 inhibitor appears to be as effective as dexamethasone in prolonging survival in a rat brain tumor model. PMID:11772429

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

    PubMed Central

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

    2009-01-01

    AIMS To investigate impacts of withdrawal and regulatory advice regarding cyclooxygenase-2 (COX-2) inhibitors on UK population rates of gastrointestinal haemorrhage and acute myocardial infarction (MI). METHODS Ecological time series study of prescribing, mortality and hospital admission trends in people aged ?55 years. RESULTS Withdrawal and regulatory advice limiting COX-2 inhibitor availability from 2004 were temporally associated with reversal of previously unfavourable trends in emergency MI admissions among people aged ?65 years. Annual admission rate trends changed from +4.6% to ?3.1% (P < 0.001) among women and from +2.1% to ?3.8% (P= 0.003) among men. Absolute changes in average annual trend in the number of individuals aged ?65 years admitted following MI were from +981 (1999–2004) to ?819 (2004–2006) per year for women and from +713 to ?995 for men. No change in trend was apparent among people aged 55–64 years, or in MI mortality trends. There was some suggestion of an unfavourable change in admission trends for gastrointestinal haemorrhage among 55?64-year-olds, although this appeared to occur prior to COX-2 inhibitor withdrawal/regulation by up to 2 years. These trends were not apparent in older people, or in gastrointestinal haemorrhage mortality rates. CONCLUSIONS Withdrawal/regulation of COX-2 inhibitors was temporally associated with a favourable reversal of population-level hospital admission trends in MI among people aged ?65 years. Unfavourable reversal of previous declines in gastrointestinal haemorrhage admissions probably occurred before changes in COX-2 inhibitor availability. Withdrawal/ regulation of COX-2 inhibitors did not appear to have any adverse impact on population health and may have been beneficial. PMID:19917000

  12. Suppression of colitis-related mouse colon carcinogenesis by a COX2 inhibitor and PPAR ligands

    Microsoft Academic Search

    Hiroyuki Kohno; Rikako Suzuki; Shigeyuki Sugie; Takuji Tanaka

    2005-01-01

    BACKGROUND: It is generally assumed that inflammatory bowel disease (IBD)-related carcinogenesis occurs as a result of chronic inflammation. We previously developed a novel colitis-related mouse colon carcinogenesis model initiated with azoxymethane (AOM) and followed by dextran sodium sulfate (DSS). In the present study we investigated whether a cyclooxygenase (COX)-2 inhibitor nimesulide and ligands for peroxisome proliferator-activated receptors (PPARs), troglitazone (a

  13. Synthesis and biological evaluation of N-substituted indole esters as inhibitors of cyclo-oxygenase-2 (COX2)

    Microsoft Academic Search

    Süreyya Ölgen; Do?u Nebio?lu

    2002-01-01

    A series of novel N-substituted indole carboxylic, acetic and propionic acid esters have been prepared as possible cyclo-oxygenase-2 (COX-2) enzyme inhibitors. Compounds 20, 23 were found slightly active against COX-2. The synthesis of indole carboxylic, acetic and propionic acid esters were furnished by using dicyclohexyl carbodiimide (DCC), dimethylamino pyridine (DMAP) as carboxylate activators. N-substitution of indole esters was verified with

  14. Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX-2 Inhibitors with Tricyclic Core Structure.

    PubMed

    Laube, Markus; Gassner, Cemena; Sharma, Sai Kiran; Günther, Robert; Pigorsch, Arne; König, Jonas; Köckerling, Martin; Wuest, Frank; Pietzsch, Jens; Kniess, Torsten

    2015-06-01

    A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20-2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein-ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of (18)F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET). PMID:25909690

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

    PubMed Central

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

    2010-01-01

    A set of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (16–32) showing anti-inflammatory activity was analyzed using a three-dimensional qualitative structure-selectivity relationship (3D QSSR) method. The CatalystHipHop approach was used to generate a pharmacophore model for cyclooxygenase-2 (COX-2) inhibitors based on a training set of 15 active inhibitors (1–15). The degree of fitting of the test set compounds (16–32) to the generated hypothetical model revealed a qualitative measure of the more or less selective COX-2 inhibition of these compounds. The results indicate that most derivatives (16, 18, 20–25, and 30–32) are able to effectively satisfy the proposed pharmacophore geometry using energy accessible conformers (Econf < 20 kcal/mol). In addition, the triazole derivatives (16–32) were docked into COX-1 and COX-2 X-ray structures, using the program GOLD. Based on the docking results it is suggested that several of these novel triazole derivatives are active COX inhibitors with a significant preference for COX-2. In principle, this work presents an interesting, comprehensive approach to theoretically predict the mode of action of compounds that showed anti-inflammatory activity in an in vivo model. PMID:21179343

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  18. Discovery of a novel COX-2 inhibitor as an orally potent anti-pyretic and anti-inflammatory drug: design, synthesis, and structure-activity relationship.

    PubMed

    Hayashi, Shigeo; Sumi, Yoko; Ueno, Naomi; Murase, Akio; Takada, Junji

    2011-10-01

    Cyclooxygenase (COX) has been considered as a significant pharmacological target because of its pivotal roles in the prostaglandin biosynthesis and following cascades that lead to various (patho)physiological effects. Non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of fever, inflammation, and pain; however, nonselective COX inhibitors exhibit serious side-effects such as gastrointestinal damage because of their inhibitory activities against COX-1. Thus, COX-1 is constitutive and expressed ubiquitously and serves a housekeeping role, while COX-2 is inducible or upregulated by inflammatory/injury stimuli such as interleukin-1?, tumor necrosis factor-?, and lipopolysaccharide in macrophage, monocyte, synovial, liver, and lung, and is associated with prostaglandin E? and prostacyclin production that evokes or sustains systemic/peripheral inflammatory symptoms. Also, hypersensitivity of aspirin is a significant concern clinically. Hence, design, synthesis, and structure-activity relationship of [2-{[(4-substituted)-pyridin-2-yl]carbonyl}-(6- or 5-substituted)-1H-indol-3-yl]acetic acid analogues were investigated to discover novel acid-type COX-2 inhibitor as an orally potent new-class anti-pyretic and anti-inflammatory drug. As significant findings, compounds 1-3 demonstrated potent COX-2 inhibitory activities with high selectivities for COX-2 over COX-1 in human cells or whole-blood in vitro, and demonstrated orally potent anti-pyretic activity against lipopolysaccharide-induced systemic-inflammatory fever model in F344 rats. Also compound 1 demonstrated orally potent anti-inflammatory activity against edema formation and a suppressive effect against PGE? production in carrageenan-induced peripheral-inflammation model on the paw of SD rats. These results suggest that compounds 1-3 are potential agents for the treatment of inflammatory disease and are useful for further pharmacological COX-2 inhibitor investigations. PMID:21741371

  19. Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors.

    PubMed

    Biava, Mariangela; Battilocchio, Claudio; Poce, Giovanna; Alfonso, Salvatore; Consalvi, Sara; Di Capua, Angela; Calderone, Vincenzo; Martelli, Alma; Testai, Lara; Sautebin, Lidia; Rossi, Antonietta; Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Giordani, Antonio; Persiani, Stefano; Colovic, Milena; Dovizio, Melania; Patrignani, Paola; Anzini, Maurizio

    2014-01-15

    We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema. PMID:24373735

  20. Aspirin, NSAIDs, and COX2 inhibitors in cardiovascular disease: Possible interactions and implications for treatment of rheumatoid arthritis

    Microsoft Academic Search

    Tobias Kurth; Charles H. Hennekens; Julie E. Buring; J. Michael Gaziano

    2004-01-01

    Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors are widely used in patients\\u000a with rheumatoid arthritis. Aspirin has the largest and most persuasive body of randomized trial evidence to support its use\\u000a in secondary prevention for cardiovascular disease (CVD) and primary prevention for myocardial infarction. There is, however,\\u000a a possible deleterious interaction between aspirin and NSAIDs on CVD that

  1. From COX-2 inhibitor nimesulide to potent anti-cancer agent: synthesis, in vitro, in vivo and pharmacokinetic evaluation

    PubMed Central

    Chennamaneni, Snigdha; Yi, Xin; Liu, lili; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

    2014-01-01

    Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure–function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC50s around 100nM to 200nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC50s around 100nM to 500nM. Intraperitoneal injection with a dosage of 5mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound. PMID:22119125

  2. A COX2Specific Inhibitor Plus a Proton-Pump Inhibitor: Is This a Reasonable Approach to Reduction in NSAIDs' GI Toxicity?

    Microsoft Academic Search

    Byron Cryer

    2006-01-01

    The two prevailing approaches to decrease risks of nonsteroidal anti-inflammatory drug (NSAID)-associated gastrointestinal (GI) events are the use of a COX-2 inhibitor or co-therapy with a proton-pump inhibitor (PPI). A major limitation of each approach is that, in patients at the highest risk for NSAID-induced ulcers, neither treatment is effective when used as a stand-alone strategy. An important question is

  3. Maturation and Fertilization of Non-Human Primate Oocytes are Compromised by Oral Administration of a COX2 Inhibitor

    PubMed Central

    Duffy, Diane M.; VandeVoort, Catherine A.

    2011-01-01

    Objective To determine if oral administration of a cyclooxygenase-2 (COX2) inhibitor affects oocyte nuclear maturation and fertilization in non-human primates. Design Laboratory research study. Setting Medical school. Animals Adult female cynomolgus monkeys (Macaca fascicularis). Interventions Monkeys received gonadotropins to stimulate multiple follicular development. An ovulatory dose of human chorionic gonadotropin (hCG) was administered either alone or concomitant with oral celecoxib, a COX2 inhibitor; oocytes were retrieved 36 hours later and exposed to sperm in vitro. Main Outcome Measures Oocytes were assessed for nuclear status at retrieval, resumption of meiosis in vitro, and success of in vitro fertilization. Results Treatment with hCG alone yielded oocytes which were primarily at the meiosis II (MII) stage of nuclear maturation (72.9%); few oocytes were obtained at the germinal vesicle (GV) and germinal vesicle break down (GVBD) stages. Treatment with hCG and celecoxib yielded fewer mature (MII) oocytes (35.6%) and more oocytes at less mature stages when compared to oocytes from monkeys treated with hCG alone. The majority (68.3±15.9%) of MII oocytes from monkeys treated with hCG alone fertilized in vitro, compared with only 11.0±5.9% of MII oocytes from monkeys treated with hCG and celecoxib. Conclusions Oral administration of a COX2 inhibitor reduced the rate of oocyte nuclear maturation and the success of in vitro fertilization. Drugs of this class may block multiple essential steps in female reproduction and be effective contraceptives for women. PMID:21236424

  4. Cox-2 inhibitors and other nonsteroidal anti-inflammatory drugs in the treatment of pain in the elderly.

    PubMed

    Bell, G M; Schnitzer, T J

    2001-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed therapies for acute and chronic pain in the elderly. NSAIDs are effective in treating many disorders, but their use often is limited by toxicities, especially gastrointestinal and renal toxicity. COX-2 inhibitors are a major therapeutic advance, providing the analgesic and anti-inflammatory activity of NSAIDs, with a significant improvement in gastrointestinal safety. These new agents may be ideal therapies for older patients at risk for NSAID-related gastrointestinal toxicity. PMID:11459717

  5. In vivo selectivity of a selective cyclooxygenase 2 inhibitor in the oral surgery model

    Microsoft Academic Search

    Asma A. Khan; Jaime S. Brahim; Janet S. Rowan; Raymond A. Dionne

    2002-01-01

    Objective: Prostanoids formed by cyclooxygenase play an important role in pain and the induction of inflammation. It is generally believed that COX-1 is constitutively expressed, whereas COX-2 is primarily inducible during inflammation. This study examined the in vivo selectivity of celecoxib, a COX-2 inhibitor, and evaluated whether estimates of selectivity that are based on in vitro and ex vivo analyses

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

    Microsoft Academic Search

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

    2005-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  8. Epidermal COX2 Induction Following Ultraviolet Irradiation: Suggested Mechanism for the Role of COX2 Inhibition in Photoprotection

    Microsoft Academic Search

    Catherine S. Tripp; Eric A. G. Blomme; Kevin S. Chinn; Medora M. Hardy; Peter LaCelle; Alice P. Pentland

    2003-01-01

    The cyclooxygenase isoforms, COX-1 and COX-2, are involved in the biosynthesis of prostaglandin E2, a major prostaglandin involved in epidermal homeostasis and repair. Cancer originating in the epidermis can develop when keratinocyte proliferation and apoptosis become dysregulated, resulting in sustained epidermal hyperplasia. COX-2 inhibitors, which demonstrate significant in vivo selectivity relative to COX-1, suppress both ultraviolet-induced epidermal tumor development and

  9. In vitro and in vivo inhibitory effect of three Cox-2 inhibitors and epithelial-to-mesenchymal transition in human bladder cancer cell lines

    PubMed Central

    Adhim, Z; Matsuoka, T; Bito, T; Shigemura, K; Lee, K-M; Kawabata, M; Fujisawa, M; Nibu, K; Shirakawa, T

    2011-01-01

    Background: Although the anti-tumour effect of cyclooxygenase-2 (Cox-2) inhibitors in invasive bladder cancer has been confirmed, its mechanisms of action are unclear. Recently, the concept of an epithelial-to-mesenchymal transition (EMT) promoting carcinoma progression has been suggested, and a key feature of the EMT is the downregulation of E-cadherin. In this study, we investigated the effect of Cox-2 inhibitors on reversal EMT and tumour growth inhibition in bladder cancer cells. Methods: We used three Cox-2 inhibitors, etodolac, celecoxib and NS-398 and three human bladder cancer cell lines, T24, 5637 and KK47, in this study. T24 xenograft tumour mouse model was used in the in vivo study. Results: Within the clinical drug concentrations, only etodolac showed the in vitro growth inhibition in T24 not in the other cell lines. Etodolac reduced SNAIL mRNA and vimentin cell surface expression, and induced E-cadherin mRNA and E-cadherin cell surface expression, in T24. Etodolac also most strongly inhibited the cell migration of T24 in vitro and showed the highest tumour growth inhibition in T24 tumour in vivo. Conclusion: Etodolac at clinical doses exhibited induced in vitro and in vivo anti-tumour effects and reversal effect of EMT in T24. These results suggest that etodolac is a good candidate for an anti-tumour or chemopreventive reagent for high-grade bladder cancer. PMID:21750550

  10. Cardiovascular Effects of the Selective Cyclooxygenase2 Inhibitors

    Microsoft Academic Search

    WILLIAM B. WHITE

    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

  11. Stretch-induced myoblast proliferation is dependent on the COX2 pathway

    SciTech Connect

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

    2005-11-01

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

  12. Short-term supplementation of COX2 inhibitor suppresses bone turnover in gonad-intact middle-aged male rats

    Microsoft Academic Search

    Chwan-Li Shen; James K. Yeh; XingJia Wang

    2006-01-01

    There is an increasing body of evidence supporting the idea that nonsteroidal antiinflammatory drugs can effectively suppress\\u000a ovariectomy-induced bone loss in adult rats. The present study investigated the effects of supplementation of selective cyclooxygenase-2\\u000a inhibitor [5,5-dimethyl-3-(3 flurophenyl)-4-(4 methylsulphonal) phenyl-2 (6H) furanone, DFU] to diets on bone metabolism, bone mineral density (BMD), and histomorphometry in middle-aged male rats. Forty\\u000a 16-month-old male

  13. Role of selective cyclooxygenase-2 inhibitors in exacerbation of inflammatory bowel disease: A systematic review and meta-analysis

    Microsoft Academic Search

    Xin-Pu Miao; Qin Ouyang; Hui-Yan Li; Zhong-Hui Wen; De-Kui Zhang; Xiao-Yan Cui

    2008-01-01

    Background: In the general population, selective cyclooxygenase (COX)-2 inhibitors have been associated with fewer gastrointestinal adverse effects (AEs) than NSAIDs, but whether they are associated with exacerbations in patients with inflammatory bowel disease (IBD) remains controversial.Objective: The aim of this study was to review published and unpublished findings to determine whether the use of COX-2 inhibitors increased the risk for

  14. Enhancement of the Sensitivity of Renal Cell Carcinoma Cells to Fas-Mediated Cytotoxicity and Apoptosis by the Selective Cyclooxygenase2 Inhibitor JTE-522

    Microsoft Academic Search

    Nodoka Sato; Yoichi Mizutani; Yong Nan Li; Jun Fujiwara; Hirokazu Ishida; Daisuke Toiyama; Koichi Abe; Issei Hayashi; Hiroyuki Nakanishi; Akihiro Kawauchi; Tsuneharu Miki

    2010-01-01

    Background: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in a variety of cancer cells. We reasoned that combination treatment of renal cell carcinoma (RCC) cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 synergizes with

  15. An overview of the recent developments in analytical methodologies for determination of COX-2 inhibitors in bulk drugs, pharmaceuticals and biological matrices.

    PubMed

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

    2005-09-15

    An extensive survey of the literature published in various analytical and pharmaceutical chemistry related journals has been conducted and the instrumental analytical methods which were developed and used for determination of COX-2 inhibitors in bulk drugs, formulations and biological fluids have been reviewed. This review covers the time period from 1995 to 2004 during which 138 analytical methods including all types of spectrophotometric and chromatographic techniques were reported. HPLC with UV detection was found to be the technique of choice for many workers and more than 100 methods were based on LC and UV. A critical analysis of the reported data has been carried out and the present state-of-art of the analytical techniques for determination of celecoxib, rofecoxib, etoricoxib, etodolac, nimesulide and meloxicam has been discussed. PMID:16009523

  16. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man

    Microsoft Academic Search

    Burkhard Hinz; Olga Cheremina; Kay Brune

    2007-01-01

    For more than three decades, acetamin- ophen (INN, paracetamol) has been claimed to be devoid of significant inhibition of peripheral prosta- noids. Meanwhile, attempts to explain its action by inhibition of a central cyclooxygenase (COX)-3 have been rejected. The fact that acetaminophen acts func- tionally as a selective COX-2 inhibitor led us to investi- gate the hypothesis of whether it

  17. The influence of Cox-2 and bioactive lipids on hematological cancersa

    PubMed Central

    Ramon, Sesquile; Woeller, Collynn F.; Phipps, Richard P.

    2014-01-01

    Inflammation is implicated in the progression of multiple types of cancers including lung, colorectal, breast and hematological malignancies. Cyclooxygenases (Cox) -1 and -2 are important enzymes involved in the regulation of inflammation. Elevated Cox-2 expression is associated with a poor cancer prognosis. Hematological malignancies, which are among the top 10 most predominant cancers in the USA, express high levels of Cox-2. Current therapeutic approaches against hematological malignances are insufficient as many patients develop resistance or relapse. Therefore, targeting Cox-2 holds promise as a therapeutic approach to treat hematological malignancies. NSAIDs and Cox-2 selective inhibitors are anti-inflammatory drugs that decrease prostaglandin and thromboxane production while promoting the synthesis of specialized proresolving mediators. Here, we review the evidence regarding the applicability of NSAIDs, such as aspirin, as well as Cox-2 specific inhibitors, to treat hematological malignancies. Furthermore, we discuss how FDA-approved Cox inhibitors can be used as anti-cancer drugs alone or in combination with existing chemotherapeutic treatments. PMID:24883266

  18. Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells.

    PubMed

    Takeda, Shuso; Okazaki, Hiroyuki; Ikeda, Eriko; Abe, Satomi; Yoshioka, Yasushi; Watanabe, Kazuhito; Aramaki, Hironori

    2014-01-01

    Metastases are known to be responsible for approximately 90% of breast cancer-related deaths. Cyclooxygenase-2 (COX-2) is involved not only in inflammatory processes, but also in the metastasis of cancer cells; it is expressed in 40% of human invasive breast cancers. To comprehensively analyze the effects of cannabidiolic acid (CBDA), a selective COX-2 inhibitor found in the fiber-type cannabis plant (Takeda et al., 2008), on COX-2 expression and the genes involved in metastasis, we performed a DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are invasive breast cancer cells that express high levels of COX-2, treated with CBDA for 48 hr at 25 µM. The results obtained revealed that COX-2 and Id-1, a positive regulator of breast cancer metastasis, were down-regulated (0.19-fold and 0.52-fold, respectively), while SHARP1 (or BHLHE41), a suppressor of breast cancer metastasis, was up-regulated (1.72-fold) and CHIP (or STUB1) was unaffected (1.03-fold). These changes were confirmed by real-time RT-PCR analyses. Taken together, the results obtained here demonstrated that i) CBDA had dual inhibitory effects on COX-2 through down-regulation and enzyme inhibition, and ii) CBDA may possess the ability to suppress genes that are positively involved in the metastasis of cancer cells in vitro. PMID:25242400

  19. The COX-2 pathway is essential during early stages of skeletal muscle regeneration.

    PubMed

    Bondesen, Brenda A; Mills, Stephen T; Kegley, Kristy M; Pavlath, Grace K

    2004-08-01

    Skeletal muscle regeneration comprises several overlapping cellular processes, including inflammation and myogenesis. Prostaglandins (PGs) may regulate muscle regeneration, because they modulate inflammation and are involved in various stages of myogenesis in vitro. PG synthesis is catalyzed by different isoforms of cyclooxygenase (COX), which are inhibited by nonsteroidal anti-inflammatory drugs. Although experiments employing nonsteroidal anti-inflammatory drugs have implicated PGs in tissue repair, how PGs regulate muscle regeneration remains unclear, and the potentially distinct roles of different COX isoforms have not been investigated. To address these questions, a localized freeze injury was induced in the tibialis anterior muscles of mice chronically treated with either a COX-1- or COX-2-selective inhibitor (SC-560 and SC-236, respectively), starting before injury. The size of regenerating myofibers was analyzed at time points up to 5 wk after injury and found to be decreased by SC-236 and in COX-2(-/-) muscles, but unaffected by SC-560. In contrast, SC-236 had no effect on myofiber growth when administered starting 7 days after injury. The attenuation of myofiber growth by SC-236 treatment and in COX-2(-/-) muscles is associated with decreases in the number of myoblasts and intramuscular inflammatory cells at early times after injury. Together, these data suggest that COX-2-dependent PG synthesis is required during early stages of muscle regeneration and thus raise caution about the use of COX-2-selective inhibitors in patients with muscle injury or disease. PMID:15084473

  20. Novel (pyrazolyl)benzenesulfonamides with a nitric oxide-releasing moiety as selective cyclooxygenase-2 inhibitors.

    PubMed

    Bechmann, Nicole; Kniess, Torsten; Köckerling, Martin; Pigorsch, Arne; Steinbach, Jörg; Pietzsch, Jens

    2015-08-15

    Inhibition of cyclooxygenase-2 (COX-2) is a promising anti-inflammatory therapeutic strategy, but long-term medication with COX-2-inhibitors (coxibs) may be associated with adverse cardiovascular effects. Functionalization of existing lead structures with nitric oxide (NO)-releasing moieties is an auspicious approach to minimize these effects. In this regard, an organic nitrate (-O-NO2) substituent was introduced at a (pyrazolyl)benzenesulfonamide lead structure. The novel NO-coxibs selectively inhibited COX-2 in a low micromolar range (IC50(COX-2): 0.22-1.27?M) and are supposed to be promising anti-inflammatory compounds with, in parallel, positive effects on vascular homeostasis. PMID:26081289

  1. Association of maternal pancreatic function and foetal growth in rats treated with DFU, a selective cyclooxygenase-2 inhibitor

    Microsoft Academic Search

    F. Burdan; J. Szumi?o; J. Dudka; M. Szumi?o; A. Korobowicz; S. Chatterjee; R. Klepacz

    2007-01-01

    Constitutive (COX-1) and inducible (COX-2) cyclooxygenase isoforms have been detected in various mammalian tissues. Their activity is blocked by non-steroidal anti-inflammatory drugs that may induce various side reactions. The aim of the study was to evaluate the effects of DFU, a selective COX-2 inhibitor, on exo- crine and endocrine pancreatic function and the immunoexpression of both COX isoforms in maternal

  2. Physiological COX-2 Expression in Breast Epithelium Associates with COX-2 Levels in Ductal Carcinoma in Situ and Invasive Breast Cancer in Young Women

    PubMed Central

    Fornetti, Jaime; Jindal, Sonali; Middleton, Kara A.; Borges, Virginia F.; Schedin, Pepper

    2015-01-01

    Cyclooxygenase-2 (COX-2) overexpression is implicated in increased risk and poorer outcomes in breast cancer in young women. We investigated COX-2 regulation in normal premenopausal breast tissue and its relationship to malignancy in young women. Quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 96 premenopausal women with known clinical reproductive histories, and on rat mammary glands with distinct ovarian hormone exposures. COX-2 expression in the normal breast epithelium varied more than 40-fold between women and was associated with COX-2 expression levels in ductal carcinoma in situ and invasive cancer. Normal breast COX-2 expression was independent of known breast cancer prognostic indicators, including tumor stage and clinical subtype, indicating that factors regulating physiological COX-2 expression may be the primary drivers of COX-2 expression in breast cancer. Ovarian hormones, particularly at pregnancy levels, were identified as modulators of COX-2 in normal mammary epithelium. However, serial breast biopsy analysis in nonpregnant premenopausal women suggested relatively stable baseline levels of COX-2 expression, which persisted independent of menstrual cycling. These data provide impetus to investigate how baseline COX-2 expression is regulated in premenopausal breast tissue because COX-2 levels in normal breast epithelium may prove to be an indicator of breast cancer risk in young women, and predict the chemopreventive and therapeutic efficacy of COX-2 inhibitors in this population. PMID:24518566

  3. Inhibition of 11?-Hydroxysteroid Dehydrogenase Type II Suppresses Lung Carcinogenesis by Blocking Tumor COX-2 Expression as Well as the ERK and mTOR Signaling Pathways

    PubMed Central

    Yang, Shilin; Yao, Bing; Zhang, Bixiang; Chen, Xiaoping; Pozzi, Ambra; Zhang, Ming-Zhi

    2015-01-01

    Lung cancer is by far the leading cause of cancer death. Early diagnosis and prevention remain the best approach to reduce the overall morbidity and mortality. Experimental and clinical evidence have shown that cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) contributes to lung tumorigenesis. COX-2 inhibitors suppress the development and progression of lung cancer. However, increased cardiovascular risks of COX-2 inhibitors limit their use in chemoprevention of lung cancers. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11?–hydroxysteroid dehydrogenase type II (11ßHSD2)-mediated metabolism. We found that 11?HSD2 expression was increased in human lung cancers and experimental lung tumors. Inhibition of 11?HSD2 activity enhanced glucocorticoid-mediated COX-2 inhibition in human lung carcinoma cells. Furthermore, 11?HSD2 inhibition suppressed lung tumor growth and invasion in association with increased tissue active glucocorticoid levels, decreased COX-2 expression, inhibition of ERK and mTOR signaling pathways, increased tumor endoplasmic reticulum stress as well as increased lifespan. Therefore, 11?HSD2 inhibition represents a novel approach for lung cancer chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity and/or inhibits the ERK and mTOR signaling pathways. PMID:26011146

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

    Microsoft Academic Search

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

    1996-01-01

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

  5. Drug Insight: cyclo-oxygenase-2 inhibitors—a critical appraisal

    Microsoft Academic Search

    Bertold Renner; Kay Brune; Burkhard Hinz

    2007-01-01

    Following the withdrawal of rofecoxib and valdecoxib, the discussion concerning selective cyclo-oxygenase (COX)-2 inhibitors was often characterized more by emotions than scientific evidence. In fact, the original rationale of these substances is still valid, in that selective COX2 inhibitors cause significantly fewer severe side effects in the gastrointestinal tract than traditional NSAIDs. Off-label long-term use of COX2 inhibitors in patients

  6. 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

    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

    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.

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

    PubMed

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

    2014-12-01

    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

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

    PubMed Central

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

    2014-01-01

    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

  9. Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-?B and COX-2 signaling.

    PubMed

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

    2014-01-01

    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

  10. Signal Transduction Pathway Analysis in Desmoid-type Fibromatosis: TGF?, COX2 and Sex Steroid Receptors

    PubMed Central

    Mignemi, Nicholas A.; Itani, Doha M.; Fasig, John H.; Keedy, Vicki L.; Hande, Kenneth R.; Whited, Brent W.; Homlar, Kelly C.; Correa, Hernan; Coffin, Cheryl M.; Black, Jennifer O.; Yi, Yajun; Halpern, Jennifer L.; Holt, Ginger E.; Schwartz, Herbert S.; Schoenecker, Jonathan G.; Cates, Justin M. M.

    2014-01-01

    Summary Despite reports of sex steroid receptor and COX2 expression in desmoid-type fibromatosis, responses to single agent therapy with anti-estrogens and nonsteroidal anti-inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co-express these targets. Clearly, a further understanding of the signaling pathways deregulated in desmoid tumors is essential for development of targeted molecular therapy. Transforming growth factor-? (TGF?) and bone morphogenetic proteins (BMPs) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGF? superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and 6 samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGF? family signaling pathways, ?-catenin, sex steroid hormone receptors and COX2 were assessed by immunohistochemistry; patterns of co-expression were explored via correlational statistical analyses. In addition to ?-catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGF? signaling) and COX2 was significantly increased in desmoid tumors compared to healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. TGF? receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor-? was present in all cases studied. TGF? signaling appears to be activated in desmoid-type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity may be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor-? and COX2 co-expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered. PMID:23035734

  11. The polypeptides COX2A and COX2B are essential components of the mitochondrial cytochrome c oxidase of Toxoplasma gondii.

    PubMed

    Morales-Sainz, Lorena; Escobar-Ramírez, Adelma; Cruz-Torres, Valentín; Reyes-Prieto, Adrián; Vázquez-Acevedo, Miriam; Lara-Martínez, Reyna; Jiménez-García, Luis Felipe; González-Halphen, Diego

    2008-02-01

    Two genes encoding cytochrome c oxidase subunits, Cox2a and Cox2b, are present in the nuclear genomes of apicomplexan parasites and show sequence similarity to corresponding genes in chlorophycean algae. We explored the presence of COX2A and COX2B subunits in the cytochrome c oxidase of Toxoplasma gondii. Antibodies were raised against a synthetic peptide containing a 14-residue fragment of the COX2A polypeptide and against a hexa-histidine-tagged recombinant COX2B protein. Two distinct immunochemical stainings localized the COX2A and COX2B proteins in the parasite's mitochondria. A mitochondria-enriched fraction exhibited cyanide-sensitive oxygen uptake in the presence of succinate. T. gondii mitochondria were solubilized and subjected to Blue Native Electrophoresis followed by second dimension electrophoresis. Selected protein spots from the 2D gels were subjected to mass spectrometry analysis and polypeptides of mitochondrial complexes III, IV and V were identified. Subunits COX2A and COX2B were detected immunochemically and found to co-migrate with complex IV; therefore, they are subunits of the parasite's cytochrome c oxidase. The apparent molecular mass of the T. gondii mature COX2A subunit differs from that of the chlorophycean alga Polytomella sp. The data suggest that during its biogenesis, the mitochondrial targeting sequence of the apicomplexan COX2A precursor protein may be processed differently than the one from its algal counterpart. PMID:18036550

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

    Microsoft Academic Search

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

    2006-01-01

    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

  13. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-?B-signaling pathways

    PubMed Central

    Suh, Yewseok; Afaq, Farrukh; Johnson, Jeremy J.; Mukhtar, Hasan

    2009-01-01

    Overexpression of cyclooxygenase 2 (COX2) and uncontrolled wingless and Int (Wnt)-signaling pathway have long been suggested to play crucial roles in colorectal cancer. Studies show that selective COX2 inhibitors possess great potential as chemopreventive agents for colon cancer. Recent studies suggest that targeting COX2 and epidermal growth factor receptor (EGFR) may provide better therapeutic strategy than inhibiting either single target and that this may alleviate the problem of COX2 inhibitor-associated side effects. Therefore, there have been intensive efforts to develop novel dietary substances that target COX2 and EGFR activation. Fisetin is a naturally occurring flavonoid commonly found in various vegetables and fruits. We found that the treatment of COX2-overexpressing HT29 human colon cancer cells with fisetin (30–120 ?M) resulted in induction of apoptosis, downregulation of COX2 protein expression without affecting COX1 and inhibited the secretion of prostaglandin E2. Treatment of cells with fisetin also inhibited Wnt-signaling activity through downregulation of ?-catenin and T cell factor 4 and decreased the expression of target genes such as cyclin D1 and matrix metalloproteinase 7. Fisetin treatment of cells also inhibited the activation of EGFR and nuclear factor-kappa B (NF-?B). Finally, the formation of colonies in soft agar was suppressed by fisetin treatment. Taken together, we provide evidence that the plant flavonoid fisetin can induce apoptosis and suppress the growth of colon cancer cells by inhibition of COX2- and Wnt/EGFR/NF-?B-signaling pathways. We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer. PMID:19037088

  14. Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2

    PubMed Central

    Zhang, Ping; Luo, He-Sheng; Li, Ming; Tan, Shi-yun

    2015-01-01

    Artesunate, a derivative of artemisinin isolated from Artemisia annua L., has been traditionally used to treat malaria, and artesunate has demonstrated cytotoxic effects against a variety of cancer cells. However, there is little available information about the antitumor effects of artesunate on human gastric cancer cells. In the present study, we investigated the antitumor effect of artesunate on human gastric cancer cells and whether its antitumor effect is associated with reduction in COX-2 expression. The effects of artesunate on the growth and apoptosis of gastric cancer cells were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis of annexin V–fluorescein isothiocyanate/propidium iodide staining, rhodamine 123 staining, and Western blot analysis. Results indicate that artesunate exhibits antiproliferative effects and apoptosis-inducing activities. Artesunate markedly inhibited gastric cancer cell proliferation in a time- and dose-dependent manner and induced apoptosis in gastric cancer cells a dose-dependent manner, which was associated with a reduction in COX-2 expression. Treatment with the selective COX-2 inhibitor celecoxib, or transient transfection of gastric cancer cells with COX-2 siRNA, also inhibited cell proliferation and induced apoptosis. Furthermore, the treatment with artesunate promoted the expression of proapoptotic factor Bax and suppressed the expression of antiapoptotic factor Bcl-2. In addition, caspase-3 and caspase-9 were activated, and artesunate induced loss of mitochondrial membrane potential, suggesting that the apoptosis is mediated by mitochondrial pathways. These results demonstrate that artesunate has an effect on anti-gastric cancer cells. One of the antitumor mechanisms of artesunate may be that its inhibition of COX-2 led to reduced proliferation and induction of apoptosis, connected with mitochondrial dysfunction. Artesunate might be a potential therapeutic agent for gastric cancer. PMID:25945055

  15. [Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors].

    PubMed

    Fukai, Ryosuke; Zheng, Xiaoxia; Motoshima, Kazunori; Kakuta, Hiroki

    2011-03-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturb- ance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4-trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N-(substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine. PMID:21372527

  16. Ku80 cooperates with CBP to promote COX-2 expression and tumor growth

    PubMed Central

    Qin, Yu; Xuan, Yang; Jia, Yunlu; Hu, Wenxian; Yu, Wendan; Dai, Meng; Li, Zhenglin; Yi, Canhui; Zhao, Shilei; Li, Mei; Du, Sha; Cheng, Wei; Xiao, Xiangsheng; Chen, Yiming; Wu, Taihua; Meng, Songshu; Yuan, Yuhui; Liu, Quentin; Huang, Wenlin; Guo, Wei; Wang, Shusen; Deng, Wuguo

    2015-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID:25797267

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

    PubMed

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

    2012-01-01

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

  18. COX-2 inhibition, H. pylori infection and the risk of gastrointestinal complications.

    PubMed

    Chan, Francis K L

    2003-01-01

    Current data on the gastric safety of cyclooxygenase-2 (COX-2) inhibitors in the presence of H. pylori infection are largely derived from animal experiments and indirect clinical evidence. In animal models of H. pylori gastritis, COX-2 inhibitors suppressed prostaglandin synthesis and aggravated mucosal damage. In the human stomach, COX-1 appears to be the predominant source of prostaglandins despite the fact that COX-2 is upregulated in H. pylori gastritis. There are conflicting data on whether H. pylori alters the risk of ulcer in patients receiving COX-2 inhibitors. Among patients with H. pylori infection, rofecoxib reduced the risk of complicated gastric but not duodenal ulcers as compared to naproxen. The advantage of rofecoxib over naproxen also disappeared in patients with H. pylori infection and prior upper gastrointestinal events. In contrast, pooled data suggested that H. pylori increases the risk of ulcer in patients receiving nonselective nonsteroidal anti-inflammatory drugs but not in patients receiving celecoxib. In rodent gastric ulcers, COX-2 was upregulated in the granulation tissue and ulcer margin. Inhibition of COX-2 delayed healing of experimental gastric ulcer. Limited data showed that COX-2 expression was also increased in human gastric ulcer regardless of the H. pylori status. The functional significance of COX-2 in human gastric ulcer is unknown. PMID:14529402

  19. Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib

    PubMed Central

    Hamilton, Lorna C; Warner, Timothy D

    1998-01-01

    Exposure of tissues to endotoxin (LPS) and/or cytokines leads to the induction of both inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). It has previously been reported that there is `cross-talk' between these two systems. However, such previous studies have been limited by the availability of highly selective inhibitors. Here we have investigated the interactions between iNOS and COX-2 in vivo using 1400W, an iNOS-selective inhibitor, and celecoxib, a COX-2-selective inhibitor.Infusion of LPS to rats for 6?h caused a time-dependent increase in the plasma concentrations of 6 keto-prostaglandin F1? (6 keto-PGF1?) and nitrite/nitrate (NO2/NO3), consistent with the induction of iNOS and COX-2. Bolus injection of arachidonic acid (AA) at t=6?h resulted in a further increase of circulating levels of 6 keto-PGF1? in LPS-treated animals.Treatment of rats with 1400W or the non-selective NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) inhibited the increase in plasma NO2/NO3 but were both without effect on the plasma concentration of 6 keto-PGF1? before or after AA.Treatment with the non-steroidal anti-inflammatory drugs (NSAIDs), A771726 or diclofenac, or with celecoxib significantly reduced the increase in circulating 6 keto-PGF1? caused by LPS, and the large increase in 6 keto-PGF1? following injection of AA. None of the COX inhibitors affected the increase in plasma NO2/NO3. Dexamethasone, however, significantly inhibited both the increase in 6 keto-PGF1? and the increase in NO2/NO3.In conclusion, the use of selective inhibitors does not support the concept of cross talk in vivo between iNOS and COX-2. PMID:9786506

  20. Potential interaction of natural dietary bioactive compounds with COX-2.

    PubMed

    Maldonado-Rojas, Wilson; Olivero-Verbel, Jesus

    2011-09-01

    Bioactive natural products present in the diet play an important role in several biological processes, and many have been involved in the alleviation and control of inflammation-related diseases. These actions have been linked to both gene expression modulation of pro-inflammatory enzymes, such as cyclooxygenase 2 (COX-2), and to an action involving a direct inhibitory binding on this protein. In this study, several food-related compounds with known gene regulatory action on inflammation have been examined in silico as COX-2 ligands, utilizing AutoDock Vina, GOLD and Surflex-Dock (SYBYL) as docking protocols. Curcumin and all-trans retinoic acid presented the maximum absolute AutoDock Vina-derived binding affinities (9.3 kcal/mol), but genistein, apigenin, cyanidin, kaempferol, and docosahexaenoic acid, were close to this value. AutoDock Vina affinities and GOLD scores for several known COX-2 inhibitors significatively correlated with reported median inhibitory concentrations (R² = 0.462, P < 0.001 and R² = 0.238, P = 0.029, respectively), supporting the computational reliability of the predictions made by our docking simulations. Moreover, docking analysis insinuate the synergistic action of curcumin on celecoxib-induced inhibition of COX-2 may occur allosterically, as this natural compound docks to a place different from the inhibitor binding site. These results suggest that the anti-inflammatory properties of some food-derived molecules could be the result of their direct binding capabilities to COX-2, and this process can be modeled using protein-ligand docking methodologies. PMID:21803623

  1. Preferential Enhancement of Tumor Radioresponse by a Cyclooxygenase2 Inhibitor

    Microsoft Academic Search

    Kazushi Kishi; Sven Petersen; Cordula Petersen; Nancy Hunter; Kathryn Mason; Jaime L. Masferrer; Philip J. Tofilon; Luka Milas

    2000-01-01

    Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, is overexpressed in many types of malignant tumors, where it mediates production of prostaglandins (PGs), which in turn may stimulate tumor growth and protect against damage by cytotoxic agents. This study inves- tigated whether SC-*236, a selective inhibitor of COX-2, potentiates anti- tumor efficacy of radiation without increasing radiation injury to normal tissue.

  2. Role of COX-2 in the bioactivation of methylenedianiline and in its proliferative effects in vascular smooth muscle cells.

    PubMed

    Hebert, Valeria Y; Jones, Brandon Chad; Mifflin, Randy C; Dugas, Tammy R

    2011-12-01

    4,4'-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane foams and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased the rates of proliferation in a manner that was inhibited by co-treatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity, and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased the rates of proliferation in VSMC isolated from wild-type but not COX-2 (-/-) mice. Paradoxically, treatment with DAPM reduced the cellular production of PGE(2) and PGF(2?), but dose-dependently increased the COX-2 protein levels. Covalent binding of [(14)C]-DAPM to VSMC biomolecules was greater in wild-type than in COX-2 (-/-) cells. However, covalent binding of [(14)C]-DAPM was not altered by co-treatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM's mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted. PMID:21720929

  3. ROLE OF COX-2 IN THE BIOACTIVATION OF METHYLENEDIANILINE AND IN ITS PROLIFERATIVE EFFECTS IN VASCULAR SMOOTH MUSCLE CELLS

    PubMed Central

    Hebert, Valeria Y.; Jones, Brandon Chad; Mifflin, Randy C.; Dugas, Tammy R.

    2011-01-01

    4,4?-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane forms and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased rates of proliferation in a manner that was inhibited by cotreatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased rates of proliferation in VSMC isolated from wildtype but not COX-2 (?/?) mice. Paradoxically, treatment with DAPM reduced cellular production of PGE2 and PGF2?, but dose-dependently increased COX-2 protein levels. Covalent binding of [14C]-DAPM to VSMC biomolecules was greater in wildtype than in COX-2 (?/?) cells. However, covalent binding of [14C]-DAPM was not altered by cotreatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM’s mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted. PMID:21720929

  4. COX-2 overexpression increases malignant potential of human glioma cells through Id1

    PubMed Central

    Xu, Kaiming; Wang, Lanfang; Shu, Hui-Kuo G.

    2014-01-01

    Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients. COX-2 is also regulated by epidermal growth factor receptor signaling which is important in the pathogenesis of GBMs. However, COX-2 expression has not been previously shown to directly alter malignancy of GBMs. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. This factor has been shown to be regulated by COX-2 in breast carcinoma cells and recent studies suggest that Id1 may also be involved in the genesis/progression of gliomas. We now show that COX-2 increases the aggressiveness of GBM cells. GBM cells with COX-2 overexpression show increased growth of colonies in soft agar. Tumorigenesis in vivo is also increased in both subcutaneous flank and orthotopic intracranial tumor models. COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis. Furthermore, we find direct evidence of a role for Id1 with significant suppression of in vitro transformation and in vivo tumorigenesis in COX-2-overexpressing GBM cells where Id1 has been knocked down. In fact, Id1 is even more efficient at enhancing transformation/tumorigenesis of GBM cells than COX-2. Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells. Thus, COX-2 enhances the malignancy of GBM cells through induction of Id1. PMID:24659686

  5. 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

    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

    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.

  6. Immunohistochemical detection of COX-2 in feline and canine actinic keratoses and cutaneous squamous cell carcinoma.

    PubMed

    Bardagí, M; Fondevila, D; Ferrer, L

    2012-01-01

    Cyclooxygenase-2 (COX-2) overexpression and its causal role in epidermal carcinogenesis have been demonstrated in human actinic keratoses (AK) and cutaneous squamous cell carcinoma (SCC). The aim of this study was to determine immunohistochemically the level of expression of COX-2 in feline and canine AK (n=18), SCC (n=36) and inflammatory dermatoses (n=24). COX-2 immunoreactivity was detected in all feline and canine SCC. In all specimens, labelled basal and suprabasal neoplastic keratinocytes were localized within and below areas of superficial erosion or ulceration and only scattered deeper tumour cells were positively labelled. In most cases, positive immunoreactivity of keratinocytes was associated with the presence of granulocytes. COX-2 expression was detected in 3/9 canine and 4/9 feline cases of AK and in only one case was associated with inflammation. Inflammatory dermatoses were characterized by positively labelled epidermal and follicular basal and suprabasal keratinocytes that were always associated with granulocyte exocytosis. These results indicate that further study of the effect of using COX-2 inhibitors in the management and prevention of feline and canine cutaneous SCC is warranted. The association between inflammatory cells and COX-2 expressing epidermal cells opens a new line of research regarding the role of COX-2 in SCC oncogenesis. Moreover, further studies should investigate the role of COX-2 in the pathogenesis and management of AK in animals. PMID:21601872

  7. 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

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

    2014-01-01

    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

  8. 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

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

    2014-01-01

    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

  9. Triple-Targeted Oncolytic Adenoviruses Featuring the Cox2 Promoter, E1A Transcomplementation, and Serotype Chimerism for Enhanced Selectivity for Ovarian Cancer Cells

    Microsoft Academic Search

    Gerd J. Bauerschmitz; Kilian Guse; Anna Kanerva; Artur Menzel; Isabell Herrmann; Renee A. Desmond; Masato Yamamoto; Dirk M. Nettelbeck; Tanja Hakkarainen; Peter Dall; David T. Curiel; Akseli Hemminki

    2006-01-01

    Conditionally replicating adenoviruses (CRAd's) feature selective replication in and killing of tumor cells. Initial clinical studies with relatively attenuated early generation agents have resulted in promising safety and efficacy data. Nevertheless, increased specificity may be advantageous for an emerging generation of infectivity-enhanced CRAd's. Further, increased specificity could translate into a larger tolerated dose. An approach for increasing specificity is dual

  10. Perioperative administration of selective cyclooxygenase-2 inhibitors for postoperative pain management in patients after total knee arthroplasty.

    PubMed

    Lin, Jun; Zhang, Lei; Yang, Huilin

    2013-02-01

    Total knee arthroplasty (TKA) is associated with considerable postoperative pain. The relative analgesic efficacy and adverse effect profile of perioperative use of selective cyclooxygenase-2 (COX-2) inhibitors for patients undergoing TKA are unclear. This is a systematic review and meta-analysis of all randomized controlled trials evaluating perioperative administration of COX-2 inhibitors for TKA. Eight studies that had enrolled a total of 571 patients were identified. There was a statistical significance in postoperative pain scores (0-24 hours: P = .0007, 24-48 hours: P = .01, 48-72 hours: P < .0001), opioid consumption (P = .006), active range of motion (P = .002), itching (P = .005), and postoperative nausea/vomiting (P = .003) between groups. There was no difference in blood loss during the first 24 hours after operation between groups. The efficacy of perioperative administration of selective COX-2 inhibitors to reduce postoperative pain and opioid consumption after TKA is validated. Furthermore, it has important outcome benefits after TKA. PMID:22682579

  11. Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor.

    PubMed

    Rordorf, Christiane M; Choi, Les; Marshall, Paul; Mangold, James B

    2005-01-01

    Lumiracoxib (Prexige) is a selective cyclo-oxygenase (COX)-2 inhibitor developed for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. Lumiracoxib possesses a carboxylic acid group that makes it weakly acidic (acid dissociation constant [pKa] 4.7), distinguishing it from other selective COX-2 inhibitors. Lumiracoxib has good oral bioavailability (74%). It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. Lumiracoxib has a short elimination half-life from plasma (mean 4 hours) and demonstrates dose-proportional plasma pharmacokinetics with no accumulation during multiple dosing. In patients with rheumatoid arthritis, peak lumiracoxib synovial fluid concentrations occur 3-4 hours later than in plasma and exceed plasma concentrations from 5 hours after dosing to the end of the 24-hour dosing interval. These data suggest that lumiracoxib may be associated with reduced systemic exposure, while still reaching sites where COX-2 inhibition is required for pain relief. Lumiracoxib is metabolised extensively prior to excretion, with only a small amount excreted unchanged in urine or faeces. Lumiracoxib and its metabolites are excreted via renal and faecal routes in approximately equal amounts. The major metabolic pathways identified involve oxidation of the 5-methyl group of lumiracoxib and/or hydroxylation of its dihaloaromatic ring. Major metabolites of lumiracoxib in plasma are the 5-carboxy, 4'-hydroxy and 4'-hydroxy-5-carboxy derivatives, of which only the 4'-hydroxy derivative is active and COX-2 selective. In vitro, the major oxidative pathways are catalysed primarily by cytochrome P450 (CYP) 2C9 with very minor contribution from CYP1A2 and CYP2C19. However, in patients genotyped as poor CYP2C9 metabolisers, exposure to lumiracoxib (area under the plasma concentration-time curve) is not significantly increased compared with control subjects, indicating no requirement for adjustment of lumiracoxib dose in these subjects. Lumiracoxib is selective for COX-2 compared with COX-1 in the human whole blood assay with a ratio of 515 : 1 in healthy subjects and in patients with osteoarthritis or rheumatoid arthritis. COX-2 selectivity was confirmed by a lack of inhibition of arachidonic acid and collagen-induced platelet aggregation. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen and a lack of effect on both small and large bowel permeability. Lumiracoxib does not exhibit any clinically meaningful interactions with a range of commonly used medications including aspirin (acetylsalicylic acid), fluconazole, an ethinylestradiol- and levonorgestrel-containing oral contraceptive, omeprazole, the antacid Maalox, methotrexate and warfarin (although, as in common practice, routine monitoring of coagulation is recommended when lumiracoxib is co-administered with warfarin). As such, dose adjustments are not required when co-administering these agents with lumiracoxib. In addition, moderate hepatic impairment and mild to moderate renal impairment do not appear to influence lumiracoxib exposure. PMID:16372823

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

    SciTech Connect

    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

    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.

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

    PubMed

    McCarty, Mark F

    2012-01-01

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

  14. Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

    PubMed Central

    Armstrong, Paul C.; Kirkby, Nicholas S.; Zain, Zetty N.; Emerson, Michael; Mitchell, Jane A.; Warner, Timothy D.

    2011-01-01

    Background Clinical use of selective inhibitors of cyclooxygenase (COX)-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. Methodology/Principal Findings A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control) diclofenac (1 mg.kg?1, i.v.) and parecoxib (0.5 mg.kg?1, i.v.) on thrombus formation induced by collagen or the thromboxane (TX) A2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. Conclusions/Significance Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA2, but not that induced by U46619, which is independent of platelet TXA2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis. PMID:21629780

  15. A quantitative analysis of kinase inhibitor selectivity

    Microsoft Academic Search

    Mazen W Karaman; Sanna Herrgard; Daniel K Treiber; Paul Gallant; Corey E Atteridge; Brian T Campbell; Katrina W Chan; Pietro Ciceri; Mindy I Davis; Philip T Edeen; Raffaella Faraoni; Mark Floyd; Jeremy P Hunt; Daniel J Lockhart; Zdravko V Milanov; Michael J Morrison; Gabriel Pallares; Hitesh K Patel; Stephanie Pritchard; Lisa M Wodicka; Patrick P Zarrinkar

    2008-01-01

    Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of

  16. Cyclooxygenase selectivity and the risk of gastro-intestinal complications of various non-steroidal anti-inflammatory drugs: A clinical consideration

    Microsoft Academic Search

    S. Kawai

    1998-01-01

    Severe gastro-intestinal complications are a major cause of NSAID-induced deaths in cases of rheumatoid arthritis. We measured COX selectivity by using an intact cell assay system, and found that NS-398 is a highly COX-2-selective inhibitor. Meloxicam, etodolac and diclofenac also showed high COX-2 selectivity. Zaltoprofen, loxoprofen-SRS (active metabolite of loxoprofen), 6-MNA (active metabolite of nabumetone) and ibuprofen showed intermediate COX-2

  17. 17-?-Estradiol upregulates COX2 in the rat oviduct

    Microsoft Academic Search

    S. Pérez Martínez; M. Hermoso; M. Farina; M. L. Ribeiro; M. Rapanelli; M. Espinosa; M. Villalón; A. Franchi

    2006-01-01

    We investigated the regulation of cyclooxygenase-2 (COX-2) by 17-?-estradiol (E2) in the rat oviduct. We observed that COX-2 is expressed mainly in proestrous and estrous stages, periods under estrogenic influence. While exogenous administration of E2 (1?g\\/rat) significantly increased COX-2 protein levels, progesterone did not modify it. COX-2 was mainly localized on oviductal epithelial cells from estrogenized rat. Induction of COX-2

  18. COX-2 expression in nonepithelial ovarian malignancies.

    PubMed

    Menczer, Joseph; Schreiber, Letizia; Sukmanov, Oleg; Czernobilsky, Bernard; Berger, Esther; Golan, Abraham; Levi, Tally

    2011-01-01

    The aim of the study was to assess the expression of cyclooxygenases (COX)-2 in nonepithelial ovarian malignancies.COX-2 immunohistochemical staining was performed on newly prepared deparaffinized slides from formalin-fixed, paraffin-embedded archival tissue blocks of unselected nonepithelial ovarian malignancies diagnosed between January 1993 and October 2009 after reconfirmation of the diagnosis. Staining was assessed according to intensity of staining and the proportion of stained cells. Staining of more than 10% of the cells was considered positive.During the study period, 26 histologically proven nonepithelial ovarian malignancies were diagnosed. Of them, 16 were granulosa cell tumors and 10 were germ cell tumors (4 dysgerminomas and 6 immature teratomas). Five (31.2%) granulosa cell tumors had positive immunohistochemical COX-2 staining. Positive staining was observed only in 1 immature teratoma and in none of the dysgerminomas.Our data seem to indicate that COX-2 expression by immunohistochemical methods is not frequent in nonepithelial ovarian malignancies. PMID:21131835

  19. Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2 and HGF Expression via a Positive Feedback Loop

    PubMed Central

    Byun, Ji Yeon; Youn, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Woo, So-Yeon; Kang, Jihee Lee

    2014-01-01

    Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition. PMID:24959005

  20. Has Cox2 a prognostic role in non-small-cell lung cancer? A systematic review of the literature with meta-analysis of the survival results

    Microsoft Academic Search

    C Mascaux; B Martin; M Paesmans; T Berghmans; M Dusart; A Haller; P Lothaire; A-P Meert; J-J Lafitte; J-P Sculier

    2006-01-01

    Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer, especially in adenocarcinoma (ADC). Our aim was to determine the prognostic value of COX-2 on survival in patients with lung cancer. Studies evaluating the survival impact of COX-2 in lung cancer, published until December 2005, were selected. Data for estimation of individual hazard ratios (HR) for survival were extracted from the publications and

  1. Amentoflavone from Biophytum sensitivum and its effect on COX-1/COX-2 catalysed prostaglandin biosynthesis.

    PubMed

    Bucar, F; Jachak, S M; Noreem, Y; Kartnig, T; Perera, P; Bohlin, L; Schubert-Zsilavecz, M

    1998-05-01

    Amentoflavone (I3', II8-biapigenin) was isolated from the roots of Biophytum sensitivum DC. (Oxalidaceae) and proved to be a selective inhibitor of cyclooxygenase (COX)-1 catalysed prostaglandin biosynthesis when tested in vitro with an IC (50) value of 12.4 microM (standard: indomethacin, IC (50) = 1.1 microM). Doses of up to 37 microM showed only a slight inhibition in the corresponding COX-2 assay. Quantification of amentoflavone was carried out by reversed phase HPLC in methanolic and aqueous extracts of the roots, stems and leaves. Highest amounts of amentoflavone were detected in methanolic extracts of roots and stems (0.26-0.35%), while considerably lower amounts were detected in the corresponding water extracts. PMID:17253252

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

    PubMed

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

    2012-09-30

    It has been proposed that the pro-inflammatory catalytic activity of cyclooxygenase-2 (COX-2) plays a key role in the aging process. However, it remains unclear whether the COX-2 activity is a causal factor for aging and whether COX-2 inhibitors could prevent aging. We here examined the effect of COX-2 inhibitors on aging in the intrinsic skin aging model of hairless mice. We observed that among two selective COX-2 inhibitors and one non-selective COX inhibitor studied, only NS-398 inhibited skin aging, while celecoxib and aspirin accelerated skin aging. In addition, NS-398 reduced the expression of p53 and p16, whereas celecoxib and aspirin enhanced their expression. We also found that the aging-modulating effect of the inhibitors is closely associated with the expression of type I procollagen and caveolin-1. These results suggest that pro-inflammatory catalytic activity of COX-2 is not a causal factor for aging at least in skin and that COX-2 inhibitors might modulate skin aging by regulating the expression of type I procollagen and caveolin-1. PMID:22771771

  3. COX2 is involved in hypoxia-induced TNF-? expression in osteoblast.

    PubMed

    Xing, Yonggang; Wang, Renxian; Chen, Dafu; Mao, Jianping; Shi, Rui; Wu, Zhihong; Kang, Jun; Tian, Wei; Zhang, Chi

    2015-01-01

    Bone regeneration involves a series of events in a coordinated manner, including recruitment of mesenchymal stem cells, induction of immune response, inflammatory activity and vascular ingrowth. The microenvironment of bone regeneration is hypoxic. Low oxygen tension (hypoxia) promotes the upregulation of several signaling molecules. The primary mediating factor is the hypoxia-inducible factor-1 (HIF-1). Hypoxia stimulates the expression of a variety of cytokines from inflammatory cells, fibroblasts, endothelial cells, and osteoblasts. TNF-? is a key proinflammatory cytokine. The molecular events involved in osteoblast dysfunction under hypoxia are not fully understood. This study determined the effects of hypoxia on TNF-? in osteoblasts, and molecular mechanisms were explored. We observed that hypoxia induced TNF-? expression in a time-dependent manner in osteoblasts. Experiments using a potent HIF-1? activator DFO demonstrated that hypoxia-induced TNF-? was mediated by HIF-1-?. In addition, this study showed that hypoxia activated cyclooxygenase-2 (COX2) expression along with TNF-?. Inhibition experiments using COX2 inhibitor N398 indicated that COX2 was involved in hypoxia-mediated TNF-? expression, and this observation was further confirmed by Small interfering RNA against COX2. On the other hand, TNF-? didn't lead to the activation of COX2 expression. We conclude that COX2 is involved in hypoxia-induced TNF-? expression in osteoblast. PMID:26066979

  4. COX2 is involved in hypoxia-induced TNF-? expression in osteoblast

    PubMed Central

    Xing, Yonggang; Wang, Renxian; Chen, Dafu; Mao, Jianping; Shi, Rui; Wu, Zhihong; Kang, Jun; Tian, Wei; Zhang, Chi

    2015-01-01

    Bone regeneration involves a series of events in a coordinated manner, including recruitment of mesenchymal stem cells, induction of immune response, inflammatory activity and vascular ingrowth. The microenvironment of bone regeneration is hypoxic. Low oxygen tension (hypoxia) promotes the upregulation of several signaling molecules. The primary mediating factor is the hypoxia-inducible factor-1 (HIF-1). Hypoxia stimulates the expression of a variety of cytokines from inflammatory cells, fibroblasts, endothelial cells, and osteoblasts. TNF-? is a key proinflammatory cytokine. The molecular events involved in osteoblast dysfunction under hypoxia are not fully understood. This study determined the effects of hypoxia on TNF-? in osteoblasts, and molecular mechanisms were explored. We observed that hypoxia induced TNF-? expression in a time-dependent manner in osteoblasts. Experiments using a potent HIF-1? activator DFO demonstrated that hypoxia-induced TNF-? was mediated by HIF-1-?. In addition, this study showed that hypoxia activated cyclooxygenase-2 (COX2) expression along with TNF-?. Inhibition experiments using COX2 inhibitor N398 indicated that COX2 was involved in hypoxia-mediated TNF-? expression, and this observation was further confirmed by Small interfering RNA against COX2. On the other hand, TNF-? didn’t lead to the activation of COX2 expression. We conclude that COX2 is involved in hypoxia-induced TNF-? expression in osteoblast. PMID:26066979

  5. Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

    PubMed

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

    2010-12-01

    Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. PMID:20600289

  6. 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

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

    2006-01-01

    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

  7. Functional Polymorphisms in COX-2 Gene Are Correlated with the Risk of Oral Cancer

    PubMed Central

    Li, Dong; Hao, Shu-Hong; Sun, Yan; Hu, Chun-Mei; Ma, Zhi-Hua; Wang, Zhi Ming; Liu, Jie; Liu, Hong Bo; Ye, Ming; Zhang, Yu Fei; Yang, Dong Sheng; Shi, Guang

    2015-01-01

    Background. This meta-analysis investigated the association between functional COX-2 gene polymorphisms and the risk of oral cancer. Methods. Several electronic databases were searched for published studies using combinations of keywords related to COX-2 gene polymorphisms and oral cancer. After selection of relevant studies, following strict inclusion and exclusion criteria, data was performed using STATA 12.0 software. Results. We retrieved 83 studies from database search using specific search terms. After multiple rounds of selection and elimination, 7 studies were finally identified as suitable to be included in our present meta-analysis, based on their relevance and data integrity. These 7 studies contained a combined total of 2,296 oral cancer patients and 3,647 healthy controls. Our findings demonstrated that +837 T > C (rs5275) polymorphism in COX-2 showed statistically significant differences in gene frequencies in case and control groups in allele model and dominant model. Similar results were obtained with COX-2 gene polymorphism 765 G > C (rs20417). On the other hand, 1195 A > G (rs689466) polymorphism in COX-2 did not confer susceptibility to oral cancers. Conclusion. Based on our results, COX-2 gene polymorphisms, +837 T > C (rs5275) and ?765G > C (rs20417), showed clear links with oral cancer susceptibility, and the 1195A > G (rs689466) polymorphism did not show such a correlation. PMID:25977924

  8. COX2 independent induction of apoptosis by etodolac in leukemia cells in vitro and growth inhibition of leukemia cells in vivo

    Microsoft Academic Search

    Satoki Nakamura; Miki Kobayashi; Kiyoshi Shibata; Naohi Sahara; Kazuyuki Shigeno; Kaori Shinjo; Kensuke Naito; Kazunori Ohnishi

    2004-01-01

    Summary Cyclooxygenase-2 (COX-2) has been reported to regulate apoptosis and influence the growth of malignancies. In this study, we demonstrated that etodolac, a COX-2 inhibitor, inhibited proliferation and induced apoptosis in leukemia K562, NB4, U937, HL60, and CEM cells via a COX-2 independent pathway. Etodolac induced apoptosis in a dose-dependent manner, which was associated with i) down-regulation of anti-apoptotic bcl-2,

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

    SciTech Connect

    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

    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.

  10. Epithelial 11?-hydroxysteroid dehydrogenase type II deletion inhibits Apc+/min mouse tumorigenesis via COX-2 pathway inhibition and induction of G1 cell cycle arrest

    PubMed Central

    Jiang, Li; Yang, Shilin; Yin, Huiyong; Fan, Xiaofeng; Wang, Suwan; Yao, Bing; Pozzi, Ambra; Chen, Xiaoping; Harris, Raymond C; Zhang, Ming-Zhi

    2013-01-01

    Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) promotes colorectal tumorigenesis. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11?–hydroxysteroid dehydrogenase type II (11ßHSD2)-mediated metabolism. We previously reported that 11ßHSD2 increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity, and 11ßHSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. 11ßHSD2 is expressed in Apc+/min mouse intestinal adenoma stromal and epithelial cells. We generated Apc+/min mice with selective deletion of 11ßHSD2 in intestinal epithelial cells (Vil-HSD2-/- Apc+/min). 11ßHSD2 deletion in intestinal epithelia led to marked inhibition of Apc+/min mouse intestinal tumorigenesis. Immunostaining indicated decreased 11ßHSD2 and COX-2 expression in adenoma epithelia, while stromal COX-2 expression was intact in Vil-HSD2-/- Apc+/min mice. In Vil-HSD2-/- Apc+/min mouse intestinal adenomas, both p53 and p21 mRNA and protein levels were increased, with concomitant decrease in phosphorylation of retinoblastoma protein, indicating glucocorticoid-mediated G1 cell cycle arrest. Regulated in development and DNA damage responses 1 (REDD1), a novel stress-induced gene that inhibits mammalian target of rapamycin (mTOR) signaling pathway, was increased, while the mTOR signaling pathway was inhibited. Therefore, in Vil-HSD2-/- Apc+/min mice, epithelial cell 11ßHSD2 deficiency leads to inhibition of adenoma initiation and growth by attenuation of COX-2 expression, increased G1 cell cycle arrest and inhibition of mTOR signaling as a result of increased tumor intracellular active glucocorticoids. 11ßHSD2 inhibition may represent a novel approach for colorectal cancer chemoprevention by increasing tumor glucocorticoid activity, which in turn inhibits tumor growth by multiple pathways. PMID:23741059

  11. STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.

    PubMed

    Wang, J-Y; Sun, J; Huang, M-Y; Wang, Y-S; Hou, M-F; Sun, Y; He, H; Krishna, N; Chiu, S-J; Lin, S; Yang, S; Chang, W-C

    2014-11-10

    Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca(2+) entry (SOCE) is the predominant Ca(2+) entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca(2+) sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.Oncogene advance online publication, 10 November 2014; doi:10.1038/onc.2014.366. PMID:25381814

  12. Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE2-dependent pathway.

    PubMed

    Maeng, Han-Joo; Lee, Wook-Joo; Jin, Qing-Ri; Chang, Ji-Eun; Shim, Won-Sik

    2014-10-01

    It is apparent that lung cancer is associated with inflammation, with accompanying hallmark elevations of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) levels. However, the effects of these changes on MRP efflux transporters have not been thoroughly investigated before. Here, we report that upregulation of COX-2 can induce overexpression of MRP4 in both A549 non-small-cell lung cancer cell lines and mouse lung cancer models. In A549 cells, phorbol 12-myristate 13-acetate (PMA) treatment induced upregulation of COX-2 and MRP4 together, but not other MRP transporters. Transient overexpression of human COX-2 cDNA also specifically increased COX-2 and MRP4. Moreover, COX inhibitor treatment and COX-2-specific siRNA significantly inhibited the upregulation of MRP4. Additionally, PMA-treatment increased extracellular PGE2 levels, likely due to increased MRP4 function. Likewise, COX-2-specific siRNA reduced extracellular PGE2 levels. Furthermore, COX-2 upregulation resulted in an increase in mPGES-1, an enzyme responsible for PGE2 production. Finally, metastasized lung cancer model mice exhibited increased expression levels of COX-2 and MRP4, as well as mPGES-1. In conclusion, the present study suggests that overexpression of MRP4 in lung cancer may be attributable to COX-2 upregulation via a PGE2-dependent pathway. PMID:24909729

  13. Synthesis and evaluation of carbaborane derivatives of indomethacin as cyclooxygenase inhibitors

    Microsoft Academic Search

    Matthias Scholz; Anna L. Blobaum; Lawrence J. Marnett; Evamarie Hey-Hawkins

    2011-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological activities by inhibiting cyclooxygenase (COX)-1 and COX-2. Previous studies have shown that esters and amides of non-selective inhibitors such as indomethacin are selective against COX-2, which is the therapeutically relevant isoform. Structure–activity analysis indicates that substituted phenyl rings are tolerated as ester components. In the present study, the introduction of inorganic ortho- and

  14. Clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues

    PubMed Central

    Ma, Xiaoping; Hui, Yuzuo; Lin, Li; Wu, Yu; Zhang, Xian; Liu, Peishu

    2015-01-01

    Objective: To analyze the clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. Methods: One hundred and eight tissue samples from the patients with endometrial cancer enrolled in our hospital from August 2011 to July 2014 were selected, including 60 normal tissue samples (normal group), 60 neoplastic tissue samples (neoplastic group) and 60 cancer tissue samples (cancer group). All the samples were subjected to immunohistochemical assay to detect the expressions of COX-2, GLUT-1 and VEGF. The clinical data were also investigated for correlation analysis. Results: The positive rates of COX-2 in normal group, neoplastic group and cancer groups were 3.3%, 21.7% and 55.0% respectively. The positive rates of GLUT-1 in normal group, neoplastic group and cancer groups were 3.3%, 25.0% and 70.0% respectively. The positive rates of VEGF in normal group, neoplastic group and cancer groups were 1.7%, 23.3% and 63.3% respectively. With increasing stage of such cancer, decreasing degree of differentiation and lymphatic metastasis, the positive expression rates of COX-2, GLUT-1 and VEGF proteins were raised significantly (P<0.05). Spearman’s correlation analysis showed that the expressions of COX-2 and GLUT-1 (r=0.207, P<0.05), COX-2 and VEGF (r=0.243, P<0.05), as well as GLUT-1 and VEGF (r=0.758, P<0.05) were positively correlated. Conclusion: COX-2, GLUT-1 and VEGF were highly prominent in endometrial cancer, especially in the patients with low degree of differentiation, late stage and metastasis. They functioned synergistically in the onset and progression of this cancer.

  15. Mucin 1 Regulates Cox-2 Gene in Pancreatic Cancer

    PubMed Central

    Nath, Sritama; Roy, Lopamudra Das; Grover, Priyanka; Rao, Shanti; Mukherjee, Pinku

    2015-01-01

    Objective Eighty percent of pancreatic ductal adenocarcinomas (PDAs) overexpress mucin 1 (MUC1), a transmembrane mucin glycoprotein. MUC1high PDA patients also express high levels of cyclooxygenase 2 (COX-2) and show poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) partakes in oncogenic signaling, resulting in accelerated cancer progression. Our aim was to understand the regulation of Cox-2 expression by MUC1. Methods Levels of COX-2 and MUC1 were determined in MUC1?/?, MUC1low, and MUC1high PDA cells and tumors using reverse transcriptase–polymerase chain reaction, Western blot, and immunohistochemistry. Proliferative and invasive potential was assessed using MTT and Boyden chamber assays. Chromatin immunoprecipitation was performed to evaluate binding of MUC1-CT to the promoter of COX-2 gene. Results Significantly higher levels of COX-2 mRNA and protein were detected in MUC1high versus MUC1low/null cells, which were recapitulated in vivo. In addition, deletion of MUC1 gene and transient knockdown of MUC1 led to decreased COX-2 level. Also, MUC1-CT associated with the COX-2 promoter at ?1000 base pairs upstream of the transcription start site, the same gene locus where nuclear factor ?B p65 associates with the COX-2 promoter. Conclusions Data supports a novel regulation of COX-2 gene by MUC1 in PDA, the intervention of which may lead to a better therapeutic targeting in PDA patients. PMID:26035123

  16. LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

    SciTech Connect

    Sun Haipeng [Interdisciplinary Graduate Program of Pharmacology and Toxicology, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724 (United States); Xu Beibei; Sheveleva, Elena [Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724 (United States); Chen, Qin M. [Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724 (United States)], E-mail: qchen@email.arizona.edu

    2008-10-01

    Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K-independent mechanisms in regulating CT-induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca{sup 2+} concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes.

  17. Selective inhibitors of picornavirus replication.

    PubMed

    De Palma, Armando M; Vliegen, Inge; De Clercq, Erik; Neyts, Johan

    2008-11-01

    Picornaviruses cover a large family of pathogens that have a major impact on human but also on veterinary health. Although most infections in man subside mildly or asymptomatically, picornaviruses can also be responsible for severe, potentially life-threatening disease. To date, no therapy has been approved for the treatment of picornavirus infections. However, efforts to develop an antiviral that is effective in treating picornavirus-associated diseases are ongoing. In 2007, Schering-Plough, under license of ViroPharma, completed a phase II clinical trial with Pleconaril, a drug that was originally rejected by the FDA after a New Drug Application in 2001. Rupintrivir, a rhinovirus protease inhibitor developed at Pfizer, reached clinical trials but was recently halted from further development. Finally, Biota's HRV drug BTA-798 is scheduled for phase II trials in 2008. Several key steps in the picornaviral replication cycle, involving structural as well as non-structural proteins, have been identified as valuable targets for inhibition. The current review aims to highlight the most important developments during the past decades in the search for antivirals against picornaviruses. PMID:18381747

  18. Original article Selection of cholesterol absorption inhibitors devoid

    E-print Network

    Paris-Sud XI, Université de

    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

  19. Pharmacokinetics of selective serotonin reuptake inhibitors

    Microsoft Academic Search

    Christoph Hiemke; Sebastian Härtter

    2000-01-01

    The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half-lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluoxetine) and between 21 (paroxetine) and 36 (citalopram) hr for the other

  20. The PI3K/Akt pathway in colitis associated colon cancer and its chemoprevention with celecoxib, a Cox-2 selective inhibitor.

    PubMed

    Setia, Shruti; Nehru, Bimla; Sanyal, Sankar Nath

    2014-07-01

    Oncogenesis and angiogenesis are the two major pathways involved in tumorigenesis. Oncogenesis involves the PI3K/Akt and Wnt/?-catenin pathways, both of which are upregulated in several types of cancers. We established animal model of ulcerative colitis, colon cancer and colitis associated colon cancer by the incorporation of dextran sufate sodium (DSS) and dimethyl hydrazine (DMH), alone as well as in combination. Apart from the gross morphological analysis, we presently explored the role of various components of the oncogenic pathways, including PI3K, p-Akt, PTEN, PDK1, mTOR, GSK-3?, Wnt and ?-catenin and found the elevated levels of these proteins, except the tumor suppressors PTEN and GSK-3?, whose levels were downregulated in both inflammatory and carcinogenic conditions. We also studied the protein expression of some major angiogenic agents, such as Vegf, MMP-2, MMP-9 and iNOS. The angiogenic pathway was also upregulated presently in the DSS, DMH and DSS+DMH groups. Also, the reactive oxygen and nitrogen species, which lead to oxidative stress, were found to be elevated in these groups. All these effects were brought towards normal by the co-administration of celecoxib, a second generation non-steroidal anti-inflammatory drug (NSAID), with DSS, DMH and their combinatorial group. PMID:25107843

  1. Effects of Cyclooxygenase Inhibitors on Apoptotic Neuroretinal Cells

    PubMed Central

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

    2008-01-01

    Glaucoma is characterized by a loss of retinal ganglion cells (RGC) which is associated with a decrease of visual function. Neuroprotective agents as a new therapeutic strategy could prevent the remaining neurons from apoptotic cell death. Previous studies have shown the involvement of the Cyclooxygenase (COX)-2 signalling in the apoptotic death of neurons. Herein we investigated the neuroprotective effect of COX-1/COX-2- and selective COX-2- inhibitors on apoptotic. R28, a neuroretinal cell line and determined the PGE2 levels by ELISA. Furthermore we investigated differences in protein expression in the cells after exposure to elevated pressure compared to untreated cells by ProteinChip analysis. In addition, a protein profiling study of the cells after exposure to elevated pressure was performed. The protein expression profiles were measured by SELDI-TOF (Surface Enhanced Laser Desorption/Ionization-time of flight) Protein Chips. The protein identification was performed by mass spectrometry (MS). It could be shown that COX-2 inhibition significantly prevented the cells from apoptosis and reduced the PGE2 concentrations. Selective COX-2 inhibitors were significant more potent than non-selective inhibitors or COX-1 inhibitors. We found differently expressed protein patterns in neuroretinal cells cultured at atmospheric pressure compared to those cells exposed to elevated pressure with or without celecoxib respectively. We identified three biomarkers, ubiquitin, HSP10 and NDKB, which were differently expressed in the groups. However, our data indicates a distinct neuroprotective effect of COX-2 inhibition. The local treatment with selective COX-2 inhibitors might provide an innovative strategy of therapeutic intervention for glaucoma. PMID:19578520

  2. Specificity Normalization for Identifying Selective Inhibitors in Virtual Screening

    E-print Network

    Ioerger, Thomas R.

    Specificity Normalization for Identifying Selective Inhibitors in Virtual Screening Reetal Pai 1 of known inhibitors in a virtual screen are correlated with the probability of finding effective inhibitors inhibitors in many virtual screen results. In this paper, we use the interaction of known inhibitors across

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

    E-print Network

    Paris-Sud XI, Université de

    1 Running title : Inhibitors of CYP2J2 SELECTIVE, COMPETITIVE AND MECHANISM-BASED INHIBITORS, and evaluated as inhibitors of recombinant human CYP2J2. Compound 14, that involves an imidazole substituent, is a good non competitive inhibitor of CYP2J2 (IC50 = 400 nM). It is not selective towards CYP2J2 as it also

  4. Assessment of MMP-9, TIMP-1, and COX-2 in normal tissue and in advanced symptomatic and asymptomatic carotid plaques

    PubMed Central

    2011-01-01

    Background Mature carotid plaques are complex structures, and their histological classification is challenging. The carotid plaques of asymptomatic and symptomatic patients could exhibit identical histological components. Objectives To investigate whether matrix metalloproteinase 9 (MMP-9), tissue inhibitor of MMP (TIMP), and cyclooxygenase-2 (COX-2) have different expression levels in advanced symptomatic carotid plaques, asymptomatic carotid plaques, and normal tissue. Methods Thirty patients admitted for carotid endarterectomy were selected. Each patient was assigned preoperatively to one of two groups: group I consisted of symptomatic patients (n = 16, 12 males, mean age 66.7 ± 6.8 years), and group II consisted of asymptomatic patients (n = 14, 8 males, mean age 67.6 ± 6.81 years). Nine normal carotid arteries were used as control. Tissue specimens were analyzed for fibromuscular, lipid and calcium contents. The expressions of MMP-9, TIMP-1 and COX-2 in each plaque were quantified. Results Fifty-eight percent of all carotid plaques were classified as Type VI according to the American Heart Association Committee on Vascular Lesions. The control carotid arteries all were classified as Type III. The median percentage of fibromuscular tissue was significantly greater in group II compared to group I (p < 0.05). The median percentage of lipid tissue had a tendency to be greater in group I than in group II (p = 0.057). The percentages of calcification were similar among the two groups. MMP-9 protein expression levels were significantly higher in group II and in the control group when compared with group I (p < 0.001). TIMP-1 expression levels were significantly higher in the control group and in group II when compared to group I, with statistical difference between control group and group I (p = 0.010). COX-2 expression levels did not differ among groups. There was no statistical correlation between MMP-9, COX-2, and TIMP-1 levels and fibrous tissue. Conclusions MMP-9 and TIMP-1 are present in all stages of atherosclerotic plaque progression, from normal tissue to advanced lesions. When sections of a plaque are analyzed without preselection, MMP-9 concentration is higher in normal tissues and asymptomatic surgical specimens than in symptomatic specimens, and TIMP-1 concentration is higher in normal tissue than in symptomatic specimens. PMID:21457581

  5. Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-?1/IL-2/COX-2/endothelin ET(B) receptor cascade.

    PubMed

    El-Gowelli, Hanan M; Helmy, Maged W; Ali, Rabab M; El-Mas, Mahmoud M

    2014-03-01

    Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET(B) receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-??, TGF-??). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET(B) receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET(B) receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ETB receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-?1/IL-2/COX-2 pathway and the endothelin ET(B) receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. PMID:24462674

  6. Effects of ?-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro.

    PubMed

    Zhang, Liuqiang; Feng, Li; Jia, Qi; Xu, Jinwen; Wang, Rui; Wang, Zhengtao; Wu, Yingchun; Li, Yiming

    2011-08-15

    Harpagide (1) and harpagoside (2) are two iridoid glycosides existing in many medicinal plants. Although they are believed to be the main bioactive compounds related to the anti-inflammatory efficacy of these plants, the mechanisms of their anti-inflammatory activities remain unclear. The results of our present study showed that 1 and 2 had no effects on inhibitions of cyclooxygenase (COX)-1/2 enzyme activity, tumor necrosis factor-? (TNF-?) release, and nitric oxide (NO) production in vitro. However, the hydrolyzed products of 1 and 2 with ?-glucosidase treatment showed a significant inhibitory effect on COX-2 activity at 2.5-100 ?M in a concentration-dependent manner. Our further study revealed that the hydrolyzed 2 product was structurally the same as the hydrolyzed 1 product (H-harpagide (3)). The structure of 3 was 2-(formylmethyl)-2,3,5-trihydroxy-5-methylcyclopentane carbaldehyde, with a backbone similar to prostaglandins and COX-2 inhibitors such as celecoxib. All of them have a pentatomic ring with two adjacent side chains. The result of molecular modeling and docking study showed that 3 could bind to the COX-2 active domain well through hydrophobic and hydrogen-bonding interactions, whereas 1 and 2 could not, implying that the hydrolysis of the glycosidic bond of 1 and 2 is a pre-requisite step for their COX-2 inhibitory activity. PMID:21775152

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

    PubMed

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

    2012-01-01

    Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-?B, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-?B-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-?B induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating 'extrinsic' as well as 'intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v-FLIP/K13-HMVEC cells expressed lower levels of endothelial-mesenchymal transition genes such as slug, snail and twist, and higher expression of the tumor-suppressor gene, E-cadherin. Taken together, our study provides strong evidences that FDA-approved COX-2 inhibitors have great potential in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13. PMID:23552603

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

    PubMed Central

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

    2012-01-01

    Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-?B, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-?B-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-?B induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating ‘extrinsic' as well as ‘intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v-FLIP/K13-HMVEC cells expressed lower levels of endothelial–mesenchymal transition genes such as slug, snail and twist, and higher expression of the tumor-suppressor gene, E-cadherin. Taken together, our study provides strong evidences that FDA-approved COX-2 inhibitors have great potential in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13. PMID:23552603

  9. Int J Cancer. Author manuscript COX-2 and p53 in human sinonasal cancer: COX-2 expression is

    E-print Network

    Paris-Sud XI, Université de

    of Occupational Health1 Finnish Institute of Occupational Health, Helsinki,FI Sant publique et pid miologie des d that activate COX-2 also induce tumour suppressor p53, a transcription factor central in cellular stress, and 27 squamous cell carcinomas (SCC); 48 analysed for COX-2; 41 for p53). Occupational histories

  10. Selective serotonin reuptake inhibitors and myocardial infarction

    Microsoft Academic Search

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

    2002-01-01

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

  11. Genetic selection for peptide inhibitors of angiogenin

    PubMed Central

    Smith, Bryan D.; Raines, Ronald T.

    2008-01-01

    The improper regulation of angiogenesis is implicit in a variety of diseases, including cancer. Angiogenin is unique among angiogenic factors in its having ribonucleolytic activity. Inhibitors of this activity could serve as chemotherapeutics. The ribonucleolytic activity of angiogenin is toxic to the Origami™ strain of Escherichia coli. Herein, this cytotoxicity was used to identify inhibitors from a random nonapeptide library tethered to the C-terminus of human angiogenin. The selected sequences fell into three classes: (1) extremely hydrophobic, (2) putative ClpXP substrates, and (3) slightly anionic. Two peptides corresponding to sequences in the last class were synthesized chemically and found to inhibit the ribonucleolytic activity of human angiogenin in vitro with micromolar values of Ki. Both peptides also inhibit bovine pancreatic ribonuclease, a homologue of angiogenin, though one exhibits selectivity for angiogenin. The affinity and selectivity of these peptides are comparable to the best known inhibitors of angiogenin. Moreover, the strategy used to identify them is general and could be applied to other cytotoxins. PMID:18308863

  12. Disseminating Drug Prescribing Information: The Cox-2 Inhibitors Withdrawals

    PubMed Central

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

    2006-01-01

    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

  13. Selective Water-Soluble Gelatinase Inhibitor Prodrugs

    PubMed Central

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

    2011-01-01

    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

  14. Induction of COX-2 in human airway cells by manganese: role of PI3K/PKB, p38 MAPK, PKCs, Src, and glutathione depletion.

    PubMed

    Jang, Byeong-Churl

    2009-02-01

    The exposure of manganese is believed to be the risk of respiratory diseases. COX-2 is a protein involved in biosynthesis of inflammatory prostaglandins. Evidence suggests that COX-2 involves in the pathogenesis of lung inflammation. In this study, the effect of manganese-chloride (manganese) on COX-2 expression in A549 human lung epithelial cells was investigated. Treatment with manganese induced COX-2 at both protein and mRNA levels that were due to COX-2 transcriptional activation. Interestingly, manganese treatment led to activation of ERKs, p38 MAPK, JNKs, ATF-2, and PKB, but not NF-kappaB, and also cellular GSH depletion in A549 cells. Importantly, the manganese-induced COX-2 expression was suppressed by treatment with the inhibitor of p38 MAPK (SB203580), PI3K/PKB (LY294002), PKCs (GO6983, GF109203X, Rottlerin), Src (PP1), or the thiol-containing compound (NAC). There was crosstalk between p38 MAPK and GSH depletion or Src in response to manganese signal. Induction of COX-2 by manganese was also seen in different human airway cells, including H292 (bronchial) or Hep2 (laryngeal). These results collectively suggest that manganese induces COX-2 by transcriptional up-regulation in human airway cells and the induction appears to be cooperatively mediated via multiple signaling pathways and GSH depletion. PMID:19084589

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

    PubMed

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

    2012-09-01

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

  16. c-Src/Pyk2/EGFR/PI3K/Akt/CREB-activated pathway contributes to human cardiomyocyte hypertrophy: Role of COX-2 induction.

    PubMed

    Chien, Peter Tzu-Yu; Lin, Chih-Chung; Hsiao, Li-Der; Yang, Chuen-Mao

    2015-07-01

    Thrombin and COX-2 regulating cardiac hypertrophy are via various signaling cascades. Several transcriptional factors including CREB involve in COX-2 expression. However, the interplay among thrombin, CREB, and COX-2 in primary human neonatal ventricular cardiomyocytes remains unclear. In this study, thrombin-induced COX-2 promoter activity, mRNA and protein expression, and PGE2 synthesis were attenuated by pretreatment with the inhibitors of c-Src (PP1), Pyk2 (PF431396), EGFR (AG1478), PI3K/Akt (LY294002/SH-5), and p300 (GR343), or transfection with siRNAs of c-Src, Pyk2, EGFR, p110, Akt, CREB, and p300. Moreover, thrombin-stimulated phosphorylation of c-Src, Pyk2, EGFR, Akt, CREB and p300 was attenuated by their respective inhibitors. These results indicate that thrombin-induced COX-2 expression is mediated through PAR-1/c-Src/Pyk2/EGFR/PI3K/Akt linking to CREB and p300 cascades. Functionally, thrombin-induced hypertrophy and ANF/BNP release were, at least in part, mediated through a PAR-1/COX-2-dependent pathway. We uncover the importance of COX-2 regarding human cardiomyocyte hypertrophy that will provide a therapeutic intervention in cardiovascular diseases. PMID:25869400

  17. Cyclooxygenase2 Inhibitor Nimesulide Suppresses Telomerase Activity by Blocking Akt\\/PKB Activation in Gastric Cancer Cell Line

    Microsoft Academic Search

    Yu Baoping; Hu Guoyong; Yu Jieping; Ran Zongxue; Luo Hesheng

    2004-01-01

    Nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to have antiproliferative effectsin neoplastic cells of different origin during the past few decades. We aimed to study the effects of theselective COX-2 inhibitor, nimesulide, on cell viability and telomerase and Akt\\/PKB activity in thehuman gastric cancer cell line MKN-45 and to explore the molecular mechanism for the antitumoractivity of the selective COX-2

  18. Direct Sequencing of Cyclooxygenase-2 (COX-2) Revealed an Intronic Variant rs201231411 in Iranian Patients with Pancreatic Cancer

    PubMed Central

    Mohamadkhani, Ashraf; Akbari, Mohammad Reza; Ghanbari, Reza; Naderi, Elnaz; Rezanejad-Asl, Parisa; Pourshams, Akram

    2015-01-01

    BACKGROUND There are hoarding documents for the biological importance of cyclooxygenase-2 (COX-2) in pancreatic carcinogenesis. We aimed to thoroughly investigate the DNA sequence variations of whole COX-2 exons in a large case-control study of pancreatic cancer by direct sequencing. METHODS The entire exonic regions of COX-2 including 10 exons were sequenced in the germline DNA of 96 patients with pancreatic cancer. Selected variants within exons six to seven (E6E7) amplicon from the test panel were genotyped in 96 controls. RESULTS The COX-2 gene was demonstrated to be genetically conserved. Four missense mutations were found in three cases. However the common variant c.724-10_724-7delATTT (rs201231411) that is located in intron 6, showed significant difference between cases and controls (21 [21.9%] vs 11 [%11.5], p=0.05). CONCLUSION This study determined that COX-2 has a conservative sequence, which is required for its enzymatic activity and supports the important role of this enzyme’s expression in pancreatic cancer rather than any changes in its activity. The effect of intronic variant rs201231411 on COX-2 expression could be analyzed in future studies. PMID:25628848

  19. Cyclooxygenase-2 inhibitors and coronary occlusion – exploring dose–response relationships

    PubMed Central

    McGettigan, Patricia; Han, Pearline; Henry, David

    2006-01-01

    Aims To investigate the relationship between acute coronary syndrome (ACS) and ingested doses of selective cyclooxygenase-2 (COX-2) inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs). Methods Case–control study, commenced August 2003. Cases were patients admitted to hospital with ACS (myocardial infarction/unstable angina). Controls were hospital patients admitted for reasons other than acute vascular ischaemia or conditions that are believed to be complications of treatment with COX-2 inhibitors or NSAIDs. Structured interviews were undertaken within 7 days of admission, collecting information on cardiovascular events and risk factors and all ingested drugs, including the doses of COX-2 inhibitors and NSAID consumed in the previous week and month. Results An interim analysis of the data was conducted in late 2004 to inform a review of the COX-2 inhibitors by the Australian drug regulatory agency. Between August 2003 and October 2004, we recruited 328 ACS cases and 478 controls. With non-use of COX-2 inhibitors or NSAIDs as the reference the adjusted odds ratios (OR) for ACS were: celecoxib 1.11 (95% confidence interval 0.59, 2.11), rofecoxib 0.63 (0.31, 1.28) and other NSAIDs 0.67 (0.41, 1.09). Among control subjects, median daily ingested doses of celecoxib and rofecoxib were 200 mg and 13.4 mg, respectively. Using these to stratify risk, adjusted ORs for ACS were: ‘low’ dose (< median) 0.44 (0.19, 1.03); ‘high’ dose (? median) 1.22 (0.67, 2.21). A test for interaction across doses was statistically significant, OR 2.8 (1.0, 7.7), suggesting that at low doses, COX-2 inhibitors may be protective, becoming risk-inducing only at higher doses. Conclusion The possibility that the gradient of cardiovascular risk with COX-2 inhibitors runs from protective to risk-inducing has biological plausibility and merits further investigation. PMID:16934052

  20. Peptidomimetics as potent and selective PTP1B inhibitors.

    PubMed

    Patel, Dipam; Jain, Mukul; Shah, Shailesh R; Bahekar, Rajesh; Jadav, Pradip; Shah, Kiran; Joharapurkar, Amit; Shaikh, Mubeen; Sairam, Kalapatapu V V M

    2013-08-01

    A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors. PMID:23030658

  1. Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by chrysin derivatives.

    PubMed

    Cho, Heeyeong; Yun, Cheol-Won; Park, Woo-Kyu; Kong, Jae-Yang; Kim, Kyoung Soon; Park, Youmie; Lee, Sanghyun; Kim, Bak-Kwang

    2004-01-01

    Chrysin, a natural flavone compound found in plants, has anti-inflammatory activity that has been previously explained in part by the suppression of promoter activities of pro-inflammatory enzymes, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Here we present evidence that several chrysin derivatives modulate the activities, as well as the expression, of COX-2 and iNOS enzymes. Nitrate production triggered by lipopolysaccharide (LPS) was suppressed by treatment of cultured Raw264.7 cells (mice macrophage/monocyte) with chrysin, 5-hydroxy-7-methoxyflavone (Ch-2), and 5,7-diacetylflavone (Ch-4). Interestingly, COX-2 enzyme was strongly inhibited by Ch-4 (IC(50)=2.7 microM) but not by other derivatives. Furthermore, the inhibition of COX enzyme by Ch-4 was selective for COX-2 over COX-1. Three-dimensional modeling showed that Ch-4 fits well into the binding pocket of COX-2. The modeling suggested that a hydrogen bond exists between the oxygen of the ketone group at the 7-position of Ch-4 and the hydroxyl group of Tyr355. Docking Ch-4 into the V523I mutant of COX-2 indicated that Ile523 of COX-1 might contribute to the selectivity of COX-2 over COX-1. Ch-4 showed no effect on iNOS activity. Chrysin and Ch-2 weakly inhibited iNOS enzyme activity in the hemoglobin assay, but the underlying mechanisms of inhibition of iNOS by chrysin are not understood. PMID:14597150

  2. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

    PubMed

    Muñoz, Mercedes; Sánchez, Ana; Pilar Martínez, María; Benedito, Sara; López-Oliva, Maria-Elvira; García-Sacristán, Albino; Hernández, Medardo; Prieto, Dolores

    2015-07-01

    Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. PMID:25841778

  3. Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: towards better tolerability?

    Microsoft Academic Search

    K. Brune; D. E. Furst

    2007-01-01

    Inhibitors of cyclooxygenases (COXs) are the most widely used drugs. They reduce discomfort and fever, inhibit peri-operative and inflammatory pain. These effects are largely mediated by inhibition of cyclooxygenase-1 and -2 (COX-1 and COX-2)-enzymes found throughout the body producing prostaglandins, which are important mediators of pain and fever, but also adaptive and protective reactions in many organs. A first step

  4. Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis.

    PubMed

    Takeda, Shuso; Misawa, Koichiro; Yamamoto, Ikuo; Watanabe, Kazuhito

    2008-09-01

    In the present study it was revealed that cannabidiolic acid (CBDA) selectively inhibited cyclooxygenase (COX)-2 activity with an IC(50) value (50% inhibition concentration) around 2 microM, having 9-fold higher selectivity than COX-1 inhibition. In contrast, Delta(9)-tetrahydrocannabinolic acid (Delta(9)-THCA) was a much less potent inhibitor of COX-2 (IC(50) > 100 microM). Nonsteroidal anti-inflammatory drugs containing a carboxyl group in their chemical structures such as salicylic acid are known to inhibit nonselectively both COX-1 and COX-2. CBDA and Delta(9)-THCA have a salicylic acid moiety in their structures. Thus, the structural requirements for the CBDA-mediated COX-2 inhibition were next studied. There is a structural difference between CBDA and Delta(9)-THCA; phenolic hydroxyl groups of CBDA are freed from the ring formation with the terpene moiety, although Delta(9)-THCA has dibenzopyran ring structure. It was assumed that the whole structure of CBDA is important for COX-2 selective inhibition because beta-resorcylic acid itself did not inhibit COX-2 activity. Methylation of the carboxylic acid moiety of CBDA led to disappearance of COX-2 selectivity. Thus, it was suggested that the carboxylic acid moiety in CBDA is a key determinant for the inhibition. Furthermore, the crude extract of cannabis containing mainly CBDA was shown to have a selective inhibitory effect on COX-2. Taken together, these lines of evidence in this study suggest that naturally occurring CBDA in cannabis is a selective inhibitor for COX-2. PMID:18556441

  5. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.

    PubMed Central

    Masferrer, J L; Zweifel, B S; Manning, P T; Hauser, S D; Leahy, K M; Smith, W G; Isakson, P C; Seibert, K

    1994-01-01

    We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-directed antiinflammatory drugs. Images PMID:8159730

  6. Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing.

    PubMed

    Colucci, Rocchina; Antonioli, Luca; Bernardini, Nunzia; Ippolito, Chiara; Segnani, Cristina; Awwad, Oriana; Tuccori, Marco; Blandizzi, Corrado; Scarpignato, Carmelo; Fornai, Matteo

    2012-07-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAID-activated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E(2) (PGE(2)) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE(2) levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing. PMID:22495067

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

    PubMed Central

    Herschman, Harvey

    2014-01-01

    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

  8. The pharmacogenetics of the selective serotonin reuptake inhibitors

    Microsoft Academic Search

    K. Brøsen

    1993-01-01

    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

  9. Synthesis and evaluation of carbaborane derivatives of indomethacin as cyclooxygenase inhibitors.

    PubMed

    Scholz, Matthias; Blobaum, Anna L; Marnett, Lawrence J; Hey-Hawkins, Evamarie

    2011-05-15

    Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their pharmacological activities by inhibiting cyclooxygenase (COX)-1 and COX-2. Previous studies have shown that esters and amides of non-selective inhibitors such as indomethacin are selective against COX-2, which is the therapeutically relevant isoform. Structure-activity analysis indicates that substituted phenyl rings are tolerated as ester components. In the present study, the introduction of inorganic ortho- and meta-carbaborane moieties was explored with the aim to create COX-2 inhibitors and more importantly to investigate the validity of using these boron clusters as drug entities. Interestingly, only the ortho-carbaborane ester was active whereas the meta isomer was not. A similar lack of inhibitory potency was observed when an adamantyl substituent or alkylene spacers at the carbaborane were introduced in the ester functionality. PMID:21524587

  10. (MIS)COMMUNICATING COX2 CLINICAL TRIAL RISKS

    Microsoft Academic Search

    Mark Hochhauser; Norman M. Goldfarb

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

  11. Cyclooxygenase2 (COX2) in Inflammatory and Degenerative Brain Diseases

    Microsoft Academic Search

    LUISA MINGHETTI

    2004-01-01

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

  12. Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids

    Microsoft Academic Search

    Julian Adams; Mark Behnke; Shaowu Chen; Amy A. Cruickshank; Lawrence R. Dick; Louis Grenier; Janice M. Klunder; Yu-Ting Ma; Louis Plamondon; Ross L. Stein

    1998-01-01

    Potent and selective dipeptidyl boronic acid proteasome inhibitors are described. As compared to peptidyl aldehyde compounds, boronic acids in this series display dramatically enhanced potency. Compounds such as 15 are promising new therapeutics for treatment of cancer and inflammatory diseases.

  13. Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression.

    PubMed

    Kang, Nam Joo; Lee, Ki Won; Shin, Bong Jik; Jung, Sung Keun; Hwang, Mun Kyung; Bode, Ann M; Heo, Yong-Seok; Lee, Hyong Joo; Dong, Zigang

    2009-02-01

    Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in many foods, including coffee. Recent studies suggested that caffeic acid exerts anticarcinogenic effects, but little is known about the underlying molecular mechanisms and specific target proteins. In this study, we found that Fyn, one of the members of the non-receptor protein tyrosine kinase family, was required for ultraviolet (UV) B-induced cyclooxygenase-2 (COX-2) expression, and caffeic acid suppressed UVB-induced skin carcinogenesis by directly inhibiting Fyn kinase activity. Caffeic acid more effectively suppressed UVB-induced COX-2 expression and subsequent prostaglandin E(2) production in JB6 P+ mouse skin epidermal (JB6 P+) cells compared with chlorogenic acid (5-O-caffeoylquinic acid), an ester of caffeic acid with quinic acid. Data also revealed that caffeic acid more effectively induced the downregulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein-1 (AP-1) and nuclear factor-kappaB transcription activity compared with chlorogenic acid. Fyn kinase activity was suppressed more effectively by caffeic acid than by chlorogenic acid, and downstream mitogen-activated protein kinases (MAPKs) were subsequently blocked. Pharmacological Fyn kinase inhibitor (3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and leflunomide) data also revealed that Fyn is involved in UVB-induced COX-2 expression mediated through the phosphorylation of MAPKs in JB6 P+ cells. Pull-down assays revealed that caffeic acid directly bound with Fyn and non-competitively with adenosine triphosphate. In vivo data from mouse skin also supported the idea that caffeic acid suppressed UVB-induced COX-2 expression by blocking Fyn kinase activity. These results suggested that this compound could act as a potent chemopreventive agent against skin cancer. PMID:19073879

  14. Melatonin-mediated Bim up-regulation and cyclooxygenase-2 (COX-2) down-regulation enhances tunicamycin-induced apoptosis in MDA-MB-231 cells.

    PubMed

    Woo, Seon Min; Min, Kyoung-jin; Kwon, Taeg Kyu

    2015-04-01

    Melatonin is involved in many physiological functions, and it has differential effects on apoptosis in normal and cancer cells. However, the mechanism of its antitumor roles is not well understood. In this study, we show that melatonin enhances tunicamycin-induced apoptosis in human breast carcinoma MDA-MB-231 cells. Melatonin up-regulates pro-apoptotic protein Bim expression at the transcriptional levels in the presence of tunicamycin. Melatonin inhibits tunicamycin-induced COX-2 expression in MDA-MB-231 cells. Furthermore, inhibition of COX-2 activity using the COX-2 inhibitor, NS398, increases tunicamycin-induced apoptosis. Interestingly, these effects were not associated with melatonin receptor signal pathways. Pertussis toxin (a general Gi protein inhibitor) or luzindole (a nonspecific melatonin receptor antagonist) did not reverse the effect of melatonin. In addition, melatonin blocked tunicamycin-induced NF-?B transcriptional activity, p65 nuclear translocation, and p38 MAPK activation. Melatonin-mediated p38 MAPK inhibition contributed to decreased COX-2 mRNA stability. Taken together, our results suggest that melatonin enhances antitumor function through up-regulation of Bim expression and down-regulation of COX-2 expression in tunicamycin-treated MDA-MB-231 cells. PMID:25711465

  15. Screening of selective histone deacetylase inhibitors by proteochemometric modeling

    PubMed Central

    2012-01-01

    Background Histone deacetylase (HDAC) is a novel target for the treatment of cancer and it can be classified into three classes, i.e., classes I, II, and IV. The inhibitors selectively targeting individual HDAC have been proved to be the better candidate antitumor drugs. To screen selective HDAC inhibitors, several proteochemometric (PCM) models based on different combinations of three kinds of protein descriptors, two kinds of ligand descriptors and multiplication cross-terms were constructed in our study. Results The results show that structure similarity descriptors are better than sequence similarity descriptors and geometry descriptors in the leftacterization of HDACs. Furthermore, the predictive ability was not improved by introducing the cross-terms in our models. Finally, a best PCM model based on protein structure similarity descriptors and 32-dimensional general descriptors was derived (R2 = 0.9897, Qtest2 = 0.7542), which shows a powerful ability to screen selective HDAC inhibitors. Conclusions Our best model not only predict the activities of inhibitors for each HDAC isoform, but also screen and distinguish class-selective inhibitors and even more isoform-selective inhibitors, thus it provides a potential way to discover or design novel candidate antitumor drugs with reduced side effect. PMID:22913517

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

    PubMed

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

    2014-10-01

    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 (1 mg/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

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

    PubMed Central

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

    2013-01-01

    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

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

    PubMed

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

    2013-01-01

    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

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

    PubMed Central

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

    2010-01-01

    Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E2 (PGE2), an autocrine inhibitor of fibrogenesis. Exogenous PGE2 or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE2, in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis. PMID:20733059

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

    Microsoft Academic Search

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

    2010-01-01

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

  1. Triazaspirodimethoxybenzoyls as Selective Inhibitors of Mycobacterial Lipoamide Dehydrogenase

    SciTech Connect

    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

    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.

  2. Design and Synthesis of Potent, Selective Inhibitors of Matriptase

    PubMed Central

    2012-01-01

    Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1–P4 substrate recognition sequence of the enzyme. Preliminary structure–activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase. PMID:24900505

  3. Selective electrochemical reactions of an alumina hydrate crystallization inhibitor

    Microsoft Academic Search

    Nicolas-Alexandre Bouchard; Anne Brisach-Wittmeyer; Raymond Breault; Hugues Ménard

    2007-01-01

    Selective reactions of catechol have been studied in regard to its inhibition properties towards alumina hydrate crystallization.\\u000a Electrochemical reactions of the inhibitor leading to products without inhibition behaviour have been obtained using different\\u000a conditions. First, a pure sodium hydroxide solution (1.0 M NaOH) was used to electrochemically react the catechol. The inhibitor\\u000a reactions were then carried out in both saturated and

  4. Discovery of a Potent And Selective Aurora Kinase Inhibitor

    SciTech Connect

    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

    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.

  5. Novel bicyclic lactam inhibitors of thrombin: highly potent and selective inhibitors.

    PubMed

    St-Denis, Yves; Lévesque, Sophie; Bachand, Benoit; Edmunds, Jeremy J; Leblond, Lorraine; Préville, Patrice; Tarazi, Micheline; Winocour, Peter D; Siddiqui, M Arshad

    2002-04-22

    The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained. PMID:11934583

  6. SAR156497, an exquisitely selective inhibitor of aurora kinases.

    PubMed

    Carry, Jean-Christophe; Clerc, François; Minoux, Hervé; Schio, Laurent; Mauger, Jacques; Nair, Anil; Parmantier, Eric; Le Moigne, Ronan; Delorme, Cécile; Nicolas, Jean-Paul; Krick, Alain; Abécassis, Pierre-Yves; Crocq-Stuerga, Véronique; Pouzieux, Stéphanie; Delarbre, Laure; Maignan, Sébastien; Bertrand, Thomas; Bjergarde, Kirsten; Ma, Nina; Lachaud, Sylvette; Guizani, Houlfa; Lebel, Rémi; Doerflinger, Gilles; Monget, Sylvie; Perron, Sébastien; Gasse, Francis; Angouillant-Boniface, Odile; Filoche-Rommé, Bruno; Murer, Michel; Gontier, Sylvie; Prévost, Céline; Monteiro, Marie-Line; Combeau, Cécile

    2015-01-01

    The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity. PMID:25369539

  7. The Bitter Barricading of Prostaglandin Biosynthesis Pathway: Understanding the Molecular Mechanism of Selective Cyclooxygenase-2 Inhibition by Amarogentin, a Secoiridoid Glycoside from Swertia chirayita

    PubMed Central

    Sundar, Durai; Thorat, Sunil S.

    2014-01-01

    Swertia chirayita, a medicinal herb inhabiting the challenging terrains and high altitudes of the Himalayas, is a rich source of essential phytochemical isolates. Amarogentin, a bitter secoiridoid glycoside from S. chirayita, shows varied activity in several patho-physiological conditions, predominantly in leishmaniasis and carcinogenesis. Experimental analysis has revealed that amarogentin downregulates the cyclooxygenase-2 (COX-2) activity and helps to curtail skin carcinogenesis in mouse models; however, there exists no account on selective inhibition of the inducible cyclooxygenase (COX) isoform by amarogentin. Hence the computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of amarogentin and to check its selectivity for the inducible isoform over the constitutive one. The generated theoretical models of both isoforms were subjected to molecular docking analysis with amarogentin and twenty-one other Food and Drug Authority (FDA) approved lead molecules. The post-docking binding energy profile of amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors. Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with amarogentin-COX-2 complex being more stable after 40ns simulation. The total binding free energy calculated by MMGBSA for the amarogentin-COX-2 complex was ?52.35 KCal/mol against a binding free energy of ?8.57 KCal/mol for amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor. Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms. Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step. To sum up briefly, this work highlights the mechanism of the possible selective COX-2 inhibition by amarogentin and endorses the possibility of obtaining efficient, futuristic and targeted therapeutic agents for relieving inflammation and malignancy from this phytochemical source. PMID:24603686

  8. Uncovering Molecular Bases Underlying Bone Morphogenetic Protein Receptor Inhibitor Selectivity

    PubMed Central

    Alsamarah, Abdelaziz; LaCuran, Alecander E.; Oelschlaeger, Peter; Hao, Jijun; Luo, Yun

    2015-01-01

    Abnormal alteration of bone morphogenetic protein (BMP) signaling is implicated in many types of diseases including cancer and heterotopic ossifications. Hence, small molecules targeting BMP type I receptors (BMPRI) to interrupt BMP signaling are believed to be an effective approach to treat these diseases. However, lack of understanding of the molecular determinants responsible for the binding selectivity of current BMP inhibitors has been a big hindrance to the development of BMP inhibitors for clinical use. To address this issue, we carried out in silico experiments to test whether computational methods can reproduce and explain the high selectivity of a small molecule BMP inhibitor DMH1 on BMPRI kinase ALK2 vs. the closely related TGF-? type I receptor kinase ALK5 and vascular endothelial growth factor receptor type 2 (VEGFR2) tyrosine kinase. We found that, while the rigid docking method used here gave nearly identical binding affinity scores among the three kinases; free energy perturbation coupled with Hamiltonian replica-exchange molecular dynamics (FEP/H-REMD) simulations reproduced the absolute binding free energies in excellent agreement with experimental data. Furthermore, the binding poses identified by FEP/H-REMD led to a quantitative analysis of physical/chemical determinants governing DMH1 selectivity. The current work illustrates that small changes in the binding site residue type (e.g. pre-hinge region in ALK2 vs. ALK5) or side chain orientation (e.g. Tyr219 in caALK2 vs. wtALK2), as well as a subtle structural modification on the ligand (e.g. DMH1 vs. LDN193189) will cause distinct binding profiles and selectivity among BMP inhibitors. Therefore, the current computational approach represents a new way of investigating BMP inhibitors. Our results provide critical information for designing exclusively selective BMP inhibitors for the development of effective pharmacotherapy for diseases caused by aberrant BMP signaling. PMID:26133550

  9. Interleukin-17 Indirectly Promotes M2 Macrophage Differentiation through Stimulation of COX-2/PGE2 Pathway in the Cancer Cells

    PubMed Central

    Li, Qingli; Liu, Lunxu; Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; You, Zongbing

    2014-01-01

    Purpose Interleukin-17 (IL-17) is a proinflammatory cytokine that plays important roles in inflammation, autoimmunity, and cancer. The purpose of this study was to determine if IL-17 indirectly regulates macrophage differentiation through up-regulation of cyclooxygenase-2 (COX-2) expression in the cancer cell lines. Materials and Methods Human cervical cancer HeLa, human lung cancer A549, and mouse prostate cancer Myc-CaP/CR cell lines were treated with recombinant IL-17; Western blot analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction analysis were utilized to examine the cellular responses. Results IL-17 up-regulated expression of COX-2 mRNA and protein in HeLa, A549, and Myc- CaP/CR cell lines. IL-17’s effects were mediated through nuclear factor-?B and ERK1/2 signaling pathways as the inhibitors of these pathways could inhibit IL-17- induced COX-2 expression. The conditional medium obtained from the cancer cells contained prostaglandin E2, the levels of which were increased by IL-17 treatment. When treated with the conditional medium, particularly with the IL-17-induced conditional medium, mouse RAW264.7 macrophages and human THP-1 monocytes expressed higher levels of IL-10 (a marker of M2 macrophages) than inducible nitric oxide synthase or tumor necrosis factor ? (markers of M1 macrophages). In contrast, when RAW264.7 and THP-1 cells were treated directly with IL-17, expression of these marker genes was not markedly changed. Conclusion The results of this study suggest that IL-17 indirectly promotes M2 macrophage differentiation through stimulation of the COX-2/PGE2 pathway in the cancer cells, thus IL-17 plays an indirect role in regulating the tumor immune microenvironment. PMID:25038765

  10. Structural determinants of PERK inhibitor potency and selectivity.

    PubMed

    Wang, Hong; Blais, Jaime; Ron, David; Cardozo, Timothy

    2010-12-01

    The unfolded protein response (UPR) is a coordinated program that promotes cell survival under conditions of endoplasmic reticulum stress and is required in tumor progression as well. To date, no specific small molecule inhibitor targeting this pathway has been identified. Pancreatic endoplasmic reticulum kinase (PERK), one of the UPR transducers, is an eIF2? kinase. Compromising PERK function inhibits tumor growth in mice, suggesting that PERK may be a cancer drug target, but identifying a specific inhibitor of any kinase is challenging. The goal of this study was to identify some pair-wise receptor-ligand atomic contacts that confer selective PERK inhibition. Compounds selectively inhibiting PERK-mediated phosphorylation in vitro were identified using an initial virtual library screen, followed by structure-activity hypothesis testing. The most potent PERK selective inhibitors utilize three specific kinase active site contacts that, when absent from chemically similar compounds, abrogates the inhibition: (i) a strong van der Waals contact with PERK residue Met7, (ii) interactions with the N-terminal portion of the activation loop, and (iii) groups providing electrostatic complementarity to Asp144. Interestingly, the activation loop contact is required for PERK selectivity to emerge. Understanding these structure-activity relationships may accelerate rational PERK inhibitor design. PMID:21070610

  11. Discovery and profiling of a selective and efficacious Syk inhibitor.

    PubMed

    Thoma, Gebhard; Smith, Alexander B; van Eis, Maurice J; Vangrevelinghe, Eric; Blanz, Joachim; Aichholz, Reiner; Littlewood-Evans, Amanda; Lee, Christian C; Liu, Hong; Zerwes, Hans-Günter

    2015-02-26

    We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo. PMID:25633741

  12. COX2 Expression Does Not Correlate with Microvessel Density in Breast Cancer

    Microsoft Academic Search

    Mangesh A. Thorat; Sanjana Mehrotra; Akira Morimiya; Sunil Badve

    2009-01-01

    Background:Cyclooxygenase-2 (COX-2), implicated in carcinogenesis and tumour progression in many cancers including breast cancer, is hypothesised to cause progression by promoting angiogenesis. The exact mechanism of such action is not known and the clinical evidence of such interaction is weak. We studied COX-2 expression and microvessel density (MVD) in malignant breast tissues. Methods:COX-2 expression was analysed by immunohistochemistry in 89

  13. Systematic review and meta-analysis of COX-2 expression and polymorphisms in prostate cancer.

    PubMed

    Shao, Ning; Feng, Ninghan; Wang, Yang; Mi, Yuanyuan; Li, Tian; Hua, LiXin

    2012-12-01

    Evidence is accumulating that cyclooxygenase-2 (COX-2) may play an important role in prostate cancer (PCa). Recently, gene polymorphisms in COX-2 have been implicated to alter the risk of PCa and overexpression of COX-2 may be associated with clinical and prognostic significance in PCa. However, the results of these studies are inconclusive or controversial. To derive a more precise estimation of the relationships, we performed an updated meta-analysis. A comprehensive search was conducted to examine all the eligible studies of COX-2 polymorphism and expression in PCa. We used odds ratios (ORs) to assess the strength of the association and the 95 % confidence intervals (CIs) give a sense of the precision of the estimate. Overall, no significant associations between COX-2 polymorphism and PCa risk were found. However, high expression of COX-2 was significantly higher in T3-T4 stages of PCa than in T1-T2 stages of PCa (OR = 2.33, 95 %CI: 1.54-3.53, P < 0.0001). COX-2 might play an important role in the progress of PCa, overexpression of COX-2 correlates with T3-T4 stages of PCa. COX-2 might be a potential therapy target for PCa and work as a prognostic factor for PCa patients. PMID:23053989

  14. Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy

    SciTech Connect

    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

    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.

  15. Chapter 2: Mechanistic Aspects of COX-2 Expression in Colorectal Neoplasia

    PubMed Central

    Dixon, Dan A.; Blanco, Fernando F.; Bruno, Annalisa; Patrignani, Paola

    2012-01-01

    The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states and a large amount of evidence has demonstrated constitutive COX-2 expression to be a contributing factor promoting colorectal cancer (CRC). Various genetic, epigenetic, and inflammatory pathways have been identified to be involved in the etiology and development of CRC. Alteration in these pathways can influence COX-2 expression at multiple stages of colon carcinogenesis allowing for elevated prostanoid biosynthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the post-transcriptional level through various RNA sequence elements present within the mRNA 3?-untranslated region(3?UTR). A conserved AU-rich element(ARE) functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. Specific microRNAs bind regions within the COX-2 3?UTR and control COX-2 expression. In this chapter, we discuss novel insights in the mechanisms of altered posttranscriptional regulation of COX-2 in CRC and how this knowledge may be used to develop novel strategies for cancer prevention and treatment. PMID:22893198

  16. Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway.

    PubMed

    Giurdanella, Giovanni; Anfuso, Carmelina Daniela; Olivieri, Melania; Lupo, Gabriella; Caporarello, Nunzia; Eandi, Chiara M; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

    2015-08-01

    Diabetic retinopathy, a major cause of vision loss, is currently treated with anti-VEGF agents. Here we tested two hypotheses: (i) high glucose damages retinal pericytes, the cell layer surrounding endothelial cells, via VEGF induction, which may be counteracted by anti-VEGFs and (ii) activation of PLA2/COX-2 pathway by high glucose might be upstream and/or downstream of VEGF in perycites, as previously observed in endothelial cells. Human retinal pericytes were treated with high glucose (25mM) for 48h and/or anti-VEGFs (40?g/ml aflibercept, 25?g/ml bevacizumab, 10?g/ml ranibizumab). All anti-VEGFs significantly prevented high glucose-induced cell damage (assessed by LDH release) and improved cell viability (assessed by MTT and Evans blue). High glucose-induced VEGF-A expression, as detected both at mRNA (qPCR) and protein (ELISA) level, while receptor (VEGFR1 and VEGFR2) expression, detected in control condition, was unaffected by treatments. High glucose induced also activation of PLA2/COX-2 pathway, as revealed by increased phosphorylation of cPLA2, COX-2 expression and PGE2 release. Treatment with cPLA2 (50?M AACOCF3) and COX-2 (5?M NS-392) inhibitors prevented both cell damage and VEGF-A induced by high glucose. Finally, challenge with exogenous VEGF-A (10ng/ml) induced VEGF-A expression, while anti-VEGFs reduced VEGF-A expression induced by either high glucose or exogenous VEGF-A. These data indicate that high glucose directly damages pericytes through activation of PLA2/COX-2/VEGF-A pathway. Furthermore, a kind of feed-forward loop between cPLA2/COX-2/PG axis and VEGF appears to operate in this system. Thus, anti-VEGFs afford protection of pericytes from high glucose by inhibiting this loop. PMID:26056075

  17. In Vitro Selection of Highly Modified Cyclic Peptides That Act as Tight Binding Inhibitors

    E-print Network

    Heller, Eric

    In Vitro Selection of Highly Modified Cyclic Peptides That Act as Tight Binding Inhibitors Yollete for the observed high-affinity binding. We demonstrate that the selected peptides are tight-binding inhibitors

  18. Discovery of Selective Menaquinone Biosynthesis Inhibitors against Mycobacterium tuberculosis

    PubMed Central

    Debnath, Joy; Siricilla, Shajila; Wan, Bajoie; Crick, Dean C.; Lenaerts, Anne J.; Franzblau, Scott G.; Kurosu, Michio

    2012-01-01

    Aurachin RE (1) is a strong antibiotic that was recently found to possess MenA (1,4-dihydroxy-2-naphthoate prenyltransferase) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9?-position. To identify selective MenA inhibitors against Mycobacterium tuberculosis, a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing non-replicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against non-replicating M. tuberculosis. PMID:22449052

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

    PubMed Central

    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

    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

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

    PubMed

    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

    2013-09-13

    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

  1. Discovery of novel and selective SIRT6 inhibitors.

    PubMed

    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

    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

  2. Novel selective inhibitors of aminopeptidases that generate antigenic Athanasios Papakyriakou a,b

    E-print Network

    Theodorakis, Emmanuel

    Novel selective inhibitors of aminopeptidases that generate antigenic peptides Athanasios reticulum aminopeptidase ERAP1 ERAP2 IRAP Selective inhibitor Rational design Molecular modeling a b s t r and substrate- selectivity data for these enzymes, we have rationally designed a new series of inhibitors

  3. Triazaspirodimethoxybenzoyls as Selective Inhibitors of Mycobacterial Lipoamide Dehydrogenase

    Microsoft Academic Search

    Ruslana Bryk; Nancy Arango; Aditya Venugopal; J. David Warren; Yun-Hee Park; Mulchand S. Patel; Christopher D. Lima; Carl Nathan

    2010-01-01

    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

  4. [The safety of selective serotonin reuptake inhibitors: hemostasis].

    PubMed

    Balashov, A M

    2011-01-01

    The literature data of the reaction of haemostatic system to antidepressants from the group of selective inhibitors of serotonin reuptake are summarized. The development of haemorrhagic complications is analyzed. The risk/benefit ratio is estimated for the treatment of depression in patients with acute myocardial infarction and stroke. A differential approach to indication of antidepressants is substantiated for the treatment of comorbid depressive disorders in different types of somatic pathology. PMID:21542373

  5. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial

    Microsoft Academic Search

    Jerrold F Rosenbaum; Maurizio Fava; Sharon L Hoog; Richard C Ascroft; William B Krebs

    1998-01-01

    Background: Recent reports describe discontinuation-emergent adverse events upon cessation of selective serotonin reuptake inhibitors including dizziness, insomnia, nervousness, nausea, and agitation. We hypothesized that interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment, based on fluoxetine’s longer half-life.Methods: In this 4-week study, 242 patients with remitted depression receiving maintenance therapy

  6. Effects of selective cyclooxygenase-2 and non-selective COX inhibition on myocardial function and perfusion

    PubMed Central

    Robich, Michael P.; Chu, Louis M.; Burgess, Thomas A.; Feng, Jun; Bianchi, Cesario; Sellke, Frank W.

    2011-01-01

    Non-selective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into three groups: no drug (control, n=7), a non-selective COX inhibitor (naproxen 400mg daily, NAP, n=7), or a selective COX-2 inhibitor (celecoxib 200mg daily, CBX, n=7). After 7 weeks physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased VEGF and phospho-eNOS expression in the NAP and CBX groups. Myocardial TNF? was increased in both the NAP and CBX groups. Immunostaining for thromboxane A2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Non-selective and selective COX inhibition does not alter myocardial perfusion, but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk. PMID:21233641

  7. KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms.

    PubMed

    Chiu, Yi-Yuan; Lin, Chih-Ta; Huang, Jhang-Wei; Hsu, Kai-Cheng; Tseng, Jen-Hu; You, Syuan-Ren; Yang, Jinn-Moon

    2013-01-01

    Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms. PMID:23193279

  8. Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells

    PubMed Central

    Onodera, Yuta; Teramura, Takeshi; Takehara, Toshiyuki; Shigi, Kanae; Fukuda, Kanji

    2015-01-01

    Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-?B through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases. PMID:26110105

  9. Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells.

    PubMed

    Onodera, Yuta; Teramura, Takeshi; Takehara, Toshiyuki; Shigi, Kanae; Fukuda, Kanji

    2015-01-01

    Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-?B through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases. PMID:26110105

  10. Action at a Distance: MUTATIONS OF PERIPHERAL RESIDUES TRANSFORM RAPID REVERSIBLE INHIBITORS TO SLOW, TIGHT BINDERS OF CYCLOOXYGENASE-2.

    PubMed

    Blobaum, Anna L; Xu, Shu; Rowlinson, Scott W; Duggan, Kelsey C; Banerjee, Surajit; Kudalkar, Shalley N; Birmingham, William R; Ghebreselasie, Kebreab; Marnett, Lawrence J

    2015-05-15

    Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity of rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, and lumiracoxib) demonstrated a significant increase in potency and time dependence of inhibition against double tryptophan murine COX-2 mutants at the 89/90 and 89/119 positions. In contrast, the slow, time-dependent COX inhibitors (diclofenac, indomethacin, and flurbiprofen) were unaffected by those mutations. Further mutagenesis studies suggested that mutation at position 89 was principally responsible for the changes in inhibitory potency of rapid, reversible inhibitors, whereas mutation at position 90 may exert some effect on the potency of COX-2-selective diarylheterocycle inhibitors; no effect was observed with mutation at position 119. Several crystal structures with or without NSAIDs indicated that placement of a bulky residue at position 89 caused a closure of a gap at the lobby, and alteration of histidine to tryptophan at position 90 changed the electrostatic profile of the side pocket of COX-2. Thus, these two residues, especially Val-89 at the lobby region, are crucial for the entrance and exit of some NSAIDs from the COX active site. PMID:25825493

  11. Phloretin inhibits interleukin-1?-induced COX-2 and ICAM-1 expression through inhibition of MAPK, Akt, and NF-?B signaling in human lung epithelial cells.

    PubMed

    Huang, Wen-Chung; Wu, Shu-Ju; Tu, Rong-Syuan; Lai, You-Rong; Liou, Chian-Jiun

    2015-06-10

    Phloretin, a flavonoid isolated from the apple tree, is reported to have anti-inflammatory, anti-oxidant, and anti-adiposity effects. In this study, we evaluated the suppressive effects of phloretin on intercellular adhesion molecule 1 (ICAM-1) and cyclooxygenase (COX)-2 expression in IL-1?-stimulated human lung epithelial A549 cells. The cells were pretreated with various concentrations of phloretin (3-100 ?M), followed by induced inflammation by IL-1?. Phloretin inhibited levels of prostaglandin E2, decreased COX-2 expression, and suppressed IL-8, monocyte chemotactic protein 1, and IL-6 production. It also decreased ICAM-1 gene and protein expression and suppressed monocyte adhesion to inflammatory A549 cells. Phloretin also significantly inhibited Akt and mitogen-activated protein kinase (MAPK) phosphorylation and decreased nuclear transcription factor kappa-B (NF-?B) subunit p65 protein translocation into the nucleus. In addition, ICAM-1 and COX-2 expression was suppressed by pretreatment with both MAPK inhibitors and phloretin in inflammatory A549 cells. However, phlorizin, a derivative of phloretin, did not suppress the inflammatory response in IL-1?-stimulated A549 cells. These results suggest that phloretin might have an anti-inflammatory effect by inhibiting proinflammatory cytokine, COX-2, and ICAM-1 expression via blocked NF-?B and MAPK signaling pathways. PMID:25996641

  12. Study of feline oral squamous cell carcinoma: Potential target for cyclooxygenase inhibitor treatment

    Microsoft Academic Search

    Lisa DiBernardi; Monique Doré; John A. Davis; Jane G. Owens; Sulma I. Mohammed; Carolyn F. Guptill; Deborah W. Knapp

    2007-01-01

    Oral squamous cell carcinoma (OSCC) is associated with high morbidity and mortality. A potential target for OSCC treatment is cyclooxygenase-2 (cox-2). Pet cats with naturally occurring OSCC may offer the opportunity to study anticancer activity of cox inhibitors. Cox-2 expression in feline OSCC was determined by immunohistochemistry. High intensity cox-2 immunoreactivity was detected in 6 of 34 (18%) feline OSCC

  13. Regulation of COX-2 expression by miR-146a in lung cancer cells.

    PubMed

    Cornett, Ashley L; Lutz, Carol S

    2014-09-01

    Prostaglandins are a class of molecules that mediate cellular inflammatory responses and control cell growth. The oxidative conversion of arachidonic acid to prostaglandin H2 is carried out by two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed, while COX-2 can be transiently induced by external stimuli, such as pro-inflammatory cytokines. Interestingly, COX-2 is overexpressed in numerous cancers, including lung cancer. MicroRNAs (miRNAs) are small RNA molecules that function to regulate gene expression. Previous studies have implicated an important role for miRNAs in human cancer. We demonstrate here that miR-146a expression levels are significantly lower in lung cancer cells as compared with normal lung cells. Conversely, lung cancer cells have higher levels of COX-2 protein and mRNA expression. Introduction of miR-146a can specifically ablate COX-2 protein and the biological activity of COX-2 as measured by prostaglandin production. The regulation of COX-2 by miR-146a is mediated through a single miRNA-binding site present in the 3' UTR. Therefore, we propose that decreased miR-146a expression contributes to the up-regulation and overexpression of COX-2 in lung cancer cells. Since potential miRNA-mediated regulation is a functional consequence of alternative polyadenylation site choice, understanding the molecular mechanisms that regulate COX-2 mRNA alternative polyadenylation and miRNA targeting will give us key insights into how COX-2 expression is involved in the development of a metastatic condition. PMID:25047043

  14. Arachidonate 12-lipoxygenases with reference to their selective inhibitors

    SciTech Connect

    Yamamoto, Shozo [Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women's University, Imakumano, Higashiyama-ku, Kyoto 605-8501 (Japan)]. E-mail: yamamosh@kyoto-wu.ac.jp; Katsukawa, Michiko [Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women's University, Imakumano, Higashiyama-ku, Kyoto 605-8501 (Japan); Nakano, Ayumi [Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women's University, Imakumano, Higashiyama-ku, Kyoto 605-8501 (Japan); Hiraki, Emi [Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women's University, Imakumano, Higashiyama-ku, Kyoto 605-8501 (Japan); Nishimura, Kohji [Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504 (Japan); Jisaka, Mitsuo [Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504 (Japan); Yokota, Kazushige [Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane 690-8504 (Japan); Ueda, Natsuo [Department of Biochemistry, School of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan)

    2005-12-09

    Lipoxygenase is a dioxygenase recognizing a 1-cis,4-cis-pentadiene of polyunsaturated fatty acids. The enzyme oxygenates various carbon atoms of arachidonic acid as a substrate and produces 5-, 8-, 12- or 15-hydroperoxy eicosatetraenoic acid with a conjugated diene chromophore. The enzyme is referred to as 5-, 8-, 12- or 15-lipoxygenase, respectively. Earlier we found two isoforms of 12-lipoxygenase, leukocyte- and platelet-type enzymes, which were distinguished by substrate specificity, catalytic activity, primary structure, gene intron size, and antigenicity. Recently, the epidermis-type enzyme was found as the third isoform. Attempts have been made to find isozyme-specific inhibitors of 12-lipoxygenase, and earlier we found hinokitol, a tropolone, as a potent inhibitor selective for the platelet-type 12-lipoxygenase. More recently, we tested various catechins of tea leaves and found that (-)-geotechnical gallate was a potent and selective inhibitor of human platelet 12-lipoxygenase with an IC{sub 5} of 0.14 {mu}M. The compound was much less active with 12-lipoxygenase of leukocyte-type, 15-, 8-, and 5-lipoxygenases, and cyclo oxygenases-1 and -2.

  15. Identification of an Adamantyl Azaquinolone JNK Selective Inhibitor

    PubMed Central

    2012-01-01

    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

  16. Melittin suppresses VEGF-A-induced tumor growth by blocking VEGFR-2 and the COX-2-mediated MAPK signaling pathway.

    PubMed

    Huh, Jeong-Eun; Kang, Jung Won; Nam, Dongwoo; Baek, Yong-Hyeon; Choi, Do-Young; Park, Dong-Suk; Lee, Jae-Dong

    2012-11-26

    Melittin (1) is a major polypeptide in honey bee venom that has been used traditionally against chronic inflammation and cancer. However, its molecular mechanism has not been determined. In this study, the antitumor effect of 1 was compared with that of NS398, a cyclooxygenase-2 (COX-2) inhibitor, in vivo and in vitro. Subcutaneous injection of 1 at 0.5 and 5 mg/kg suppressed significantly vascular endothelial growth factor (VEGF)-A-transfected highly metastatic Lewis lung cancer (VEGF-A-hm LLC) tumor growth by 25% and 57%, respectively. Also, 1 inhibited significantly the number of vessels around VEGF-A-hm LLC cells. The results were superior to those obtained in the mice treated with NS398. Compound 1 dose-dependently inhibited proliferation and tube formation in human umbilical vein endothelial cells (VEGF-A-HUVECs), without affecting cell viability in native HUVECs. In addition, 1 decreased the expression of VEGF receptor-2 (VEGFR-2), COX-2, and prostaglandin E2 (PGE2) in VEGF-A-transfected HUVECs. These effects were accompanied by a reduction of the phosphorylation of extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase, whereas it increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). SB203580 abolished the downregulation of COX-2 and VEGFR-2 and the inhibition of cell proliferation by 1. The antitumor activity of 1 may be associated with antiangiogenic actions via inhibiting VEGFR-2 and inflammatory mediators involved in the MAPK signaling pathway. PMID:23110475

  17. Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages.

    PubMed

    Pan, Min-Hsiung; Chang, Yen-Hui; Tsai, Mei-Ling; Lai, Ching-Shu; Ho, Sheng-Yow; Badmaev, Vladimir; Ho, Chi-Tang

    2008-08-27

    Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also to induce apoptosis in various types of cancer cells. Here, we investigated the inhibitory effects of pterostilbene on the induction of NO synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and real-time polymerase chain reaction (PCR) analyses demonstrated that pterostilbene significantly blocked the protein and mRNA expression of iNOS and COX-2 in LPS-induced macrophages. Treatment with pterostilbene resulted in the reduction of LPS-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunit and the dependent transcriptional activity of NFkappaB by blocking phosphorylation of inhibitor kappaB (IkappaB)alpha and p65 and subsequent degradation of IkappaB alpha. Transient transfection experiments using NFkappaB reporter constructs indicated that pterostilbene inhibits the transcriptional activity of NFkappaB in LPS-stimulated mouse macrophages. We found that pterostilbene also inhibited LPS-induced activation of PI3K/Akt, extracellular signal-regulated kinase 1/2 and p38 MAPK. Taken together, these results show that pterostilbene down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NFkappaB by interfering with the activation of PI3K/Akt/IKK and MAPK. These results have an important implication for using pterostilbene toward the development of an effective anti-inflammatory agent. PMID:18656926

  18. Benzothiophene inhibitors of MK2. Part 2: Improvements in kinase selectivity and cell potency

    SciTech Connect

    Anderson, David R.; Meyers, Marvin J.; Kurumbail, Ravi G.; Caspers, Nicole; Poda, Gennadiy I.; Long, Scott A.; Pierce, Betsy S.; Mahoney, Matthew W.; Mourey, Robert J.; Parikh, Mihir D.; Pfizer

    2010-10-01

    Optimization of kinase selectivity for a set of benzothiophene MK2 inhibitors provided analogs with potencies of less than 500 nM in a cell based assay. The selectivity of the inhibitors can be rationalized by examination of X-ray crystal structures of inhibitors bound to MK2.

  19. Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: design, synthesis and evaluation as potential anti-inflammatory agents.

    PubMed

    Hassan, Ghaneya Sayed; Abou-Seri, Sahar Mahmoud; Kamel, Gehan; Ali, Mamdouh Moawad

    2014-04-01

    Novel series of celecoxib analogs endowed with benzofuran moiety 3a-e and 9a-d were synthesized and evaluated for COX-1/COX-2 inhibitory activity in vitro. The most potent and selective COX-2 inhibitors - compounds 3c, 3d, 3e, 9c and 9d - were assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivatives 3c and 3e exhibited the highest anti-inflammatory activity, that is equipotent to celecoxib. Furthermore, the tested compounds proved to have better gastric safety profile compared to celecoxib. In particular, compound 3e demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug. Finally, molecular docking simulation of the new compounds in COX-2 active site and drug likeness studies showed good agreement with the obtained pharmaco-biological results. PMID:24607877

  20. Design, synthesis, and biological evaluation of linear 1-(4-, 3- or 2-methylsulfonylphenyl)-2-phenylacetylenes: A novel class of cyclooxygenase-2 inhibitors

    Microsoft Academic Search

    Qiao-Hong Chen; P. N. Praveen Rao; Edward E. Knaus

    2005-01-01

    A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO2Me pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent (3-F, 3-OMe, 3-OH, 3-OAc, 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target linear 1,2-diarylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction followed by oxidation

  1. PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation.

    PubMed

    Sun, Qingzhu; Liu, Li; Roth, Michael; Tian, Jia; He, Qirui; Zhong, Bo; Bao, Ruanjuan; Lan, Xi; Jiang, Congshan; Sun, Jian; Yang, Xudong; Lu, Shemin

    2015-07-01

    Protein arginine methyltransferase (PRMT)1, methylating both histones and key cellular proteins, has emerged as a key regulator of various cellular processes. This study aimed to identify the mechanism that regulates PRMT1 in chronic Ag-induced pulmonary inflammation (AIPI) in the E3 rat asthma model. E3 rats were challenged with OVA for 1 or 8 wk to induce acute or chronic AIPI. Expression of mRNAs was detected by real-time quantitative PCR. PRMT1, TGF-?, COX2, and vascular endothelial growth factor protein expression in lung tissues was determined by immunohistochemistry staining and Western blotting. In the in vitro study, IL-4-stimulated lung epithelial cell (A549) medium (ISEM) with or without anti-TGF-? Ab was applied to human fibroblasts from lung (HFL1). The proliferation of HFL1 was determined by MTT. AMI-1 (pan-PRMT inhibitor) was administered intranasally to chronic AIPI rats to determine PRMT effects on asthmatic parameters. In lung tissue sections, PRMT1 expression was significantly upregulated, mainly in epithelial cells, in acute AIPI lungs, whereas it was significantly upregulated mainly in fibroblasts in chronic AIPI lungs. The in vitro study revealed that ISEM elevates PRMT1, COX2, and vascular endothelial growth factor expressions, and it promoted fibroblast proliferation. The application of anti-TGF-? Ab suppressed COX2 upregulation by ISEM. AMI-1 inhibited the expression of COX2 in TGF-?-stimulated cells. In the in vivo experiment, AMI-1 administered to AIPI rats reduced COX2 production and humoral immune response, and it abrogated mucus secretion and collagen generation. These findings suggested that TGF-?-induced PRMT1 expression participates in fibroblast proliferation and chronic airway inflammation in AIPI. PMID:26026059

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

    PubMed

    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

    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

  3. Utility of selective serotonin reuptake inhibitors in premature ejaculation.

    PubMed

    Waldinger, Marcel D; Olivier, Berend

    2004-07-01

    The introduction of selective serotonin reuptake inhibitors (SSRIs) has revolutionized our understanding of the treatment of premature ejaculation. Lifelong premature ejaculation may be a neurobiological phenomenon, namely part of a biological variability of the intravaginal ejaculation latency time in men. Animal studies support this view, and an animal model for premature and delayed ejaculation has recently been developed. It is proposed that drug treatment of premature ejaculation should consist of 5-hydroxytryptamine (5-HT)2c receptor stimulation and/or 5-HT1A receptor inhibition. A meta-analysis of 35 daily treatment studies with selective serotonin reuptake inhibitors (SSRIs) and clomipramine demonstrated comparable efficacy of clomipramine with the SSRIs sertraline and fluoxetine in delaying ejaculation, whereas the efficacy of the SSRI paroxetine was greater than all other SSRIs and clomipramine. It is postulated that acute treatment with SSRIs, including those with short half-lives, will not produce an ejaculation delay equivalent to that induced by daily treatment of SSRIs. PMID:15298071

  4. Ciglitazone mediates COX-2 dependent suppression of PGE2 in human Non-Small Cell Lung Cancer cells

    PubMed Central

    Hazra, Saswati; Dubinett, Steven M

    2007-01-01

    Summary Background Cycloxygenase-2 (COX-2) overexpression and subsequent prostaglandin E2 (PGE2) production are frequently associated with human non-small cell lung cancer (NSCLC) and are involved in tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here we report that ciglitazone downregulates PGE2 in NSCLC cells. Methods PGE2 ELISA assay and COX-2 ELISA assay were performed for measuring PGE2 and COX-2 respectively in NSCLC. The mRNA level of COX-2 was measured by semi-quantitative RT-PCR. The transient transfection experiments were performed to measure COX-2 and PPRE promoter activity in NSCLC. Western blots were unitized to measure PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein expression. Results COX-2 ELISA assays suggested that ciglitazone-dependent inhibition of PGE2 occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 mRNA expression and COX-2 promoter activity while upregulating peroxisome proliferator-response element (PPRE) promoter activity. Ciglitazone did not modify the expression of enzymes downstream of COX-2 including PGES and 15-PGDH. Utilization of a dominant-negative PPAR? showed that the suppression of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways. Conclusion Taken together, our findings suggest that ciglitazone is a negative modulator of COX-2/PGE2 in NSCLC. PMID:17697767

  5. Sphingosine-1-phosphate mediates COX-2 expression and PGE2 /IL-6 secretion via c-Src-dependent AP-1 activation.

    PubMed

    Hsu, Chih-Kai; Lee, I-Ta; Lin, Chih-Chung; Hsiao, Li-Der; Yang, Chuen-Mao

    2015-03-01

    Sphingosine-1-phosphate (S1P) has been shown to regulate cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2 ) expression and IL-6 secretion in various respiratory diseases. However, the mechanisms underlying S1P-induced COX-2 expression and PGE2 production in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here we demonstrated that S1P markedly induced COX-2 expression. S1P also induced PGE2 and IL-6 secretion which were reduced by the inhibitors of COX-2 (NS-398 and celecoxib). Pretreatment with the inhibitor of S1PR1 (W123), S1PR3 (CAY10444), c-Src (PP1), PYK2 (PF431396), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of S1PR1, S1PR3, c-Src, PYK2, p38, p42, JNK2, c-Jun, or c-Fos reduced S1P-induced COX-2 expression and PGE2 /IL-6 secretion. Moreover, S1P induced c-Src, PYK2, p42/p44 MAPK, JNK1/2, p38 MAPK, and c-Jun phosphorylation. We observed that S1P-induced p42/p44 MAPK and JNK1/2, but not p38 MAPK activation was mediated via a c-Src/PYK2-dependent pathway. S1P also enhanced c-Fos, but not c-Jun mRNA and protein expression and the AP-1 promoter activity. S1P-induced c-Fos mRNA and protein expression, c-Jun phosphorylation, and AP-1 promoter activity was reduced by W123, CAY10444, PP1, PF431396, U0126, SP600125, or SB202190. These results demonstrated that S1P-induced COX-2 expression and PGE2 /IL-6 generation was mediated through S1PR1/3/c-Src/PYK2/p42/p44 MAPK- or JNK1/2- and S1PR1/3/c-Src/p38 MAPK-dependent AP-1 activation. PMID:25201048

  6. 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...

  7. Expression of COX-2 and HER-2 in colorectal cancer and their correlation

    PubMed Central

    Wu, Qi-Bing; Sun, Guo-Ping

    2015-01-01

    AIM: To detect the expression of COX-2 and HER-2 in colorectal cancer and to analyze their correlation and clinical significance. METHODS: A total of 1026 colorectal cancer surgical specimens were collected from patients treated from December 2002 to December 2007 at the First Affiliated Hospital of Anhui Medical University. All specimens were made into 4-?m slices. The expression of COX-2 and HER-2 were detected by immunohistochemistry using the streptavidin-biotin-peroxidase method. The correlations between COX-2 and HER-2 expression and colorectal cancer clinical features were analyzed. RESULTS: The positive rates of COX-2 and HER-2 expression in colorectal cancer were 77.97% (800/1026) and 46.20% (474/1026), respectively. There was a significant correlation between COX-2 and HER-2 expression in colorectal cancer (P < 0.05). In patients with tumor size ? 5 cm, the positive rates of COX-2 and HER-2 expression were 81.48% (308/378) and 57.94% (219/378), respectively. In patients with serosal invasion, the positive COX-2 and HER-2 expression rates were 80.53% (612/760) and 49.21% (374/760), respectively. In patients with lymph node metastasis, the positive expression rates were 85.04% (506/595) and 54.62% (325/595), respectively, and the positive expression rates differed significantly between patients with lymph node metastasis and those without (P < 0.05). In patients with Duke’s C and D colorectal cancer, the positive COX-2 and HER-2 expression rates were 82.80% (443/535) and 57.94% (310/535), respectively. In patients with poorly differentiated colorectal cancer, the positive expression rates were 74.49% (210/282) and 52.84% (149/282), respectively (P < 0.05). In patients with distant metastasis, the positive expression rates were 82.27% (116/141) and 53.90% (76/141), respectively (P < 0.05). These findings suggest that COX-2 and HER-2 have synergistic effects in colorectal cancer. COX-2 and HER-2 expression had no significant correlation with sex, age, or tumor location. CONCLUSION: COX-2 and HER-2 are important markers for invasion and metastasis of colorectal cancer, and they act together to regulate the invasion and metastasis of colorectal cancer.

  8. Gene transfer from mitochondrion to nucleus: novel mechanisms for gene activation from Cox2

    Microsoft Academic Search

    Daniel O. Daley; Keith L. Adams; Rachel Clifton; Svenja Qualmann; A. Harvey Millar; Jeffrey D. Palmer; Elke Pratje; James Whelan

    2002-01-01

    Summary The evolutionarily recent transfer of the gene for cytochrome c oxidase subunit 2 (cox2) from the mitochondrion to the nucleus in legumes is shown to have involved novel gene-activation steps. The acquired mitochondrial targeting presequence is bordered by two introns. Characterization of the import of soybean Cox2 indicates that the presequence is cleaved in a three-step process which is

  9. Expression of IL-17 and COX2 gene in peripheral blood leukocytes of vitiligo patients.

    PubMed

    Esmaeili, Behnaz; Rezaee, Seyed Abdol Rahim; Layegh, Pouran; Tavakkol Afshari, Jalil; Dye, Phil; Ghayoor Karimiani, Ehsan; Kalalinia, Fatemeh; Rafatpanah, Houshang

    2011-06-01

    Vitiligo is a pigmentation disorder in which inflammatory mediators such as cytokines have a pivotal role in disease's pathogenesis. Interleukin 17 (IL-17A) is a proinflammatory cytokine which is involved in the induction of several proinflamatory mediators such as cyclooxygenase 2 (COX2). The aim of this study was to investigate the gene expression of IL-17 and COX2 in peripheral blood leukocytes of vitiligo's patients.Peripheral blood leukocytes from 15 patients with vitiligo and 15 healthy controls were separated using a gradient density centrifugation method. After total RNA isolation and cDNA synthesis, IL-17 and COX2 gene expression were quantified by real-time polymerase chain reaction (PCR). There were no significant differences in IL-17 and COX2 gene expression in lymphocytes of patients with vitiligo compared with control group (p<0.05). However there was an increased IL-17 and COX2 gene expression in neutrophils of patients compared to controls, but it did not reach statistical significance (p=0.05). We could not find any differences in IL-17 and Cox2 gene expression between clinical diseases subtypes, sex and age. There was a significant correlation between IL-17 and COX2 genes expression in the neutrophils of patients (p=0.00, r=0.80). Our results showed an increased expression in IL-17 and Cox-2 genes in neurophils of patients with vitiligo. This suggested that these two factors are involved in the inflammatory process. Further studies with a larger sample size might help to establish the role of these factors in the pathogenesis of diseases. PMID:21625016

  10. Association between COX-2 polymorphisms and non-small cell lung cancer susceptibility

    PubMed Central

    Zhang, Tiancheng; Li, Jing; Xia, Tian; Zhang, Nan; Zhang, Yaozhou; Zhao, Jian

    2015-01-01

    Aim: To explore the association between COX-2 polymorphisms and non-small cell lung cancer (NSCLC) susceptibility. Methods: We collected fasting peripheral venous blood from 60 cases with NSCLC and 62 healthy controls through physical examinations, and applied PCR-RFLP to analyze COX-2 polymorphisms of two groups. Results: With respect to detecting COX-2 rs689466 and rs5275 polymorphisms, the distribution frequency of mutant genotype AA of COX-2 rs689466 in case group was higher than that in control group, which possessed significant difference between two groups (P < 0.05). Carriers with AA genotype were 4.05 times at risk of NSCLC than those with GG genotype (P = 0.04, OR=4.05, 95% CI = 1.14-14.43). The distribution of mutant genotype CC of COX-2 rs5275 was different between two groups, and carriers with genotype CC were at 5.70 times higher risk of NSCLC than those with genotype TT. After corrected by sex, gender, smoking and drinking factors, AA genotype of COX-2 rs689466 and CC genotype of COX-2 rs5275 still contributed to increased risk of NSCLC (OR=4.22, 95% CI=1.10-16.17, OR=6.95, 95% CI=1.27-38.11). After analyzed of linkage disequilibrium (LD) and haplotypes of alleles in two SNPs, the distribution frequency of A-C haplotype in case group was higher than that in control group, with significant difference between two groups (P < 0.05). After corrected by sex, gender, smoking and drinking factors, statistical difference was still found in the total distribution of A-C haplotype between two groups (P = 0.03, OR=6.11, 95% CI=1.16-32.2). Conclusions: COX-2 rs689466 and rs5275 polymorphisms may be related to NSCLC susceptibility. And A-C haplotype might be a susceptibility haplotype for NSCLC.

  11. Discovery of Selective Inhibitors of the Clostridium difficile Dehydroquinate Dehydratase

    PubMed Central

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

    2014-01-01

    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

  12. The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention.

    PubMed

    Kong, Gu; Kim, Hee-Tae; Wu, Kendall; DeNardo, David; Hilsenbeck, Susan G; Xu, Xiao-Chun; Lamph, William W; Bissonnette, Reid; Dannenberg, Andrew J; Brown, Powel H

    2005-04-15

    Retinoids and their derivatives can suppress the development of cancer in animals and in humans. We and others have shown that retinoid X receptor (RXR)-selective retinoids or "rexinoids" suppress the development of breast cancer in several animal models with minimal toxicity. LGD1069 (Bexarotene) is a potent RXR-selective retinoid with reduced toxicity compared with naturally occurring retinoids. In this study, we investigated the expression of LGD1069-modulated biomarkers. We previously did cDNA array analysis of LGD1069-treated breast cells using Affymetrix microarrays. These studies identified many LGD1069-regulated genes, one of which was cyclooxygenase-2 (COX-2). Because COX-2 inhibitors have been shown to prevent cancer in other model systems, we investigated whether LGD1069 inhibits the expression of COX-2 in mammary tissue and in normal human mammary epithelial cells (HMEC). In mouse mammary tumor virus-erbB2 mice treated with LGD1069, there was a marked decrease of COX-2 expression in both normal and malignant mammary tissues. The effect of LGD1069 on COX-2 expression was also investigated in normal human breast cells. COX-2 expression was markedly reduced by treatment with LGD1069 at the RNA and protein level in normal HMECs; LGD1069 suppressed COX-2 promoter activity. We also showed that LGD1069 inhibited activator protein (AP-1)-dependent transcription in these breast cells, and that suppression of COX-2 expression was due to sequestration of CBP/p300. These results from in vivo and in vitro studies suggest that LGD1069, an RXR-selective retinoid, inhibits COX-2 expression by suppression of COX-2 transcription in part through transrepression of the AP-1 transcription factor. Thus, RXR-selective retinoids that inhibit AP-1 activity and suppress COX-2 expression may be particularly promising drugs for breast cancer prevention. Furthermore, such RXR-selective retinoids may be most useful in combination with antiestrogens for more effective prevention of breast cancer in women at high risk of this disease. PMID:15833882

  13. Targeted disruption of glutathione peroxidase 4 (GPx4) in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2

    PubMed Central

    Sengupta, Aniruddha; Lichti, Ulrike F.; Carlson, Bradley A.; Cataisson, Christophe; Ryscavage, Andrew O.; Mikulec, Carol; Conrad, Marcus; Fischer, Susan M.; Hatfield, Dolph L.; Yuspa, Stuart H.

    2013-01-01

    Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development and caused premature death. In the current study we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte-specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin while GPx4 loss in epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal lifespan. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4 knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and COX-2 levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis. PMID:23364477

  14. Enrichment of Echinacea angustifolia with Bauer alkylamide 11 and Bauer ketone 23 increased anti-inflammatory potential through interference with cox-2 enzyme activity.

    PubMed

    Lalone, Carlie A; Huang, Nan; Rizshsky, Ludmila; Yum, Man-Yu; Singh, Navrozedeep; Hauck, Cathy; Nikolau, Basil J; Wurtele, Eve S; Kohut, Marian L; Murphy, Patricia A; Birt, Diane F

    2010-08-11

    Bauer alkylamide 11 and Bauer ketone 23 were previously found to be partially responsible for Echinacea angustifolia anti-inflammatory properties. This study further tested their importance using the inhibition of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) production by RAW264.7 mouse macrophages in the absence and presence of lipopolysaccharide (LPS) and E. angustifolia extracts, phytochemical enriched fractions, or pure synthesized standards. Molecular targets were probed using microarray, qRT-PCR, Western blot, and enzyme assays. Fractions with these phytochemicals were more potent inhibitors of LPS-induced PGE(2) production than E. angustifolia extracts. Microarray did not detect changes in transcripts with phytochemical treatments; however, qRT-PCR showed a decrease in TNF-alpha and an increase of iNOS transcripts. LPS-induced COX-2 protein was increased by an E. angustifolia fraction containing Bauer ketone 23 and by pure phytochemical. COX-2 activity was decreased with all treatments. The phytochemical inhibition of PGE(2) production by Echinacea may be due to the direct targeting of COX-2 enzyme. PMID:20681645

  15. Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia.

    PubMed

    Xia, Q; Hu, Q; Wang, H; Yang, H; Gao, F; Ren, H; Chen, D; Fu, C; Zheng, L; Zhen, X; Ying, Z; Wang, G

    2015-01-01

    Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS. PMID:25811799

  16. Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia

    PubMed Central

    Xia, Q; Hu, Q; Wang, H; Yang, H; Gao, F; Ren, H; Chen, D; Fu, C; Zheng, L; Zhen, X; Ying, Z; Wang, G

    2015-01-01

    Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS. PMID:25811799

  17. Antinociceptive Effect of Tetrandrine on LPS-Induced Hyperalgesia via the Inhibition of IKK? Phosphorylation and the COX-2/PGE2 Pathway in Mice

    PubMed Central

    Zhao, Hengguang; Luo, Fuling; Li, Hongzhong; Zhang, Li; Yi, Yongfen; Wan, Jingyuan

    2014-01-01

    Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid that is isolated from the Stephania Tetrandra. It is known to possess anti-inflammatory and immunomodulatory effects. We have shown that TET can effectively suppress the production of bacterial lipopolysaccharide (LPS)-induced inflammatory mediators, including cyclooxygenases (COXs), in macrophages. However, whether TET has an antinociceptive effect on LPS-induced hyperalgesia is unknown. In the present study, we investigated the potential antinociceptive effects of TET and the mechanisms by which it elicits its effects on LPS-induced hyperalgesia. LPS effectively evoked hyperalgesia and induced the production of PGE2 in the sera, brain tissues, and cultured astroglia. TET pretreatment attenuated all of these effects. LPS also activated inhibitor of ?B (I?B) kinase ? (IKK?) and its downstream components in the I?B/nuclear factor (NF)-?B signaling pathway, including COX-2; the increase in expression levels of these components was significantly abolished by TET. Furthermore, in primary astroglia, knockdown of IKK?, but not IKK?, reversed the effects of TET on the LPS-induced increase in I?B phosphorylation, P65 phosphorylation, and COX-2. Our results suggest that TET can effectively exert antinociceptive effects on LPS-induced hyperalgesia in mice by inhibiting IKK? phosphorylation, which leads to the reduction in the production of important pain mediators, such as PGE2 and COX-2, via the IKK?/I?B/NF-?B pathway. PMID:24722146

  18. Antinociceptive effect of tetrandrine on LPS-induced hyperalgesia via the inhibition of IKK? phosphorylation and the COX-2/PGE? pathway in mice.

    PubMed

    Zhao, Hengguang; Luo, Fuling; Li, Hongzhong; Zhang, Li; Yi, Yongfen; Wan, Jingyuan

    2014-01-01

    Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid that is isolated from the Stephania Tetrandra. It is known to possess anti-inflammatory and immunomodulatory effects. We have shown that TET can effectively suppress the production of bacterial lipopolysaccharide (LPS)-induced inflammatory mediators, including cyclooxygenases (COXs), in macrophages. However, whether TET has an antinociceptive effect on LPS-induced hyperalgesia is unknown. In the present study, we investigated the potential antinociceptive effects of TET and the mechanisms by which it elicits its effects on LPS-induced hyperalgesia. LPS effectively evoked hyperalgesia and induced the production of PGE2 in the sera, brain tissues, and cultured astroglia. TET pretreatment attenuated all of these effects. LPS also activated inhibitor of ?B (I?B) kinase ? (IKK?) and its downstream components in the I?B/nuclear factor (NF)-?B signaling pathway, including COX-2; the increase in expression levels of these components was significantly abolished by TET. Furthermore, in primary astroglia, knockdown of IKK?, but not IKK?, reversed the effects of TET on the LPS-induced increase in I?B phosphorylation, P65 phosphorylation, and COX-2. Our results suggest that TET can effectively exert antinociceptive effects on LPS-induced hyperalgesia in mice by inhibiting IKK? phosphorylation, which leads to the reduction in the production of important pain mediators, such as PGE2 and COX-2, via the IKK?/I?B/NF-?B pathway. PMID:24722146

  19. Selectively Targeting Prostate Cancer with Antiandrogen Equipped Histone Deacetylase Inhibitors

    PubMed Central

    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

    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

  20. Apolipoprotein E3 Inhibits Rho to Regulate the Mechanosensitive Expression of Cox2

    PubMed Central

    Mui, Keeley L.; Liu, Shu-Lin; Assoian, Richard K.

    2015-01-01

    Apolipoprotein E3 (apoE3) is thought to protect against atherosclerosis by enhancing reverse cholesterol transport. However, apoE3 also has cholesterol-independent effects that contribute to its anti-atherogenic properties. These include altering extracellular matrix protein synthesis and inhibiting vascular smooth muscle cell proliferation. Both of these cholesterol-independent effects result from an apoE3-mediated induction of cyclooxygenase-2 (Cox2). Nevertheless, how apoE3 regulates Cox2 remains unknown. Here, we show that apoE3 inhibits the activation of Rho, which reduces the formation of actin stress fibers and focal adhesions and results in cellular softening. Inhibition of Rho-Rho kinase signaling or direct cellular softening recapitulates the effect of apoE3 on Cox2 expression while a constitutively active Rho mutant overrides the apoE3 effect on both intracellular stiffness and Cox2. Thus, our results describe a previously unidentified mechanism by which an atheroprotective apolipoprotein uses Rho to control cellular mechanics and Cox2. PMID:26068461

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

    SciTech Connect

    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

    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.

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

    PubMed Central

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

    2014-01-01

    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

  3. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria.

    PubMed Central

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

    2000-01-01

    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

  4. Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors.

    PubMed

    Bertrand, J A; Thieffine, S; Vulpetti, A; Cristiani, C; Valsasina, B; Knapp, S; Kalisz, H M; Flocco, M

    2003-10-17

    GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors. PMID:14529625

  5. Selectivity Profiling and Biological Activity of Novel ?-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors

    PubMed Central

    Rüben, Katharina; Wurzlbauer, Anne; Walte, Agnes; Sippl, Wolfgang; Bracher, Franz; Becker, Walter

    2015-01-01

    DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer’s disease. The ?-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A) with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau) without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized ?-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies. PMID:26192590

  6. Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors.

    PubMed

    Ahmed, Waseem; Khan, Ishtiaq Ahmad; Arshad, Muhammad Nadeem; Siddiqui, Waseeq Ahmad; Haleem, Muhammad Abdul; Azim, Muhammad Kamran

    2013-07-01

    Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC50 values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 ?M. N-(3-chlorophenyl)-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC50 1.25 ?M. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9±1.16 to -35.1±0.13 in case of Cathepsin D, while from -24.0±0.10 to -29.5±0.10 in case of Plasmepsin-II. PMID:23811443

  7. Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors

    PubMed Central

    Janakiram, Naveena B.; Rao, Chinthalapally V.

    2013-01-01

    Nitric oxide (NO) is a short-lived pleiotropic regulator and is required for numerous pathophysiological functions, including macrophage-mediated immunity and cancer. It is a highly reactive free radical produced from l-arginine by different isoforms of NO synthases (NOSs). Sustained induction of inducible NOS (iNOS) during chronic inflammatory conditions leads to the formation of reactive intermediates of NO, which are mutagenic and cause DNA damage or impairment of DNA repair, alter cell signaling, and promote proinflammatory and angiogenic properties of the cell, thus contributing to carcinogenesis. Besides its well-established role in inflammation, increased expression of iNOS has been observed in colorectal tumors and other cancers. NO-related signaling pathways involved in colon tumorigenesis seem to progress through stimulation of proinflammatory cytokines and via posttranslational protein modifications of important antiapoptotic molecules in the tumors. NO can stimulate and enhance tumor cell proliferation by promoting invasive, angiogenic, and migratory activities. In contrast, studies also suggest that high levels of NO may be protective against tumor growth by inducing tumor cell death. However, a number of in vitro studies and particularly experimental animal data support the notion that NO and its reactive metabolite peroxynitrite stimulate cyclooxygenase-2 activity, leading to generation of prostaglandins that enhance tumor growth. These prostaglandins further augment tumor promotion and invasive properties of tumor cells. Hence, selective inhibitors of iNOS and combination strategies to inhibit both iNOS and cyclooxygenase-2 may have a preventive role in colon cancer. PMID:23678395

  8. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

    SciTech Connect

    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

    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.

  9. Isolation, synthesis and characterization of impurities in Celecoxib a cox-2 inhibitor

    Microsoft Academic Search

    U Satyanarayana; D. Sreenivas Rao; Y. Ravindra Kumar; J. Moses Babu; P. Rajender Kumar; J. Tirupathi Reddy

    2004-01-01

    During the impurity profile of Celecoxib, four polar impurities (impurity I, II, III and IV) and one non-polar impurity (impurity V) with respect to Celecoxib were detected by HPLC. LC-MS has been employed in this impurity profile study. The three polar impurities (I, II and III) were found to be process related while impurities (IV and V) turned out to

  10. Complications of the COX2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery

    Microsoft Academic Search

    Nancy A. Nussmeier; Andrew A. Whelton; Mark T. Brown; Richard M. Langford; Andreas Hoeft; Joel L. Parlow; Steven W. Boyce; Kenneth M. Verburg

    2010-01-01

    background Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain but may involve risk after coronary-artery bypass grafting (CABG). We conducted a ran- domized trial to assess the safety of these drugs after CABG. methods In this randomized, double-blind study involving 10 days of treatment and 30 days of follow-up, 1671 patients were randomly assigned to receive

  11. Case Report: Disseminating Drug Prescribing Information: The Cox2 Inhibitors Withdrawals

    Microsoft Academic Search

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

    2006-01-01

    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

  12. Chemoprevention of colon cancer by a novel COX-2 inhibitor | Division of Cancer Prevention

    Cancer.gov

    Skip to main content Division of Cancer Prevention Search form Search Main menu Home Major Programs Research Networks Map Alliance of Glycobiologists for Detection of Cancer Barrett's Esophagus Translational Research Network (BETRNet) Cancer Prevention

  13. 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

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

    2012-03-01

    Aldo-keto reductase 1C3 (AKR1C3; type 5 17?-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5?-dihydrotestosterone. Selective AKR1C3 inhibitors are required because 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 nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues 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 toward new therapeutics for CRPC. PMID:22263837

  14. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study

    PubMed Central

    Huang, Jian; Zhang, Di; Xie, Fuqiang

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.

  15. Aspects of corrosion inhibitor selection at elevated temperatures

    SciTech Connect

    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

    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.

  16. Selection of corrosion inhibitors to control microbiologically influenced corrosion

    SciTech Connect

    Prasad, R. [Champion Technologies, Inc., Fresno, TX (United States)

    1998-12-31

    Microbiologically Influenced Corrosion (MIC) is a serious problem. The establishment of a biofilm on a metal surface plays a critical role in MIC. Quaternary amines have been reported to inhibit the bacterial adhesion to the metal surface. However, most of the quaternary amines are quite toxic. In light of growing concerns of environmental impact and safety, a series of experiments was conducted to evaluate various corrosion inhibitors for their inhibition capability of bacterial adhesion as well as bacterial kill. The results indicate that some inhibitors are capable of inhibiting biofilm formation on mild steel coupons. In addition, these inhibitors have biocidal properties. Initial toxicity studies suggest that some of these inhibitors are less toxic than most industrial biocides. This paper discusses the cost-effectiveness of use of these inhibitors in some systems.

  17. Monofluorophosphate is a selective inhibitor of respiratory sulfate-reducing microorganisms.

    PubMed

    Carlson, Hans K; Stoeva, Magdalena K; Justice, Nicholas B; Sczesnak, Andrew; Mullan, Mark R; Mosqueda, Lorraine A; Kuehl, Jennifer V; Deutschbauer, Adam M; Arkin, Adam P; Coates, John D

    2015-03-17

    Despite the environmental and economic cost of microbial sulfidogenesis in industrial operations, few compounds are known as selective inhibitors of respiratory sulfate reducing microorganisms (SRM), and no study has systematically and quantitatively evaluated the selectivity and potency of SRM inhibitors. Using general, high-throughput assays to quantitatively evaluate inhibitor potency and selectivity in a model sulfate-reducing microbial ecosystem as well as inhibitor specificity for the sulfate reduction pathway in a model SRM, we screened a panel of inorganic oxyanions. We identified several SRM selective inhibitors including selenate, selenite, tellurate, tellurite, nitrate, nitrite, perchlorate, chlorate, monofluorophosphate, vanadate, molydate, and tungstate. Monofluorophosphate (MFP) was not known previously as a selective SRM inhibitor, but has promising characteristics including low toxicity to eukaryotic organisms, high stability at circumneutral pH, utility as an abiotic corrosion inhibitor, and low cost. MFP remains a potent inhibitor of SRM growing by fermentation, and MFP is tolerated by nitrate and perchlorate reducing microorganisms. For SRM inhibition, MFP is synergistic with nitrite and chlorite, and could enhance the efficacy of nitrate or perchlorate treatments. Finally, MFP inhibition is multifaceted. Both inhibition of the central sulfate reduction pathway and release of cytoplasmic fluoride ion are implicated in the mechanism of MFP toxicity. PMID:25698072

  18. Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

    SciTech Connect

    Selness, Shaun R.; Devraj, Rajesh V.; Monahan, Joseph B.; Boehm, Terri L.; Walker, John K.; Devadas, Balekudru; Durley, Richard C.; Kurumbail, Ravi; Shieh, Huey; Xing, Li; Hepperle, Michael; Rucker, Paul V.; Jerome, Kevin D.; Benson, Alan G.; Marrufo, Laura D.; Madsen, Heather M.; Hitchcock, Jeff; Owen, Tom J.; Christie, Lance; Promo, Michele A.; Hickory, Brian S.; Alvira, Edgardo; Naing, Win; Blevis-Bal, Radhika; Pfizer

    2010-10-18

    The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38{alpha}. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.

  19. Design and synthesis of potent, selective phenylimidazole-based FVIIa inhibitors.

    PubMed

    Glunz, Peter W; Cheng, Xuhong; Cheney, Daniel L; Weigelt, Carolyn A; Wei, Anzhi; Luettgen, Joseph M; Wong, Pancras C; Wexler, Ruth R; Priestley, E Scott

    2015-05-15

    Heterocyclic amide isosteres were incorporated into a phenylglycine-based tissue factor/factor VIIa (TF-FVIIa) inhibitor chemotype, providing potent inhibitors. An X-ray co-crystal structure of phenylimidazole 19 suggested that an imidazole nitrogen atom effectively mimics an amide carbonyl, while the phenyl ring forms key hydrophobic interactions with the S1' pocket. Exploration of phenylimidazole substitution led to the discovery of potent, selective and efficacious inhibitors of TF-FVIIa. PMID:25881820

  20. Corrosion inhibitor testing and selection for exploration and production: A user's perspective

    SciTech Connect

    Kapusta, S.D.

    1999-06-01

    Inhibitor users need simple, reliable, and representative tests to select the best product from a number of candidates. This article describes a procedure that can help users test and select inhibitors for carbon dioxide/hydrogen sulfide (CO[sub 2]/H[sub 2]S) corrosion in oil and gas production, in a fast and cost-effective manner. The selection is based on two criteria: performance (effectiveness) against corrosion, and compatibility with other chemicals. The compatibility of the inhibitor with the injection and production systems must be confirmed.

  1. The role of COX2 in intestinal inflammation and colorectal cancer

    Microsoft Academic Search

    D Wang; R N DuBois

    2010-01-01

    Colorectal cancer (CRC) is a heterogeneous disease, including at least three major forms: hereditary, sporadic and colitis-associated CRC. A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC. As elevated cyclooxygenase-2 (COX-2) expression was found in most CRC tissue and is associated with worse survival among CRC patients,

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

    SciTech Connect

    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

    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.

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

    Microsoft Academic Search

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

    2006-01-01

    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

  4. RNA editing of mitochondrial functional genes atp6 and cox2 in maize ( Zea mays L.)

    Microsoft Academic Search

    Jing Wang; Mo Ju Cao; Guang Tang Pan; Yan Li Lu; Ting Zhao Rong

    2009-01-01

    RNA editing of two mitochondrial or organs genes, atp6 and cox2, in different tissues were analyzed using homonucleic but alloplasmic, and homoplasmic but heteronucleic maize (zea mays L.) as experimental materials. A total of 18 and 26 editing sites for atp6 conservative region transcript were identified by direct and clone sequencing, respectively. By direct sequencing 23 and 22 editing sites

  5. Food contaminant acrylamide increases expression of Cox-2 and nitric oxide synthase in breast epithelial cells.

    PubMed

    Lyn-Cook, Lascelles E; Tareke, Eden; Word, Beverly; Starlard-Davenport, Athena; Lyn-Cook, Beverly D; Hammons, George J

    2011-02-01

    Acrylamide has been discovered in foods cooked at high temperature. A potentially harmful effect of this dietary component has been suggested by data indicating its association with increased breast cancer. This study investigated the potential effects of acrylamide in nontumorigenic breast cells by assessing expression levels of inducible nitric oxide synthase (iNOS) and cycloogenase-2 (Cox-2) and NOS activity, which are known to be early molecular changes in disease formation. Treatment of cells with acrylamide increased levels of iNOS (both expression and activity) and Cox-2. Its potent metabolite, glycidamide, also induced both iNOS and Cox-2, with induction of iNOS occurring at a lower concentration. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), another food-borne carcinogen, was found to induce Cox-2 expression. Combining acrylamide with PhIP did not result in a further increase. These studies suggest that further research is needed to determine the role of carcinogens formed from cooking foods in inducing early molecular changes associated with breast cancer. PMID:20713430

  6. Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4.

    PubMed

    Wang, Qingsong; He, Yuhu; Shen, Yujun; Zhang, Qianqian; Chen, Di; Zuo, Caojian; Qin, Jing; Wang, Hui; Wang, Junwen; Yu, Ying

    2014-04-25

    Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)2D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)2D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target I?B? in macrophages were markedly suppressed by 1,25(OH)2D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)2D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-?B/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease. PMID:24619416

  7. Cyclooxygenase-2 and tissue inhibitor of matrix metalloproteinases-1 confer the antimigratory effect of cannabinoids on human trabecular meshwork cells.

    PubMed

    Ramer, Robert; Hinz, Burkhard

    2010-09-15

    Cannabinoids have received considerable attention as potential antiglaucomatous drugs. Recently, prostaglandins (PG) have been suggested to contribute to this effect. Within the factors conferring the development of glaucoma, depletion of the aqueous humor outflow-regulating trabecular meshwork (TM) cells elicited by migration from the outflow system is considered to play a pivotal role. This study therefore investigates the impact of two cannabinoids, Delta(9)-tetrahydrocannabinol (THC) and R(+)-methanandamide (MA), on the migration of human TM cells and the involvement of the PG-synthesizing enzyme cyclooxygenase-2 (COX-2) and one of its potential downstream targets, the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), to this response. Using Boyden chamber assays cannabinoids were shown to elicit an antimigratory effect that was reversed by antagonists for CB(1) as well as CB(2) receptors and accompanied by upregulation of COX-2 and TIMP-1 expression and PGE(2) synthesis. Knockdown of cannabinoid-induced COX-2 or TIMP-1 expression by siRNA or inhibition of COX-2 activity by NS-398 led to a significant suppression of this antimigratory action. Migration was also diminished by the major COX-2 product PGE(2) and by recombinant TIMP-1. Experiments using selective E prostanoid (EP) receptor agonists and antagonists revealed that decreased migration by PGE(2), THC and MA was mediated via EP(2) and EP(4) receptors. Finally, the cannabinoid-mediated increases of TIMP-1 levels were abolished by NS-398, and PGE(2) was shown to elicit a concentration-dependent increase of TIMP-1. Collectively, this data demonstrate a COX-2-dependent upregulation of TIMP-1 conferring the antimigratory action of cannabinoids. A decreased migration reducing TM cell loss in glaucoma might be involved in the antiglaucomatous action of cannabinoids. PMID:20488167

  8. Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.

    PubMed

    Brasca, Maria Gabriella; Nesi, Marcella; Avanzi, Nilla; Ballinari, Dario; Bandiera, Tiziano; Bertrand, Jay; Bindi, Simona; Canevari, Giulia; Carenzi, Davide; Casero, Daniele; Ceriani, Lucio; Ciomei, Marina; Cirla, Alessandra; Colombo, Maristella; Cribioli, Sabrina; Cristiani, Cinzia; Della Vedova, Franco; Fachin, Gabriele; Fasolini, Marina; Felder, Eduard R; Galvani, Arturo; Isacchi, Antonella; Mirizzi, Danilo; Motto, Ilaria; Panzeri, Achille; Pesenti, Enrico; Vianello, Paola; Gnocchi, Paola; Donati, Daniele

    2014-09-01

    We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile. PMID:25009002

  9. Arylcarboxyamino-substituted diaryl ureas as potent and selective FLT3 inhibitors

    Microsoft Academic Search

    Hitesh K. Patel; Robert M. Grotzfeld; Andiliy G. Lai; Shamal A. Mehta; Zdravko V. Milanov; Qi Chao; Kelly G. Sprankle; Todd A. Carter; Anne Marie Velasco; Miles A. Fabian; Joyce James; Daniel K. Treiber; David J. Lockhart; Patrick P. Zarrinkar; Shripad S. Bhagwat

    2009-01-01

    A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.

  10. Flavocoxid Inhibits Phospholipase A2, Peroxidase Moieties of the Cyclooxygenases (COX), and 5-Lipoxygenase, Modifies COX-2 Gene Expression, and Acts as an Antioxidant

    PubMed Central

    Burnett, Bruce P.; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M.; Pillai, Lakshmi

    2011-01-01

    The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA2) (IC50 = 60??g/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC50 = 12.3) and COX-2 (IC50 = 11.3??g/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC50 = 110??g/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC50 = 38??g/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS). PMID:21765617

  11. 9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors.

    PubMed

    Zimmermann, Kurt; Sang, Xiaopeng; Mastalerz, Harold A; Johnson, Walter L; Zhang, Guifen; Liu, Qingjie; Batt, Douglas; Lombardo, Louis J; Vyas, Dinesh; Trainor, George L; Tokarski, John S; Lorenzi, Matthew V; You, Dan; Gottardis, Marco M; Lippy, Jonathan; Khan, Javed; Sack, John S; Purandare, Ashok V

    2015-07-15

    The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family. PMID:25987372

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

    PubMed Central

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

    2011-01-01

    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

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

    E-print Network

    Long, Jody Renee

    1987-01-01

    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 Committee) @q ~ y. g~p( A. Naqi (Member) C. R. cger (Head of De rtment) C. R. cger (Hember) December 1987 ABSTRACT Effects of Selected Enzyme Inhibitors on Blood and Eggshell Parameters in the Laying Hen. (December, 1987) Jody R. Long, B. S...

  14. The p110? structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

    Microsoft Academic Search

    Alex Berndt; Simon Miller; Olusegun Williams; Daniel D Le; Benjamin T Houseman; Joseph I Pacold; Fabrice Gorrec; Wai-Ching Hon; Pingda Ren; Yi Liu; Christian Rommel; Pascale Gaillard; Thomas Rückle; Matthias K Schwarz; Kevan M Shokat; Jeffrey P Shaw; Roger L Williams

    2010-01-01

    Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to

  15. Evaluation of NHS Carbamates as a Potent and Selective Class of Endocannabinoid Hydrolase Inhibitors

    PubMed Central

    2013-01-01

    Monoacylglycerol lipase (MAGL) is a principal metabolic enzyme responsible for hydrolyzing the endogenous cannabinoid (endocannabinoid) 2-arachidonoylglycerol (2-AG). Selective inhibitors of MAGL offer valuable probes to further understand the enzyme’s function in biological systems and may lead to drugs for treating a variety of diseases, including psychiatric disorders, neuroinflammation, and pain. N-Hydroxysuccinimidyl (NHS) carbamates have recently been identified as a promising class of serine hydrolase inhibitors that shows minimal cross-reactivity with other proteins in the proteome. Here, we explore NHS carbamates more broadly and demonstrate their potential as inhibitors of endocannabinoid hydrolases and additional enzymes from the serine hydrolase class. We extensively characterize an NHS carbamate 1a (MJN110) as a potent, selective, and in-vivo-active MAGL inhibitor. Finally, we demonstrate that MJN110 alleviates mechanical allodynia in a rat model of diabetic neuropathy, marking NHS carbamates as a promising class of MAGL inhibitors. PMID:23731016

  16. Acquisition of a “Group A”-Selective Src Kinase Inhibitor via A Global Targeting Strategy

    PubMed Central

    Hah, Jung-Mi; Sharma, Vyas; Li, Haishan; Lawrence, David S.

    2008-01-01

    A “global” strategy for the acquisition of selective high affinity inhibitors for the Src kinase subfamily of tyrosine kinases is described. Members of the Src family exhibit a strong amino acid sequence homology. However, recent studies have revealed differences in the relative spatial relationships of the three distinct protein-binding domains present in these enzymes. We have constructed an inhibitor, using an amalgamation of combinatorial methods and directed design, which simultaneously associates with the active site and an ancillary protein-binding region (SH2 domain). The inhibitor exhibits high inhibitory potency and selectivity for the Group A versus Group B subset of Src kinases. PMID:16669643

  17. Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1? expression through the induction of glucocorticoidinduced leucine zipper

    PubMed Central

    Lim, Wonchung; Park, Choa; Shim, Myeong Kuk; Lee, Yong Hee; Lee, You Mie; Lee, YoungJoo

    2014-01-01

    Background and Purpose The COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. However, the mechanism by which glucocorticoid receptors (GRs) inhibit COX-2 during hypoxia has not been elucidated. Hence, we explored the mechanisms underlying glucocorticoid-mediated inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells. Experimental Approach The expressions of COX-2 and glucocorticoid-induced leucine zipper (GILZ) in A549 cells were determined by Western blot and/or quantitative real time-PCR respectively. The anti-invasive effect of GILZ on A549 cells was evaluated using the matrigel invasion assay. Key Results The hypoxia-induced increase in COX-2 protein and mRNA levels and promoter activity were suppressed by dexamethasone, and this effect of dexamethasone was antagonized by the GR antagonist RU486. Overexpression of GILZ in A549 cells also inhibited hypoxia-induced COX-2 expression levels and knockdown of GILZ reduced the glucocorticoid-mediated inhibition of hypoxia-induced COX-2 expression, indicating that the inhibitory effects of dexamethasone on hypoxia-induced COX-2 are mediated by GILZ. GILZ suppressed the expression of hypoxia inducible factor (HIF)-1? at the protein level and affected its signalling pathway. Hypoxia-induced cell invasion was also dramatically reduced by GILZ expression. Conclusion and Implications Dexamethasone-induced upregulation of GILZ not only inhibits the hypoxic-evoked induction of COX-2 expression and cell invasion but further blocks the HIF-1 pathway by destabilizing HIF-1? expression. Taken together, these findings suggest that the suppression of hypoxia-induced COX-2 by glucocorticoids is mediated by GILZ. Hence, GILZ is a potential key therapeutic target for suppression of inflammation under hypoxia. PMID:24172143

  18. 3,4-disubstituted azetidinones as selective inhibitors of the cysteine protease cathepsin K. Exploring P2 elements for selectivity.

    PubMed

    Setti, Eduardo L; Davis, Dana; Chung, Tobee; McCarter, John

    2003-06-16

    A novel series of 3,4-disubstituted azetidinones based inhibitors of the cysteine protease cathepsin K (Cat K) has been identified. Although not optimized, some of these compounds show at least 100-fold selectivity against other cathepsins. The use of cyclic moieties as P2 elements has proven to be crucial to achieve a high degree of selectivity. PMID:12781193

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

    SciTech Connect

    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

    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.

  20. ?–3 Fatty Acids, Genetic Variants in COX-2 and Prostate Cancer

    PubMed Central

    Reese, Adam C.; Fradet, Vincent; Witte, John S.

    2009-01-01

    Dietary intake of fish and ?–3 polyunsaturated fatty acids (?–3 PUFAs) may decrease the risk of prostate cancer development and progression to advanced stage disease. This could reflect the anti-inflammatory effects of PUFAs, possibly through mediation of cyclooxygenase (COX), a key enzyme in fatty acid metabolism and inflammation. Despite promising experimental evidence, epidemiological studies have reported somewhat conflicting results regarding the effects of fish/PUFAs on prostate cancer development and progression. The literature suggests that fish, and particularly long-chain ?–3 PUFAs, may have a more pronounced protective effect on biologically aggressive tumors or on their progression, and less on early steps of carcinogenesis. Moreover, the impact of LC ?–3 PUFAs may be modified by variation of the COX-2 gene. Overall, results to date support the hypothesis that long-chain ?–3 PUFAs may impact prostate inflammation and carcinogenesis via the COX-2 enzymatic pathway. PMID:19776642

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

    PubMed Central

    2010-01-01

    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

  2. Verhogen selectieve COX2-remmers en traditionele NSAID’s het risico op vasculaire problemen?

    Microsoft Academic Search

    P. L. B. Bruijnzeel

    2007-01-01

    Samenvatting  Kearny et al. onderzochten met behulp van een metaanalyse van gerandomiseerde onderzoeken in hoeverre selectieve COX-2-remmers\\u000a en traditionele NSAID’s het risico op vaatproblemen verhoogden 1. De gegevens die voor deze analyse gebruikt werden, waren\\u000a gebaseerd op resultaten die in Medline en Embase waren gerapporteerd tussen januari 1966 en april 2005, daarnaast gegevens\\u000a van de FDA en data van Novartis, Pfizer

  3. Citral, a component of lemongrass oil, activates PPAR? and ? and suppresses COX2 expression

    Microsoft Academic Search

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

    2010-01-01

    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

  4. COX2\\/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

    Microsoft Academic Search

    Satoko Yoshida; Hideki Amano; Izumi Hayashi; Hidero Kitasato; Mariko Kamata; Madoka Inukai; Hirokuni Yoshimura; Masataka Majima

    2003-01-01

    Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis

  5. Linkage Disequilibrium and Haplotype Analysis of COX-2 and Risk of Colorectal Adenoma Development

    PubMed Central

    Kwagyan, John; Apprey, Victor; Ashktorab, Hassan

    2012-01-01

    Single nucleotide polymorphisms (SNPs) in the promoter and untranslated region of cyclooxygenase (COX)-2, an inducible enzyme responsible for the synthesis of prostaglandins, have been reported to modulate the risk for many human cancers. We performed comprehensive linkage disequilibrium (LD) and haplotype analyses of 13 single nucleotide polymorphisms of the COX-2 gene and examined its susceptibility to adenoma development in 72 African American cases and 142 controls. Results revealed significant variation in LD patterns with consequence for adenoma development. Two distinct haplotype blocks were identified; one block covered the coding regions of exon 1, introns and a section of the 3?-unstranslated region (3?-UTR), whereas the second block resided solely in the 3?-UTR region. A haplotype in block 1 increased the risk of adenoma development by threefold (odds ratio [OR] = 2.9, confidence interval [CI] = 1.8–3.7, P = 0.002). Regression analysis showed, increase in copies of minor alleles of 6,064(T>C) polymorphism associated with increased odds of adenoma development by 80% (OR = 1.80, CI = 1.09–3.21, P = 0.034), 10,848(G>A) by 84% (OR = 1.84, CI = 1.05–3.23, P = 0.034) and 10,935(A>G) by 32% (OR = 1.32, CI = 1.12–3.69, P = 0.036). These results support the hypothesis that COX-2 gene might play a role in the etiology of colon cancer and warrant further investigation in other cancers. Besides, these variations should be taken into account for disease-based association studies in which the COX-2 polymorphism is considered as a candidate gene. PMID:22376259

  6. Design and synthesis of close analogs of LCRF-0004, a potent and selective RON receptor tyrosine kinase inhibitor.

    PubMed

    Raeppel, Stéphane L; Raeppel, Franck; Therrien, Eric

    2015-06-15

    New carboxamide head group analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent and selective inhibitors of RON enzyme versus c-Met RTK were obtained. PMID:25953155

  7. Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2.

    PubMed

    Ward, Richard A; Colclough, Nicola; Challinor, Mairi; Debreczeni, Judit E; Eckersley, Kay; Fairley, Gary; Feron, Lyman; Flemington, Vikki; Graham, Mark A; Greenwood, Ryan; Hopcroft, Philip; Howard, Tina D; James, Michael; Jones, Clifford D; Jones, Christopher R; Renshaw, Jonathan; Roberts, Karen; Snow, Lindsay; Tonge, Michael; Yeung, Kay

    2015-06-11

    The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action. PMID:25977981

  8. The effects of COX-2 anti-inflammatory drugs on soft tissue healing: a review of the literature.

    PubMed

    Randelli, Pietro; Randelli, F; Cabitza, P; Vaienti, L

    2010-01-01

    COX-2 specific inhibitors (coxibs) have become a popular treatment for musculoskeletal disorders given that the incidence of gastrointestinal side effects is lower with these drugs than with traditional non-steroidal anti-inflammatory drugs. The aim of this review is to discuss the results of animal studies investigating the role of coxibs in the healing of soft tissues. MEDLINE was searched (years 2001-2009) for studies analyzing the effect of coxibs on the healing of soft tissues. There are relatively few data in the literature suggesting that coxibs can impair soft tissue healing and the data existing have the limitation of having been generated in animal studies. In fact, the method of administration and the doses used make it difficult to translate these results to the clinical setting. Short-term use of coxibs following lesions to ligaments or tendons remains a prudent choice. Traditional anti-inflammatory drugs are a safer treatment for patients with a high cardiovascular risk. These drugs should, however, be evaluated carefully with regards to gastrointestinal events and their still poorly defined effect on tissue healing. PMID:20487623

  9. Tetrandrine inhibits proinflammatory cytokines, iNOS and COX-2 expression in human monocytic cells.

    PubMed

    Wu, Shu-Jing; Ng, Lean-Teik

    2007-01-01

    Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the dried root of hang-fang-chi (Stephania tetrandra S. Moore), is traditionally used in China for treating inflammation, hypertension and silicosis. In this study, our aim was to examine the anti-inflammatory mechanism of TET through measuring the inducible nitric oxide synthase (iNOS), cyclooxygenase-1, and -2 (COX-1 and COX-2) expression, cytokines (TNF-alpha, IL-4 and IL-8) formation, nitric oxide (NO) release and prostaglandin E2 (PGE2) generation in lipopolysaccharide (LPS)-induced human monocytic (THP-1) cells. Results showed that TET remarkably suppressed the LPS (1 microg/ml) induction of NO release and PGE2 generation. It also significantly attenuated the LPS-induced transcription of proinflammatory cytokines (TNF-alpha, IL-4 and IL-8) in a dose-dependent manner. Furthermore, TET at 100 microM significantly blocked the LPS induction of iNOS and COX-2 expression, but not the COX-1. Taken together, these results suggest that TET exerts anti-inflammatory effects probably through the suppression of COX-2 and iNOS expression. PMID:17202660

  10. Structural Characterization of the GSK-3? Active Site Using Selective and Non-selective ATP-mimetic Inhibitors

    Microsoft Academic Search

    J. A. Bertrand; S. Thieffine; A. Vulpetti; C. Cristiani; B. Valsasina; S. Knapp; H. M. Kalisz; M. Flocco

    2003-01-01

    GSK-3? is a regulatory serine\\/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3? may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3?, we determined crystal structures of unphosphorylated GSK-3? in complex with selective and non-selective ATP-mimetic

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

    PubMed Central

    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

    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

  12. Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol.

    PubMed

    Goedken, Eric R; Argiriadi, Maria A; Banach, David L; Fiamengo, Bryan A; Foley, Sage E; Frank, Kristine E; George, Jonathan S; Harris, Christopher M; Hobson, Adrian D; Ihle, David C; Marcotte, Douglas; Merta, Philip J; Michalak, Mark E; Murdock, Sara E; Tomlinson, Medha J; Voss, Jeffrey W

    2015-02-20

    The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases. PMID:25552479

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

    PubMed Central

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

    2014-01-01

    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

  14. Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors.

    PubMed

    Patel, Dipam; Jain, Mukul; Shah, Shailesh R; Bahekar, Rajesh; Jadav, Pradip; Joharapurkar, Amit; Dhanesha, Nirav; Shaikh, Mubeen; Sairam, Kalapatapu V V M; Kapadnis, Prashant

    2012-01-15

    A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM. PMID:22189136

  15. Basal Bone Phenotype and Increased Anabolic Responses to Intermittent Parathyroid Hormone in Healthy Male COX-2 Knockout Mice

    PubMed Central

    Xu, Manshan; Choudhary, Shilpa; Voznesensky, Olga; Gao, Qi; Adams, Douglas; Diaz-Doran, Vilmaris; Wu, Qian; Goltzman, David; Raisz, Lawrence G.; Pilbeam, Carol C.

    2011-01-01

    Cyclooxygenase-2 (COX-2) knockout (KO) mice in inbred strains can have renal dysfunction with secondary hyperparathyroidism (HPTH), making direct effects of COX-2 KO on bone difficult to assess. COX-2 KO mice in an outbred CD-1 background did not have renal dysfunction but still had two-fold elevated PTH compared to wild type (WT) mice. Compared to WT mice, KO mice had increased serum markers of bone turnover, decreased femoral bone mineral density (BMD) and cortical bone thickness, but no differences in trabecular bone volume by ?CT or dynamic histomorphometry. Because PTH is a potent inducer of COX-2 and prostaglandin (PG) production, we examined effects of COX-2 KO on bone responses after three weeks of intermittent PTH. Intermittent PTH increased femoral BMD and cortical bone area more in KO mice than in WT mice and increased trabecular bone volume in the distal femur in both WT and KO mice. Although not statistically significant, PTH-stimulated increases in trabecular bone tended to be greater in KO mice than in WT mice. PTH increased serum markers of bone formation and resorption more in KO than in WT mice but increased the ratio of osteoblastic surface to osteoclastic surface only in KO mice. PTH also increased femoral mineral apposition rates and bone formation rates in KO mice more than in WT mice. Acute mRNA responses to PTH of genes that might mediate some anabolic and catabolic effects of PTH tended to be greater in KO than WT mice. We conclude that (1) the basal bone phenotype in male COX-2 KO mice might reflect HPTH, COX-2 deficiency or both, and (2) increased responses to intermittent PTH in COX-2 KO mice, despite the presence of chronic HPTH, suggest that absence of COX-2 increased sensitivity to PTH. It is possible that manipulation of endogenous PGs could have important clinical implications for anabolic therapy with PTH. PMID:20471507

  16. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials

    Microsoft Academic Search

    Dean Fergusson; Steve Doucette; Kathleen Cranley Glass; Stan Shapiro; David Healy; Paul Hebert; Brian Hutton

    2005-01-01

    Objective To establish whether an association exists between use of selective serotonin reuptake inhibitors (SSRIs) and suicide attempts. Design Systematic review of randomised controlled trials. Data sources Medline and the Cochrane Collaboration's register of controlled trials (November 2004) for trials produced by the Cochrane depression, anxiety, and neurosis group. Selection of studies Studies had to be randomised controlled trials comparing

  17. Use of the selective serotonin reuptake inhibitor citalopram in the treatment of generalized social phobia

    Microsoft Academic Search

    Colin Bouwer; Dan J Stein

    1998-01-01

    Background: There is increasing evidence that social phobia responds to treatment with selective serotonin reuptake inhibitors (SSRIs). However, the efficacy of citalopram, the most selective of the SSRIs, in social phobia has not been well documented. Methods: Citalopram was used on an open-label naturalistic basis in 22 social phobia patients presenting for treatment (40 mg daily for 12 weeks). Patients

  18. A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis.

    PubMed

    Hernández-Torres, Gloria; Cipriano, Mariateresa; Hedén, Erika; Björklund, Emmelie; Canales, Ángeles; Zian, Debora; Feliú, Ana; Mecha, Miriam; Guaza, Carmen; Fowler, Christopher J; Ortega-Gutiérrez, Silvia; López-Rodríguez, María L

    2014-12-01

    Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18??M) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS. PMID:25298214

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

    PubMed

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

    2003-01-01

    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

  20. Insight into Binding of Phosphodiesterase-9A Selective Inhibitors by Crystal Structures and Mutagenesis

    SciTech Connect

    Wang, H.; Luo, X; Ye, M; Hou, J; Robinson, H; Ke, H

    2010-01-01

    PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC{sub 50} = 22 nM) and 1s (IC{sub 50} = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from few-fold to 3 orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity.

  1. Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors

    SciTech Connect

    Thal, David M.; Yeow, Raymond Y.; Schoenau, Christian; Huber, Jochen; Tesmer, John J.G. (Sanofi); (Michigan)

    2012-07-11

    G protein-coupled receptors (GPCRs) are key regulators of cell physiology and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compounds developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we determined crystal structures of the bovine GRK2-G{beta}{gamma} complex in the presence of two of these inhibitors. Comparison with the apoGRK2-G{beta}{gamma} structure demonstrates that the compounds bind in the kinase active site in a manner similar to that of the AGC kinase inhibitor balanol. Both balanol and the Takeda compounds induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homology modeling, we identified five amino acids surrounding the inhibitor binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain.

  2. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.

    PubMed

    Zhang, Zhuming; Ding, Qingjie; Liu, Jin-Jun; Zhang, Jing; Jiang, Nan; Chu, Xin-Jie; Bartkovitz, David; Luk, Kin-Chun; Janson, Cheryl; Tovar, Christian; Filipovic, Zoran M; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir T; Graves, Bradford

    2014-08-01

    The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994. PMID:24997575

  3. Natural and synthetic geiparvarins are strong and selective MAO-B inhibitors. Synthesis and SAR studies.

    PubMed

    Carotti, Angelo; Carrieri, Antonio; Chimichi, Stefano; Boccalini, Marco; Cosimelli, Barbara; Gnerre, Carmela; Carotti, Andrea; Carrupt, Pierre Alain; Testa, Bernard

    2002-12-16

    Natural geiparvarin 1 and a number of its analogues were prepared and tested as inhibitors of both monoamine oxidase isoforms, MAO-B and MAO-A. The desmethyl congener 6 of geiparvarin, proved potent and selective MAO-B inhibitor (pIC(50)=7.55 vs 4.62). X-ray crystallography and molecular modelling studies helped the understanding of the observed structure-activity relationships. PMID:12443774

  4. Discovery of selective irreversible inhibitors for EGFR-T790M

    Microsoft Academic Search

    Wenjun Zhou; Dalia Ercan; Pasi A. Jänne; Nathanael S. Gray

    2011-01-01

    Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M ‘gatekeeper’ resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was

  5. Corrosion inhibitor selection for arctic and subsea high-velocity flowlines

    SciTech Connect

    Dougherty, J.A.

    2000-03-01

    Qualifying corrosion inhibitors for use in high-velocity multiphase flowlines in arctic or subsea environments is discussed. The criteria include high-velocity flow loop corrosion tests, pumpability through 0.125-in. (0.318-cm) capillary at low temperatures, compatibility with nylon 11, emulsion tendency testing, and partitioning characteristics. Laboratory and field data show the importance of using these criteria for inhibitor selection.

  6. E2F1 Inhibits c-Myc-driven Apoptosis via PIK3CA/Akt/mTOR and COX-2 in a Mouse Model of Human Liver Cancer

    PubMed Central

    Ladu, Sara; Calvisi, Diego F.; Conner, Elizabeth A.; Farina, Miriam; Factor, Valentina M.; Thorgeirsson, Snorri S.

    2008-01-01

    Background & Aims Resistance to apoptosis is essential for cancer growth. We previously reported that hepatic co-expression of c-Myc and E2F1, two key regulators of proliferation and apoptosis, enhanced HCC development in transgenic mice. Here, we investigated the molecular mechanisms underlying oncogenic cooperation between c-Myc and E2F1 in relationship to human liver cancer. Methods Activation of pro- and anti-apoptotic cascades was assessed by immunoblotting in in vivo and in vitro HCC models, and in primary human HCC. Effect of antisense oligodeoxy nucleotides against c-Myc and E2F1 was studied in human HCC cell lines. Suppression of PIK3CA/AKT, mTOR, and COX-2 pathways was achieved by pharmacological inhibitors and specific siRNAs in human and mouse HCC cell lines. Results Co-expression with E2F1 did not increase proliferation triggered by c-Myc overexpression but conferred a strong resistance to c-Myc-initiated apoptosis via concomitant induction of PIK3CA/Akt/mTOR and c-Myb/COX-2 survival pathways. COX-2 was not induced in c-Myc and rarely in E2F1 tumors. In human HCC, PIK3CA/Akt/mTOR and c-Myb/COX-2 pathways were similarly activated, with levels of PIK3CA/Akt, mTOR, and c-Myb being inversely associated with patients’ survival length. Knocking down c-Myc and E2F1 oncoproteins reduced PIK3CA/Akt and mTOR and completely abolished c-Myb and COX-2 expression in human HCC cell lines. Finally, simultaneous inhibition of PIK3CA/Akt/mTOR and COX-2 activity in in vitro models caused massive apoptosis of neoplastic hepatocytes. Conclusion E2F1 may function as a critical anti-apoptotic factor both in human and rodent liver cancer through its ability to counteract c-Myc-driven apoptosis via activation of PIK3CA/Akt/mTOR and c-Myb/COX-2 pathways. PMID:18722373

  7. Cell death induction in resting lymphocytes by pan-Cdk inhibitor, but not by Cdk4/6 selective inhibitor.

    PubMed

    Kobayashi, Makiko; Takahashi-Suzuki, Ikuko; Shimomura, Toshiyasu; Iwasawa, Yoshikazu; Hirai, Hiroshi

    2011-10-01

    Immunosuppression is one of the common side effects of many anti-tumor agents targeting proliferating cells. We previously reported the development of a new class of pan-cyclin-dependent kinase (Cdk) inhibitor compounds that induce immunosuppression in rodents. Here, we demonstrated that a pan-Cdk inhibitor, Compound 1 very rapidly reduced white blood cells in mice, only 8 h after administration. Compound 1 induced death of peripheral blood cells or purified resting (non-stimulated) lymphocytes ex vivo. Cell death was induced very rapidly, after 4 h of incubation, suggesting that acute immunosuppression observed in rodents might be, at least in part, due to direct cytotoxic effects of Compound 1 on resting lymphocytes. While cell cycle-related Cdks were not activated, the carboxyl terminal domain (CTD) of the largest subunit of RNA polymerase II was phosphorylated, indicating activation of Cdk7 or Cdk9, which phosphorylates this domain, in resting lymphocytes. Indeed, the pan-Cdk inhibitor suppressed CTD phosphorylation in resting cells at the dose required for cell death induction. Inhibition of Cdk7 or Cdk9 by Compound 1 was also confirmed by suppression of nuclear factor-kappa B (NF-?B)-dependent transcription activity in the human cancer cell line U2OS. Interestingly, a Cdk4/6 inhibitor with selectivity against Cdk7 and Cdk9 did not induce cell death in resting lymphocytes. These results suggest that CTD phosphorylation possibly by Cdk7 or Cdk9 might be important for survival of resting lymphocytes and that Cdk inhibitors without inhibitory activity on these kinases might be an attractive agent for cancer chemotherapy. PMID:20524038

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

    PubMed

    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

    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

  9. Chemical inhibitors of CYP450 enzymes in liver microsomes: combining selectivity and unbound fractions to guide selection of appropriate concentration in phenotyping assays.

    PubMed

    Nirogi, Ramakrishna; Palacharla, Raghava Choudary; Uthukam, Venkatesham; Manoharan, Arunkumar; Srikakolapu, Surya Rao; Kalaikadhiban, Ilayaraja; Boggavarapu, Rajesh Kumar; Ponnamaneni, Ranjith Kumar; Ajjala, Devender Reddy; Bhyrapuneni, Gopinadh

    2015-02-01

    1.?Chemical inhibition is the widely used method in reaction phenotyping assays for estimation of specific enzyme contribution to a given metabolic pathway. The results from phenotyping assays depend on the selectivity of chemical inhibitor and the concentration of inhibitor used in the incubation. 2.?The higher protein concentrations used in the in vitro phenotyping assays will impact the inhibitory potency of chemical inhibitors. The objective of the study is to evaluate comprehensively the selectivity of chemical inhibitors and to guide in selecting appropriate concentration of the chemical inhibitors to be used in the phenotyping assays based on unbound fractions. 3.?Selectivity of chemical inhibitors against nine major CYP450 isoforms was determined in liver microsomes using standard probe substrates. The unbound fractions of the selective inhibitors were determined in human liver microsomes using high-throughput equilibrium dialysis. Combining unbound inhibitor concentrations that are required to inhibit the CYP450 activities by 90% and unbound fractions of the chemical inhibitors in liver microsomes appropriate total concentrations of the inhibitors to be used in the phenotyping assays were reported. 4.?The findings suggest that non-specific binding of the chemical inhibitors need to be taken into account while selecting concentrations for phenotyping assays. PMID:25070627

  10. Virtual screening of selective multitarget kinase inhibitors by combinatorial support vector machines.

    PubMed

    Ma, X H; Wang, R; Tan, C Y; Jiang, Y Y; Lu, T; Rao, H B; Li, X Y; Go, M L; Low, B C; Chen, Y Z

    2010-10-01

    Multitarget agents have been increasingly explored for enhancing efficacy and reducing countertarget activities and toxicities. Efficient virtual screening (VS) tools for searching selective multitarget agents are desired. Combinatorial support vector machines (C-SVM) were tested as VS tools for searching dual-inhibitors of 11 combinations of 9 anticancer kinase targets (EGFR, VEGFR, PDGFR, Src, FGFR, Lck, CDK1, CDK2, GSK3). C-SVM trained on 233-1,316 non-dual-inhibitors correctly identified 26.8%-57.3% (majority >36%) of the 56-230 intra-kinase-group dual-inhibitors (equivalent to the 50-70% yields of two independent individual target VS tools), and 12.2% of the 41 inter-kinase-group dual-inhibitors. C-SVM were fairly selective in misidentifying as dual-inhibitors 3.7%-48.1% (majority <20%) of the 233-1,316 non-dual-inhibitors of the same kinase pairs and 0.98%-4.77% of the 3,971-5,180 inhibitors of other kinases. C-SVM produced low false-hit rates in misidentifying as dual-inhibitors 1,746-4,817 (0.013%-0.036%) of the 13.56 M PubChem compounds, 12-175 (0.007%-0.104%) of the 168 K MDDR compounds, and 0-84 (0.0%-2.9%) of the 19,495-38,483 MDDR compounds similar to the known dual-inhibitors. C-SVM was compared to other VS methods Surflex-Dock, DOCK Blaster, kNN and PNN against the same sets of kinase inhibitors and the full set or subset of the 1.02 M Zinc clean-leads data set. C-SVM produced comparable dual-inhibitor yields, slightly better false-hit rates for kinase inhibitors, and significantly lower false-hit rates for the Zinc clean-leads data set. Combinatorial SVM showed promising potential for searching selective multitarget agents against intra-kinase-group kinases without explicit knowledge of multitarget agents. PMID:20712327

  11. Effects of selective cyclooxygenase-2 and non-selective COX inhibition on ischemic myocardium

    PubMed Central

    Robich, Michael P.; Chu, Louis M.; Feng, Jun; Burgess, Thomas A.; Laham, Roger J.; Bianchi, Cesario; Sellke, Frank W.

    2010-01-01

    Objective We sought to explore the effects of non-selective COX and selective COX-2 inhibition on collateral development in a model of chronic myocardial ischemia. We hypothesized that COX-2 inhibitors will negatively effect angiogenic and inflammatory pathways. Methods Yorkshire swine were made chronically ischemic by placing an ameroid constrictor on the left circumflex coronary artery. Swine were divided into three groups and given: no drug (control, n=7), a non-selective COX inhibitor (naproxen 400mg daily, NAP, n=7), or a selective COX-2 inhibitor (celecoxib 200mg daily, CBX, n=7). After 7 weeks, coronary angiography was performed. Myocardial function and microvascular reactivity were assessed. Serum and myocardial tissue were analyzed for prostaglandin levels and markers of inflammation and angiogenesis. Results The CBX group demonstrated significantly increased mean arterial pressure and decreased left ventricular function. Myocardial perfusion in the CBX group was similar to the control, but less than in the NAP group. Coronary microvascular contraction in the collateral dependent territory was increased in the NAP group, but minimally affected in the CBX group. Oxidative stress and apoptosis were increased in the CBX group. Expression of angiogenic markers, VEGF and phospho-eNOS (ser1177), and tissue levels of prostacyclin were decreased in both the CBX and NAP groups. The NAP group had diminished expression of endostatin. Conclusion The effects of selective and non-selective COX inhibition are more complex than previously published, but they do not decrease collateral dependent blood flow to the myocardium in our model of chronic myocardial ischemia. PMID:20804993

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

    PubMed Central

    Ji, Haitao; Gómez-Vidal, José A.; Martásek, Pavel; Roman, Linda J.; Silverman, Richard B.

    2008-01-01

    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

  13. Specific inhibition of cyclooxygenase-2 (COX2) expression by dietary curcumin in HT29 human colon cancer cells q

    Microsoft Academic Search

    Ajay Goel; C. Richard Boland; Dharam P. Chauhan

    2001-01-01

    Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti- cancer activities. Cyclooxygenase (COX)-2 plays an important role in colon carcinogenesis. To investigate the effect of curcumin on COX-2 expression, we treated HT-29 human colon cancer cells with various concentrations of curcumin. Curcumin inhibited the cell growth of HT-29 cells in a

  14. Effects of COX2 inhibition on expression of vascular endothelial growth factor and interleukin-8 in lung cancer cells

    Microsoft Academic Search

    Yong Ming Zhu; Nor Saadah M Azahri; Danny CW Yu; Penella J Woll

    2008-01-01

    BACKGROUND: Cyclooxygenase (COX)-2 has been implicated in tumour progression, angiogenesis and metastasis in non-small cell lung cancer (NSCLC). We speculated that inhibition of COX-2 activity might reduce expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in lung cancer cells. METHODS: The levels of IL-8, VEGF and prostaglandin E2 (PGE2) were measured by ELISA. Expression of

  15. Quantitative Analysis of Breast Cancer Tissue Microarrays Shows High Cox2 Expression Is Associated with Poor Outcome

    Microsoft Academic Search

    Maciej P. Zerkowski; Robert L. Camp; Barbara A. Burtness; David L. Rimm; Gina G. Chung

    2007-01-01

    Epidemiologic and preclinical studies suggest that cyclooxygenase-2 (Cox-2) may promote tumor growth and spread by affecting angiogenesis and apoptosis in breast cancer. Using a tissue microarray (TMA), we analyzed the expression and subcellular localization of Cox-2 by AQUA and X-tile, our algorithms for quantitative analysis of protein expression and determi- nation of optimal cutpoints. Our TMA consisted of 669 Stage

  16. Expression of COX2 in gastric mucosa of atrophic gastritis caused by hot high-salt water in rats

    Microsoft Academic Search

    Mei Tao; Li Zhang; Ling-Xia Zhang; Mei Jiang; Guang-Zhou Cao

    2004-01-01

    AIM: To measure the expression of COX-2 in gastric mucosa of chronic atrophic gastritis (CAG) caused by hot high-salt water in rats and to study the pathogenesis of atrophic gastritis caused by hot high-salt diet. METHODS: The atrophic gastritis rat model was made by hot high-salt water ig perfusion. The expression of COX-2 in gastric mucosa in 4, 8, 12,

  17. Modulation of the activity of pro-inflammatory enzymes, COX2 and iNOS, by chrysin derivatives

    Microsoft Academic Search

    Heeyeong Cho; Cheol-Won Yun; Woo-Kyu Park; Jae-Yang Kong; Kyoung Soon Kim; Sanghyun Lee; Bak-Kwang Kim

    2004-01-01

    Chrysin, a natural flavone compound found in plants, has anti-inflammatory activity that has been previously explained in part by the suppression of promoter activities of pro-inflammatory enzymes, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Here we present evidence that several chrysin derivatives modulate the activities, as well as the expression, of COX-2 and iNOS enzymes. Nitrate production triggered by

  18. Specific inhibition of cyclooxygenase-2 (COX2) expression by dietary curcumin in HT29 human colon cancer cells

    Microsoft Academic Search

    Ajay Goel; C. Richard Boland; Dharam P Chauhan

    2001-01-01

    Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Cyclooxygenase (COX)-2 plays an important role in colon carcinogenesis. To investigate the effect of curcumin on COX-2 expression, we treated HT-29 human colon cancer cells with various concentrations of curcumin. Curcumin inhibited the cell growth of HT-29 cells in a concentration-

  19. Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase.

    PubMed

    Veale, Clinton G L; Zoraghi, Roya; Young, Ryan M; Morrison, James P; Pretheeban, Manoja; Lobb, Kevin A; Reiner, Neil E; Andersen, Raymond J; Davies-Coleman, Michael T

    2015-03-27

    As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity. PMID:25372480

  20. The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity

    SciTech Connect

    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

    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.

  1. Role of COX-1 and COX-2 on skin PGs biosynthesis by mechanical scratching in mice.

    PubMed

    Sugimoto, M; Arai, I; Futaki, N; Hashimoto, Y; Honma, Y; Nakaike, S

    2006-07-01

    We examined the involvement of cyclooxygenase (COX)-1 and COX-2 on mechanical scratching-induced prostaglandins (PGs) production in the skin of mice. The dorsal regions of mice were scratched using a stainless brush. COXs expressions in the skin were analyzed using real-time PCR and Western blotting. The effect of acetylsalicylic acid (ASA) on the ability of PGs production were determined based on skin PGs level induced by arachidonic acid (AA) application. Mechanical scratching increased PGD2, PGE2, PGI2 and PGF(2 alpha). COX-1 was constitutively expressed and COX-2 expression was enhanced by scratching. Intravenous administration of ASA inhibited PGs biosynthesis in the normal skin. PGs levels of the skin 6h after ASA administration (ASA 6 h) were almost equal to those of the skin 10 min after ASA administration (ASA 10 min). In the scratched skin, AA-induced PGE2 and PGI2 of ASA 6 h were significantly higher than those of ASA 10 min. The skin PGD2 and PGF(2 alpha) of ASA 10 min were almost same to those of ASA 6 h. In the normal skin of COX-1-deficient mice, skin PGD2 level was lower than that of wild-type mice, although PGE2, PGI2 and PGF(2 alpha) levels were almost equal to those of wild type. In the scratched skin of COX-1-deficient mice, PGD2, PGE2, PGI2 and PGF(2 alpha) levels were lower than those of wild-type mice. These results suggested that cutaneous PGD2 could be mainly produced by COX-1, and PGE2 and PGI2 could be produced by COX-1 and COX-2, respectively, in mice. PMID:16815697

  2. Contribution of tomato phenolics to suppression of COX-2 expression in KB cells.

    PubMed

    Shen, Y-C; Chen, S-L; Zhuang, S-R; Wang, C-K

    2008-01-01

    Tomatoes, which are consumed worldwide, contain abundant phenolics. The objective of this study was to understand the suppression effect of phenolics in fresh and heated tomatoes on the expression of cyclooxygenase 2 (COX-2). Both small and big tomatoes of fresh or heated (in boiling water for 30 min) treatments were used. Sephadex LH-20 gel was used to separate the noncondensed tannin containing and the condensed tannin containing fractions from the crude phenolic extracts of tomatoes. The condensed tannin containing fraction was rich in condensed tannins and simple phenolics. The noncondensed tannin containing fraction contained abundant nontannin flavans. This study explored the effect of tomato phenolic extracts on the regulation of 12-o-teradecanoylphorbol-13-acetate (TPA)-induced inflammatory responses in KB cells. HPLC showed that tomato phenolic profiles were similar between small and big tomatoes either by fresh or heated treatment. Fresh tomato extracts had 70.8 +/- 4.8% (mean +/- SD) noncondensed tannin containing polyphenols (6.68 +/- 0.09 mg/g dry weight), 27.4 +/- 6.9% condensed tannin containing polyphenols (3.52 +/- 0.24 mg/g dry weight), and 1.7 +/- 0.6% other residues. Instead, heated tomato had 53.3 +/- 4.3% noncondensed tannin containing polyphenols (2.70 +/- 0.20 mg/g dry weight), 24.2 +/- 1.7% condensed tannin containing polyphenols (7.37 +/- 0.03 mg/g dry weight), and 22.5 +/- 4.8% other residues. Cell studies showed that phenolic extracts of heated tomatoes resulted in increased suppression of COX-2 expression compared with that of fresh tomato. Noncondensed tannin containing fraction of fresh tomato greatly suppressed COX-2 expression (P < 0.05) that compared to the negative control, but both noncondensed tannin containing and condensed tannin containing fractions of heated tomatoes showed suppression on COX-2 expression. These results suggest that tomato phenolics may play an important role in the chemoprevention of cancer. PMID:18211342

  3. [The possibility of selective Rho-associated kinase (ROCK) inhibitors as a medical treatment for glaucoma].

    PubMed

    Honjo, Megumi

    2009-11-01

    Some of the cytokines and growth factors in the aqueous humor activate Rho, and the Rho/ROCK signal transduction participates in signaling pathways via rearrangement of actin cytoskeleton that leads to various cellular reactions. In a previous study, we demonstrated that a selective ROCK inhibitor significantly reduced intraocular pressure, the mechanism of which was attributed to improved outflow. ROCK inhibitors induced the actomyosin assembly, cell adhesive interactions, and the expression of extracellular matrix (ECM) proteins in cultured TM cells. The inhibition of Rho also has been implicated in pathological wound healing by regulating neovascularization, migration, and ECM in scar tissue. In this study, we investigated the role of ROCK inhibitor in regulating human Tenon fibroblast (HTF) activity and postoperative scar formation in a rabbit sclerostomy model. ROCK inhibitor showed decreased aSMA expression in HTF, and prevented enhanced contractility, assembly of actin stress fibers, and myofibroblastic transdifferentiation. In vivo sclerostomy studies showed that the bleb survival was significantly improved in ROCK inhibitor-treated eyes. In another study by us, ROCK inhibitor showed neuroprotective effects against rat retinal ischemia reperfusion injury. Collectively, ROCK inhibitors are thus a potential new strategy for developing medical therapy for glaucomatous dis- PMID:19994585

  4. Development of a cell-selective and intrinsically active multikinase inhibitor bioconjugate.

    PubMed

    Harmsen, Stefan; Dolman, M Emmy M; Nemes, Zoltan; Lacombe, Marie; Szokol, Bálint; Pató, János; Kéri, György; Orfi, László; Storm, Gert; Hennink, Wim E; Kok, Robbert J

    2011-04-20

    Multikinase inhibitors are potent anticancer drugs that simultaneously intervene in multiple related signaling cascades, thus being capable of blocking salvage pathways that may play a role in the development of drug resistance. Multikinase inhibitors are increasingly evaluated for indications other than cancer, but long-term safety risks dictated by off-organ toxicities of these agents may prevent their safe and effective use. Here, we describe a new approach in which platinum coordination chemistry is applied for the development of a cell-selective multikinase inhibitor bioconjugate. The platinum(II) kinase inhibitor bioconjugate was designed to be active with the linker attached to the inhibitor and displayed improved activity by enhanced cell specificity as well as enhanced intracellular retention, thereby prolonging its pharmacological activity. In addition, the utilized platinum-based linkage technology potentiated the inhibitory activity of the multikinase inhibitor. These features in combination with carrier-mediated uptake in the target cells may revolutionize dosing regimens and safety profiles of (multi)kinase inhibitors. PMID:21443263

  5. The selectivity of statine-based inhibitors against various human aspartic proteinases.

    PubMed

    Jupp, R A; Dunn, B M; Jacobs, J W; Vlasuk, G; Arcuri, K E; Veber, D F; Perlow, D S; Payne, L S; Boger, J; de Laszlo, S

    1990-02-01

    The interactions of five human enzymes (renin, pepsin, gastricsin, cathepsin D and cathepsin E) and the aspartic proteinase from Endothia parasitica with several series of synthetic inhibitors were examined. All of the inhibitors contained the dipeptide analogue statine or its phenylalanine or cyclohexylalanine homologues in the P1-P1' positions. The residues occupying the peripheral sub-sites (P4 to P3') were varied systematically and inhibitory constants were determined for the interactions with each of the proteinases. Inhibitors were elucidated that specifically inhibited human renin and did not affect any of the other human enzymes or the fungal proteinase. With suitable selection of residues to occupy individual sub-sites, effective inhibitors of specific human aspartic proteinases may now be designed. PMID:2407237

  6. The selectivity of statine-based inhibitors against various human aspartic proteinases.

    PubMed Central

    Jupp, R A; Dunn, B M; Jacobs, J W; Vlasuk, G; Arcuri, K E; Veber, D F; Perlow, D S; Payne, L S; Boger, J; de Laszlo, S

    1990-01-01

    The interactions of five human enzymes (renin, pepsin, gastricsin, cathepsin D and cathepsin E) and the aspartic proteinase from Endothia parasitica with several series of synthetic inhibitors were examined. All of the inhibitors contained the dipeptide analogue statine or its phenylalanine or cyclohexylalanine homologues in the P1-P1' positions. The residues occupying the peripheral sub-sites (P4 to P3') were varied systematically and inhibitory constants were determined for the interactions with each of the proteinases. Inhibitors were elucidated that specifically inhibited human renin and did not affect any of the other human enzymes or the fungal proteinase. With suitable selection of residues to occupy individual sub-sites, effective inhibitors of specific human aspartic proteinases may now be designed. PMID:2407237

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

    PubMed Central

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

    2013-01-01

    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

  8. Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors

    PubMed Central

    Liu, Feng; Li, Fengling; Ma, Anqi; Dobrovetsky, Elena; Dong, Aiping; Gao, Cen; Korboukh, Ilia; Liu, Jing; Smil, David; Brown, Peter J.; Frye, Stephen V.; Arrowsmith, Cheryl H.; Schapira, Matthieu; Vedadi, Masoud; Jin, Jian

    2015-01-01

    Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in cancer via interaction with the DAL-1 tumor suppressor protein. However, few selective inhibitors of PRMTs have been discovered. We recently disclosed the first selective PRMT3 inhibitor, which occupies a novel allosteric binding site and is noncompetitive with both the peptide substrate and cofactor. Here we report comprehensive structure–activity relationship studies of this series, which resulted in the discovery of multiple PRMT3 inhibitors with submicromolar potencies. An X-ray crystal structure of compound 14u in complex with PRMT3 confirmed that this inhibitor occupied the same allosteric binding site as our initial lead compound. These studies provide the first experimental evidence that potent and selective inhibitors can be created by exploiting the allosteric binding site of PRMT3. PMID:23445220

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

    PubMed Central

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

    2010-01-01

    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

  10. Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor

    SciTech Connect

    Lountos, George T.; Tropea, Joseph E.; Zhang, Di; Jobson, Andrew G.; Pommier, Yves; Shoemaker, Robert H.; Waugh, David S.; (NCI)

    2009-03-05

    Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC{sub 50} = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

  11. Selective inhibitors of digestive enzymes from Aedes aegypti larvae identified by phage display.

    PubMed

    Soares, Tatiane Sanches; Soares Torquato, Ricardo Jose; Alves Lemos, Francisco Jose; Tanaka, Aparecida Sadae

    2013-01-01

    Dengue is a serious disease transmitted by the mosquito Aedes aegypti during blood meal feeding. It is estimated that the dengue virus is transmitted to millions of individuals each year in tropical and subtropical areas. Dengue control strategies have been based on controlling the vector, Ae. aegypti, using insecticide, but the emergence of resistance poses new challenges. The aim of this study was the identification of specific protease inhibitors of the digestive enzymes from Ae. aegypti larvae, which may serve as a prospective alternative biocontrol method. High affinity protein inhibitors were selected by all of the digestive serine proteases of the 4th instar larval midgut, and the specificity of these inhibitors was characterized. These inhibitors were obtained from a phage library displaying variants of HiTI, a trypsin inhibitor from Haematobia irritans, that are mutated in the reactive loop (P1-P4'). Based on the selected amino acid sequence pattern, seven HiTI inhibitor variants were cloned, expressed and purified. The results indicate that the HiTI variants named T6 (RGGAV) and T128 (WNEGL) were selected by larval trypsin-like (IC(50) of 1.1 nM) and chymotrypsin-like enzymes (IC(50) of 11.6 nM), respectively. The variants T23 (LLGGL) and T149 (GGVWR) inhibited both larval chymotrypsin-like (IC(50) of 4.2 nM and 29.0 nM, respectively) and elastase-like enzymes (IC(50) of 1.2 nM for both). Specific inhibitors were successfully obtained for the digestive enzymes of Ae. aegypti larvae by phage display. Our data also strongly suggest the presence of elastase-like enzymes in Ae. aegypti larvae. The HiTI variants T6 and T23 are good candidates for the development as a larvicide to control the vector. PMID:23142191

  12. Copper-aspirin complex inhibits cyclooxygenase-2 more selectively than aspirin.

    PubMed

    Yun, Yu; Chen, Peng; Zheng, Chun Lan; Yang, Yong; Duan, Wei Gang; Wang, Lei; He, Bo; Ma, Jia Qing; Wang, Dian Hua; Shen, Zhi Qiang

    2007-11-01

    The antiinflammatory effects of the copper-aspirin complex (Cu-Asp) were more potent than that of Asp in rats or mice with fewer classic adverse effects. The aim of this study was to determine the cause by evaluating Cu-Asp selective inhibition on cyclooxygenases (COX). COX-1 inhibition was evaluated based on 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)) in an endothelial cell model, and COX-2 inhibition was based on prostaglandin E(2) (PGE(2)) in a macrophage model. Radioimmunoassay (RIA) was applied to determine 6-keto-PGF(1alpha) in resting human umbilical vein endothelial cell line (ECV304), and PGE(2) in activated macrophages. The results showed that the inhibition of 6-keto-PGF(1alpha) yield by Cu-Asp (3 to 0.01 mM) was markedly weaker than that by aspirin (Asp); while the inhibition of PGE(2) yield by Cu-Asp (10 to 0.1 mM) was significantly stronger than that by Asp. Based on the inhibition on 6-keto-PGF(1alpha) and PGE(2), the medium inhibitory concentration (IC(50)) of Cu-Asp on COX-1 and on COX-2 was 1.03+/-0.15 mM, and 0.32+/-0.04 mM, respectively. The selective inhibition index on COX-2, IC(50) (COX-1)/IC(50) (COX-2), of Cu-Asp was 3.33+/-0.89, while that of Asp was 0.42+/-0.12. The results suggest that, unlike Asp, Cu-Asp is a relatively selective inhibitor of COX-2 in the present models; the selectivity of Cu-Asp is about seven-fold greater than that of Asp. PMID:17978563

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

    PubMed Central

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

    2013-01-01

    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

  14. Influence of selective inhibitors of phosphodiesterase 3 and 4 on cough and airway reactivity.

    PubMed

    Mokry, J; Mokra, D; Nosalova, G; Beharkova, M; Feherova, Z

    2008-12-01

    As the administration of many antitussive drugs is often associated with adverse effects, new alternatives are evaluated in experimental and clinical conditions. The aim of this study was to assess the influence of selective inhibitors of PDE3 (cilostazol) and PDE4 (citalopram) on cough and airway reactivity. The number of cough efforts, specific airway resistance, in vitro airway reactivity, and differential blood cells count were measured in healthy and in ovalbumin-sensitized guinea pigs before and after administration of cilostazol or citalopram (1 mg/kg). Cilostazol significantly suppressed citric acid induced cough only in healthy guinea pigs, whereas citalopram in both healthy and ovalbumin-sensitized animals. Both PDE inhibitors decreased in vivo and in vitro airway reactivity to histamine and the count of monocytes and neutrophils, confirming their anti-inflammatory potential. Administration of selective PDE3 and PDE4 inhibitors may influence cough and airway reactivity in the model of ovalbumin-sensitized guinea pigs. PMID:19218671

  15. 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site

    PubMed Central

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

    2011-01-01

    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 noncompetitive 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

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

    PubMed Central

    2014-01-01

    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

  17. Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.

    PubMed

    Brullo, Chiara; Massa, Matteo; Villa, Carla; Ricciarelli, Roberta; Rivera, Daniela; Pronzato, Maria Adelaide; Fedele, Ernesto; Barocelli, Elisabetta; Bertoni, Simona; Flammini, Lisa; Bruno, Olga

    2015-07-01

    A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity. PMID:25936260

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

    ERIC Educational Resources Information Center

    Scharko, Alexander M.

    2004-01-01

    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.…

  19. The treatment of depression in UK general practice: selective serotonin reuptake inhibitors and tricyclic antidepressants compared

    Microsoft Academic Search

    R. A Lawrenson; F Tyrer; R. B Newson; R. D. T Farmer

    2000-01-01

    Background: Antidepressants are commonly prescribed by general practitioners as treatment for depression. Controversy exists as to the effectiveness in everyday use of the older tricyclic antidepressants (TCAs) when compared to the newer selective serotonin reuptake inhibitors (SSRIs). Aim: To investigate the patterns of current prescribing of antidepressants for the treatment of depression and compare TCAs with the newer SSRIs. Method:

  20. Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety

    Microsoft Academic Search

    Justine M Kent; Jeremy D Coplan; Jack M Gorman

    1998-01-01

    The selective serotonin reuptake inhibitors (SSRIs) are now being employed in the treatment of the full spectrum of anxiety disorders. In comparative trials, the SSRIs are proving to be equal or superior in efficacy to traditional antianxiety medications. Due to their favorable side effect profile, safety, and tolerability, they are rapidly replacing older agents in the treatment of anxiety. Neuroanatomical

  1. Preoperative use of selective COX-II inhibitors for pain management in laparoscopic nissen fundoplication

    Microsoft Academic Search

    Z. Alanoglu; Y. Ate?; B. C. Orbey; A. G. Türkçapar

    2005-01-01

    Background: This randomized, double-blind, prospective, placebo controlled study was planned to determine the effectiveness of selective COX-II inhibitors used preoperatively to alleviate pain after Nissen fundoplication surgery. Methods: For this study, 60 patients were allocated to four groups at random: group C (celecoxib, 200 mg by mouth), group R (rofecoxib, 50 mg by mouth), group P (placebo, pill), or group

  2. Lines of Evidence on the Risks of Suicide with Selective Serotonin Reuptake Inhibitors

    Microsoft Academic Search

    David Healy

    2003-01-01

    Background: There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. Methods: Starting from the clinical studies that gave rise to this issue, this paper reviews an unselected cohort of randomized clinical trials (RCTs), a series of meta-analyses undertaken to investigate aspects of the problem, studies in recurrent

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

    PubMed Central

    2011-01-01

    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

  4. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: A systematic review

    Microsoft Academic Search

    H. G. Ruhe; Jochanan Huyser; Jan A. Swinkels; Aart H. Schene

    2006-01-01

    Objective: Selective serotonin reuptake inhibitors (SSRIs) are frequently used as a first antidepressant for major depressive disorder but have response rates of 50% to 60% in daily practice. For patients with insufficient response to SSRIs, switching is often applied. This article aims to systematically review the evidence for switching pharmacotherapy after a first SSRI. Data Sources: A systematic literature search

  5. A New Generation of Hsp90 Inhibitors: Addressing Isoform Selectivity and Heat Shock Induction

    E-print Network

    Duerfeldt, Adam Scott

    2011-12-31

    necrosis factor receptor-associated protein (TRAP-1) is the Hsp90 isoform localized to the mitchondria and to date, no specific clients or selective inhibitors have been identified. The fourth isoform is glucose-regulated protein 94 kDa (Grp94), which...

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

    ERIC Educational Resources Information Center

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

    2014-01-01

    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.…

  7. Molecular dynamics simulations of human DNA methyltransferase 3B with selective inhibitor nanaomycin A

    Microsoft Academic Search

    Thomas Caulfield; José L. Medina-Franco

    2011-01-01

    DNA methyltransferases (DNMTs) are involved in epigenetic regulation of the genome and are promising targets for therapeutic intervention in cancer and other diseases. Until now, very limited information is available concerning the molecular dynamics of DNMTs. The natural product nanaomycin A is the first selective inhibitor of DNMT3B that induce genomic demethylation. Herein we report long (>100ns) molecular dynamics simulations

  8. Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells

    Microsoft Academic Search

    Adamantios Serafeim; Michelle J. Holder; Gillian Grafton; Anita Chamba; Mark T. Drayson; Quang T. Luong; Christopher M. Bunce; Christopher D. Gregory; Nicholas M. Barnes; John Gordon

    2003-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety- related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structur- ally distinct SSRIs—fluoxetine, parox- etine, and citalopram—act directly on Bur- kitt lymphoma (BL) cells to trigger

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

    PubMed

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

    2013-12-01

    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

  10. SD0006: A Potent, Selective and Orally Available Inhibitor of p38 Kinase

    Microsoft Academic Search

    Barry L. Burnette; Shaun Selness; Raj Devraj; Gail Jungbluth; Ravi Kurumbail; Loreen Stillwell; Gary Anderson; Stephen Mnich; Jeffrey Hirsch; Robert Compton; Pamela De Ciechi; Heidi Hope; Michael Hepperle; Robert H. Keith; Win Naing; Huey Shieh; Joseph Portanova; Yan Zhang; Jian Zhang; Richard M. Leimgruber; Joseph Monahan

    2009-01-01

    SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-? (p38?). In vitro, SD0006 was selective for p38? kinase over 50 other kinases screened (including p38? and p38? with modest selectivity over p38?). Crystal structures with p38? show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38? that can confer

  11. Synthesis of selective SRPK-1 inhibitors: novel tricyclic quinoxaline derivatives.

    PubMed

    Székelyhidi, Zsolt; Pató, János; Wáczek, Frigyes; Bánhegyi, Péter; Hegymegi-Barakonyi, Bálint; Erös, Dániel; Mészáros, György; Hollósy, Ferenc; Hafenbradl, Doris; Obert, Sabine; Klebl, Bert; Kéri, György; Orfi, László

    2005-07-01

    SR protein-specific kinase-1 (SRPK-1) has been identified as a validated target for hepatitis B virus (HBV). A series of novel tricyclic quinoxaline derivatives was designed and synthesised as potential kinase inhibitory antiviral agents and was found to be active and selective for SRPK-1 kinase. Most of these novel compounds have drug-like properties according to experimentally determined LogP and LogS values. PMID:15925511

  12. Tethering Small Molecules to a Phage Display Library: Discovery of a Selective Bivalent Inhibitor of Protein Kinase A

    E-print Network

    Ghosh, Indraneel

    Tethering Small Molecules to a Phage Display Library: Discovery of a Selective Bivalent Inhibitor pocket, often displaying high affinity. While this has produced therapeutically useful inhibitors describe a noncovalent tethering strategy that would select for cyclic peptides from a phage display

  13. Cox2 and ?-Catenin/T-cell Factor Signaling Intestinalize Human Esophageal Keratinocytes When Cultured under Organotypic Conditions12

    PubMed Central

    Kong, Jianping; Crissey, Mary Ann S; Stairs, Douglas B; Sepulveda, Antonia R; Lynch, John P

    2011-01-01

    The incidence of esophageal adenocarcinoma (EAC) is rising in the United States. An important risk factor for EAC is the presence of Barrett esophagus (BE). BE is the replacement of normal squamous esophageal epithelium with a specialized columnar epithelium in response to chronic acid and bile reflux. However, the emergence of BE from squamous keratinocytes has not yet been demonstrated. Our research has focused on this. Wnt and cyclooxygenase 2 (Cox2) are two pathways whose activation has been associated with BE and progression to EAC, but their role has not been tested experimentally. To explore their contribution, we engineered a human esophageal keratinocyte cell line to express either a dominant-active Wnt effector CatCLef or a Cox2 complementary DNA. In a two-dimensional culture environment, Cox2 expression increases cell proliferation and migration, but neither transgene induces known BE markers. In contrast, when these cells were placed into three-dimensional organotypic culture conditions, we observed more profound effects. CatCLef-expressing cells were more proliferative, developed a thicker epithelium, and upregulated Notch signaling and several BE markers including NHE2. Cox2 expression also increased cell proliferation and induced a thicker epithelium. More importantly, we observed cysts form within the epithelium, filled with intestinal mucins including Muc5B and Muc17. This suggests that Cox2 expression in a three-dimensional culture environment induces a lineage of mucin-secreting cells and supports an important causal role for Cox2 in BE pathogenesis. We conclude that in vitro modeling of BE pathogenesis can be improved by enhancing Wnt signaling and Cox2 activity and using three-dimensional organotypic culture conditions. PMID:21969813

  14. Selectivity and binding kinetics of mTOR inhibitors Kinome-wide selectivity profiling of ATP-competitive mTOR (mammalian target of rapamycin)

    E-print Network

    Sabatini, David M.

    -582-8590, Fax: 617-582- 8615, Email: Nathanael_Gray@dfci.harvard.edu. Key Words: mTOR, PI3K, RET, JAKs, Torin1Selectivity and binding kinetics of mTOR inhibitors 1 Kinome-wide selectivity profiling of ATP-competitive mTOR (mammalian target of rapamycin) inhibitors and characterization of their binding kinetics

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

    PubMed Central

    Siu, Fung-Ming; Pommier, Yves

    2013-01-01

    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

  16. Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.

    PubMed

    Dudutien?, Virginija; Matulien?, Jurgita; Smirnov, Alexey; Timm, David D; Zubrien?, Asta; Baranauskien?, Lina; Mork?naite, Vaida; Smirnovien?, Joana; Michailovien?, Vilma; Juozapaitien?, Vaida; Mickevi?i?t?, Aurelija; Kazokait?, Justina; Bakšyt?, Sandra; Kasiliauskait?, Aist?; Jachno, Jelena; Revuckien?, Jurgita; Kišonait?, Migl?; Pilipuityt?, Vilma; Ivanauskait?, Egl?; Milinavi?i?t?, Goda; Smirnovas, Vytautas; Petrikait?, Vilma; Kairys, Visvaldas; Petrauskas, Vytautas; Norvaišas, Povilas; Ling?, Darius; Gibieža, Paulius; Capkauskait?, Edita; Zakšauskas, Audrius; Kazlauskas, Egidijus; Manakova, Elena; Gražulis, Saulius; Ladbury, John E; Matulis, Daumantas

    2014-11-26

    Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX. PMID:25358084

  17. 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance.

    PubMed

    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

    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

  18. Kinetic basis for selective inhibition of cyclo-oxygenases.

    PubMed Central

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

    1999-01-01

    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

  19. Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung.

    PubMed

    Shiosaki, K; Tasker, A S; Sullivan, G M; Sorensen, B K; von Geldern, T W; Wu-Wong, J R; Marselle, C A; Opgenorth, T J

    1993-02-19

    Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors. PMID:8474103

  20. Use of selective opiate receptor inhibitors to prevent postoperative ileus.

    PubMed

    Akça, O; Doufas, A G; Sessler, D I

    2002-04-01

    Ileus is a common postoperative complication after major abdominal surgery. Surgical manipulation of the bowel and stimulation of opiod receptor are the main causes of ileus. An investigational drug (ADL 8-2698, Alvinopam) a selective opioid antagonist with a very low oral absorption was recently introduced to clinical medicine. Unlike other opioid antagonist its activity is restricted to GI tract, it is potent, has a long duration of action, is orally effective, does not readily cross the blood-brain barrier even after intravenous administration in animals. Two randomized controlled clinical studies tested its effects in humans. Liu et al.'s study confirmed peripheral restriction of ADL 8-2698 by its lack of central effect on morphine analgesia and pupil miosis. They also showed that ADL 8-2698 prevents increases in gastrointestinal transit time. Taguchi et al. concluded that high dose (6 mg) of ADL 8-2698 archived fast recovery of gastrointestinal function, without antagonising analgesic efficacy of systemic opioid. In summary, selective inhibition of gastrointestinal opioid receptor by a peripherally restricted oral antagonist speeds recovery of bowel function, shortens times of hospitalization and preserves the analgesic effects of opiods. PMID:12024075

  1. 5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors

    SciTech Connect

    Das, Jagabandhu; Moquin, Robert V.; Dyckman, Alaric J.; Li, Tianle; Pitt, Sidney; Zhang, Rosemary; Shen, Ding Ren; McIntyre, Kim W.; Gillooly, Kathleen; Doweyko, Arthur M.; Newitt, John A.; Sack, John S.; Zhang, Hongjian; Kiefer, Susan E.; Kish, Kevin; McKinnon, Murray; Barrish, Joel C.; Dodd, John H.; Schieven, Gary L.; Leftheris, Katerina (BMS)

    2012-02-07

    The synthesis and structure-activity relationships (SAR) of p38{alpha} MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38{alpha} MAP kinase with excellent cellular potency toward the inhibition of TNF{alpha} production. Compound 2j was highly efficacious in vivo in inhibiting TNF{alpha} production in an acute murine model of TNF{alpha} production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38{alpha} is also disclosed.

  2. Pyrazolo-Pyrimidines: A Novel Heterocyclic Scaffold for Potent and Selective p38alpha Inhibitors

    SciTech Connect

    Das,J.; Moquin, R.; Pitt, S.; Zhang, R.; Shen, D.; McIntyre, K.; Gillooly, K.; Doweyko, A.; Sack, J.; et al

    2008-01-01

    The synthesis and structure-activity relationships (SAR) of p38a MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38a MAP kinase with excellent cellular potency toward the inhibition of TNFa production. Compound 2x was highly efficacious in vivo in inhibiting TNFa production in an acute murine model of TNFa production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38a is also disclosed.

  3. MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase.

    PubMed

    Ellsworth, K; Azzolina, B; Baginsky, W; Bull, H; Chang, B; Cimis, G; Mitra, S; Toney, J; Bakshi, R K; Rasmusson, G R; Tolman, R L; Harris, G S

    1996-07-01

    Steroid 5alpha-reductase is required for the conversion of testosterone to dihydrotestosterone. Localization of type 1 5alpha-reductase in the sebaceous gland of skin offers the possibility for selective inhibition of this isozyme as a treatment for acne. The goals of these studies are to demonstrate the mechanism of inhibition of MK386 and its selectivity for type 1 5alpha-reductase. The apparent potency of MK386 differed depending on the source of the enzyme (i.e. recombinant vs. native), yet selectivity for type 1 5alpha-reductase was unchanged. Our results indicate that the apparent potency of MK386 is modulated by the membrane concentration of the assay. These results suggest that MK386 has a high affinity for the lipid-rich membrane environment of 5alpha-reductase. MK386 was also found to be a slow binding inhibitor of type 1 5alpha-reductase. However, the cause of this time-dependent inhibition is unrelated to partitioning of the inhibitor into the membrane because similar studies with type 2 5alpha-reductase indicate that MK386 is a reversible, competitive inhibitor. A number of counterscreens were developed to demonstrate that MK386 is a poor inhibitor of other steroid metabolizing enzymes. PMID:8903421

  4. Transforming growth factor ?2 promotes transcription of COX2 and EP4, leading to a prostaglandin E2-driven autostimulatory loop that enhances virulence of Theileria annulata-transformed macrophages.

    PubMed

    Haidar, Malak; Echebli, Nadia; Ding, Ying; Kamau, Everlyn; Langsley, Gordon

    2015-05-01

    Transforming growth factor beta (TGF-?) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-? consequently plays a central role in carcinogenesis, and a dampened TGF-?2 response by Theileria annulata-infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-?2 production, there is ablated expression of COX2 and EP4, which leads to a drop in cyclic AMP (cAMP) levels and, consequently, reduced activation of protein kinase A (PKA) and EPAC. This ablated phenotype can be rescued in attenuated macrophages by the addition of exogenous TGF-?2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-?2 therefore promotes the adhesion and invasiveness of virulent macrophages by modulating COX2, EP4, and PKIG transcription to initiate a prostaglandin E2 (PGE2)-driven autostimulatory loop that augments PKA and EPAC activities. A virulence phenotype stemming from the double activation of PKA and EPAC is the induction of a CREB-mediated transcriptional program and the upregulation of JAM-L- and integrin 4??1-mediated adhesion of Theileria-infected macrophages. PMID:25690101

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

    PubMed Central

    2011-01-01

    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

  6. Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors

    PubMed Central

    2013-01-01

    Natural products have long been recognized as a rich source of potent therapeutics but further development is often limited by high structural complexity and high molecular weight. In contrast, at the core of the thujaplicins is a lead-like tropolone scaffold characterized by relatively low molecular weight, ample sites for diversification, and metal-binding functionality poised for targeting a range of metalloenzyme drug targets. Here, we describe the development of this underutilized scaffold for the discovery of tropolone derivatives that function as isozyme-selective inhibitors of the validated anticancer drug target, histone deacetylase (HDAC). Several monosubstituted tropolones display remarkable levels of selectivity for HDAC2 and potently inhibit the growth of T-cell lymphocyte cell lines. The tropolones represent a new chemotype of isozyme-selective HDAC inhibitors. PMID:24900743

  7. Korean Red Ginseng water extract inhibits COX-2 expression by suppressing p38 in acrolein-treated human endothelial cells.

    PubMed

    Lee, Seung Eun; Park, Yong Seek

    2014-01-01

    Cigarette smoke is considered a major risk factor for vascular diseases. There are many toxic compounds in cigarette smoke, including acrolein and other ?,?-unsaturated aldehydes, which are regarded as mediators of inflammation and vascular dysfunction. Furthermore, recent studies have revealed that acrolein, an ?,?-unsaturated aldehyde in cigarette smoke, induces inflammatory mediator expression, which is known to be related to vascular diseases. In this study, we investigated whether Korean Red Ginseng (KRG) water extract suppressed acrolein-induced cyclooxygenase (COX)-2 expression in human umbilical vein endothelial cells (HUVECs). Acrolein-induced COX-2 expression was accompanied by increased levels of phosphorylated p38 in HUVECs and KRG inhibited COX-2 expression in HUVECs. These results suggest that KRG suppresses acrolein-induced COX-2 expression via inhibition of the p38 mitogen-activated protein kinase signaling pathway. In addition, KRG exhibited an inhibitory effect on acrolein-induced apoptosis, as demonstrated by annexin V-propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Consistent with these results, KRG may exert a vasculoprotective effect through inhibition of COX-2 expression in acrolein-stimulated human endothelial cells. PMID:24558308

  8. Cooperation between COA6 and SCO2 in COX2 Maturation during Cytochrome c Oxidase Assembly Links Two Mitochondrial Cardiomyopathies.

    PubMed

    Pacheu-Grau, David; Bareth, Bettina; Dudek, Jan; Juris, Lisa; Vögtle, F-Nora; Wissel, Mirjam; Leary, Scot C; Dennerlein, Sven; Rehling, Peter; Deckers, Markus

    2015-06-01

    Three mitochondria-encoded subunits form the catalytic core of cytochrome c oxidase, the terminal enzyme of the respiratory chain. COX1 and COX2 contain heme and copper redox centers, which are integrated during assembly of the enzyme. Defects in this process lead to an enzyme deficiency and manifest as mitochondrial disorders in humans. Here we demonstrate that COA6 is specifically required for COX2 biogenesis. Absence of COA6 leads to fast turnover of newly synthesized COX2 and a concomitant reduction in cytochrome c oxidase levels. COA6 interacts transiently with the copper-containing catalytic domain of newly synthesized COX2. Interestingly, similar to the copper metallochaperone SCO2, loss of COA6 causes cardiomyopathy in humans. We show that COA6 and SCO2 interact and that corresponding pathogenic mutations in each protein affect complex formation. Our analyses define COA6 as a constituent of the mitochondrial copper relay system, linking defects in COX2 metallation to cardiac cytochrome c oxidase deficiency. PMID:25959673

  9. Cycloxygenase-2 (COX-2)--a potential target for screening of small molecules as radiation countermeasure agents: an in silico study.

    PubMed

    Joshi, Jayadev; Barik, Tapan K; Shrivastava, Nitisha; Dimri, Manali; Ghosh, Subhajit; Mandal, Rahul S; Ramachandran, Srinivasan; Kumar, Indracanti P

    2013-03-01

    Cyclooxygenase-2 (COX-2) is well established for its role in inflammation, cancer and has also been reported to play a significant role in radiation induced inflammation and bystander effect. It has already been reported to have a role in protection against radiation induced damage, suggesting it to be an important target for identifying novel radiation countermeasure agents. Present study aims at identifying novel small molecules from pharmacopeia using COX-2 as target in silico. Systematic search of the molecules that are reported to exhibit radiation protection revealed that around 30% (40 in 130) of them have a role in inflammation and a small percentage of these molecules (20%; 8 in 40) are reported to act as non-steroidal anti-inflammatory drugs (NSAIDS). Docking studies further clarified that antiinflammatory compounds exhibited higher binding energy (BE). Out of 15 top hits, 14 molecules are reported to have anti-inflammatory property, suggesting the significant role of COX-2 in radiation protection. Further, Johns Hopkins Clinical Compound Library (JHCCL), a collection of small molecule clinical compounds, was screened virtually for COX-2 inhibition by docking approach. Docking of around 1400 small molecules against COX-2, leads to identification of a number of previously unreported molecules, which are likely to act as radioprotectors. PMID:23905928

  10. Korean Red Ginseng water extract inhibits COX-2 expression by suppressing p38 in acrolein-treated human endothelial cells

    PubMed Central

    Lee, Seung Eun; Park, Yong Seek

    2013-01-01

    Cigarette smoke is considered a major risk factor for vascular diseases. There are many toxic compounds in cigarette smoke, including acrolein and other ?,?-unsaturated aldehydes, which are regarded as mediators of inflammation and vascular dysfunction. Furthermore, recent studies have revealed that acrolein, an ?,?-unsaturated aldehyde in cigarette smoke, induces inflammatory mediator expression, which is known to be related to vascular diseases. In this study, we investigated whether Korean Red Ginseng (KRG) water extract suppressed acrolein-induced cyclooxygenase (COX)-2 expression in human umbilical vein endothelial cells (HUVECs). Acrolein-induced COX-2 expression was accompanied by increased levels of phosphorylated p38 in HUVECs and KRG inhibited COX-2 expression in HUVECs. These results suggest that KRG suppresses acrolein-induced COX-2 expression via inhibition of the p38 mitogen-activated protein kinase signaling pathway. In addition, KRG exhibited an inhibitory effect on acrolein-induced apoptosis, as demonstrated by annexin V–propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Consistent with these results, KRG may exert a vasculoprotective effect through inhibition of COX-2 expression in acrolein-stimulated human endothelial cells. PMID:24558308

  11. Screening baccharin analogs as selective inhibitors against type 5 17?-hydroxysteroid dehydrogenase (AKR1C3).

    PubMed

    Zang, Tianzhu; Verma, Kshitij; Chen, Mo; Jin, Yi; Trippier, Paul C; Penning, Trevor M

    2015-06-01

    Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17?-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5?-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3?-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3. PMID:25555457

  12. (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

    PubMed

    Choi, Ha-Soon; Rucker, Paul V; Wang, Zhicheng; Fan, Yi; Albaugh, Pamela; Chopiuk, Greg; Gessier, Francois; Sun, Fangxian; Adrian, Francisco; Liu, Guoxun; Hood, Tami; Li, Nanxin; Jia, Yong; Che, Jianwei; McCormack, Susan; Li, Allen; Li, Jie; Steffy, Auzon; Culazzo, AnneMarie; Tompkins, Celine; Phung, Van; Kreusch, Andreas; Lu, Min; Hu, Bin; Chaudhary, Apurva; Prashad, Mahavir; Tuntland, Tove; Liu, Bo; Harris, Jennifer; Seidel, H Martin; Loren, Jon; Molteni, Valentina

    2015-05-14

    Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs. PMID:26005534

  13. Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors

    PubMed Central

    2013-01-01

    Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t1/2 in dog PK studies. PMID:24900796

  14. Design of selective PI3K? inhibitors starting from a promiscuous pan kinase scaffold.

    PubMed

    Barlaam, Bernard; Cosulich, Sabina; Fitzek, Martina; Green, Stephen; Harris, Craig S; Hudson, Kevin; Lambert-van der Brempt, Christine; Ouvry, Gilles; Page, Ken; Ruston, Linette; Ward, Lara; Delouvrié, Bénédicte

    2015-07-01

    Starting from compound 1, a potent PI3K? inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3K? and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3K?, with excellent kinase selectivity. PMID:25980912

  15. Analysis by phage display selection and site-directed retromutagenesis of the Mustard Trypsin Inhibitor 2 reactive site.

    PubMed

    Volpicella, Mariateresa; Leoni, Claudia; Arnesano, Fabio; Gallerani, Raffaele; Ceci, Luigi R

    2010-11-15

    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

  16. Relationship of the Topological Distances and Activities between mPGES-1 and COX-2 versus COX-1: Implications of the Different Post-Translational Endoplasmic Reticulum Organizations of COX-1 and COX-2.

    PubMed

    Akasaka, Hironari; So, Shui-Ping; Ruan, Ke-He

    2015-06-16

    In vascular inflammation, prostaglandin E2 (PGE2) is largely biosynthesized by microsomal PGE2 synthase-1 (mPGES-1), competing with other downstream eicosanoid-synthesizing enzymes, such as PGIS, a synthase of a vascular protector prostacyclin (PGI2), to isomerize the cyclooxygenase (COX)-2-derived prostaglandin H2 (PGH2). In this study, we found that a majority of the product from the cells co-expressing human COX-2, mPGES-1, and PGIS was PGE2. We hypothesize that the molecular and cellular mechanisms are related to the post-translational endoplasmic reticulum (ER) arrangement of those enzymes. A set of fusion enzymes, COX-2-linker [10 amino acids (aa)]-PGIS and COX-2-linker (22 amino acids)-PGIS, were created as "The Bioruler", in which the 10 and 22 amino acids are defined linkers with known helical structures and distances (14.4 and 30.8 Å, respectively). Our experiments have shown that the efficiency of PGI2 biosynthesis was reduced when the separation distance increased from 10 to 22 amino acids. When COX-2-10aa-PGIS (with a 14.4 Å separation) was co-expressed with mPGES-1 on the ER membrane, a major product was PGE2, but not PGI2. However, expression of COX-2-10aa-PGIS and mPGES-1 on a separated ER with a distance of ?30.8 Å reduced the level of PGE2 production. These data indicated that the mPGES-1 is "complex-likely" colocalized with COX-2 within a distance of 14.4 Å. In addition, the cells co-expressing COX-1-10aa-PGIS and mPGES-1 produced PGI2 mainly, but not PGE2. This indicates that mPGES-1 is expressed much farther from COX-1. These findings have led to proposed models showing the different post-translational ER organization between COX-2 and COX-1 with respect to the topological arrangement of the mPGES-1 during vascular inflammation. PMID:25988363

  17. 6-thioguanine selectively kills BRCA2 defective tumours and overcomes PARP inhibitor resistance

    PubMed Central

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

    2010-01-01

    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 are tested for these tumours 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 (DSBs) that we show are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumours in a xenograft model. Spontaneous BRCA1 defective mammary tumours gain resistance to PARP inhibitors through increased p-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1 defective PARP inhibitor resistant (PIR) tumours. We also show that 6TG can kill cells and tumours that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PIR 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 required for survival also to mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in 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 tumours and suggest that 6TG may be effective in the treatment of advanced tumours that have developed resistance to PARP inhibitors or platinum-based chemotherapy. PMID:20631063

  18. Discovery and Characterization of a Potent and Selective Inhibitor of Aedes aegypti Inward Rectifier Potassium Channels

    PubMed Central

    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

    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

  19. Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation[S

    PubMed Central

    Morisseau, Christophe; Wecksler, Aaron T.; Deng, Catherine; Dong, Hua; Yang, Jun; Lee, Kin Sing S.; Kodani, Sean D.; Hammock, Bruce D.

    2014-01-01

    Epoxy FAs (EpFAs) are important lipid mediators that are mainly metabolized by soluble epoxide hydrolase (sEH). Thus, sEH inhibition is a promising therapeutic target to treat numerous ailments. Several sEH polymorphisms result in amino acid substitutions and alter enzyme activity. K55R and R287Q are associated with inflammatory, cardiovascular, and metabolic diseases. R287Q seems to affect sEH activity through reducing formation of a catalytically active dimer. Thus, understanding how these SNPs affect the selectivity of sEH for substrates and inhibitors is of potential clinical importance. We investigated the selectivity of four sEH SNPs toward a series of EpFAs and inhibitors. We found that the SNPs alter the catalytic activity of the enzyme but do not alter the relative substrate and inhibitor selectivity. We also determined their dimer/monomer constants (KD/M). The WT sEH formed a very tight dimer, with a KD/M in the low picomolar range. Only R287Q resulted in a large change of the KD/M. However, human tissue concentrations of sEH suggest that it is always in its dimer form independently of the SNP. These results suggest that the different biologies associated with K55R and R287Q are not explained by alteration in dimer formation or substrate selectivity. PMID:24771868

  20. Selection of human elastase inhibitors from a conformationally constrained combinatorial peptide library.

    PubMed

    McBride, J D; Freeman, H N; Leatherbarrow, R J

    1999-12-01

    A resin-bound cyclic peptide library was constructed based on the sequence of the reactive-site loop of Bowman-Birk inhibitor, a proteinase inhibitor protein. The constrained loop sequence, which incorporates the minimal proteinase-binding motif, was retained throughout the library, but selected residues known to be important for inhibitor specificity were randomised. The approach was used to create a 'one bead, one peptide' library with 8000 variants resulting from randomization at three target locations in the sequence (P4, P1 and P2'). This library allows us to examine the degree to which variations in this proteinase-binding motif can redirect activity, as well as providing information about the binding specificity of a proteinase target. Screening this library for binding to human leucocyte elastase identified sequences with a strong consensus, and on resynthesis all were found to act as inhibitors, with Ki values as low as 65 nM. Human leucocyte elastase is known to have a substrate preference for small alkyl chains at the P1 locus, with valine being preferred. However, alanine and not the expected valine was found in 21 out of 23 identified sequences. The remaining two sequences had threonine at P1, a finding that would be hard to predict based on substrate specificity alone. Further analysis of resynthesized peptides demonstrated that valine substitution results in an analogue that is hydrolysed far more rapidly than ones having library-selected P1 residues. Testing of the human leucocyte elastase-selected sequences as inhibitors of porcine pancreatic elastase demonstrates a significant difference in the specificity of the P4 locus between these two proteinases. PMID:10561580

  1. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response

    SciTech Connect

    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. (Cellzome AG); (MSKCC); (GSK); (Oxford)

    2012-10-11

    The jumonji (JMJ) family of histone demethylases are Fe{sup 2+}- and {alpha}-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.

  2. A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties

    PubMed Central

    Pitman, Melissa R.; Powell, Jason A.; Coolen, Carl; Moretti, Paul A.B.; Zebol, Julia R.; Pham, Duyen H.; Finnie, John W.; Don, Anthony S.; Ebert, Lisa M.; Bonder, Claudine S.; Gliddon, Briony L.; Pitson, Stuart M.

    2015-01-01

    The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft model by both inducing tumour cell apoptosis and inhibiting tumour angiogenesis. Thus, this selective ATP competitive SK inhibitor provides a promising candidate for potential development as an anti-cancer therapy, and also, due to its different mode of inhibition to other known SK inhibitors, both validates the SKs as targets for anti-cancer therapy, and represents an important experimental tool to study these enzymes. PMID:25788259

  3. Effects of Enriched Environment on COX-2, Leptin and Eicosanoids in a Mouse Model of Breast Cancer

    PubMed Central

    Nachat-Kappes, Rachida; Pinel, Alexandre; Combe, Kristell; Lamas, Bruno; Farges, Marie-Chantal; Rossary, Adrien; Goncalves-Mendes, Nicolas; Caldefie-Chezet, Florence; Vasson, Marie-Paule; Basu, Samar

    2012-01-01

    Cyclooxygenase-2 (COX-2) and adipokines have been implicated in breast cancer. This study investigated a possible link between COX-2 and adipokines in the development of mammary tumors. A model of environmental enrichment (EE), known to reduce tumor growth was used for a syngeneic murine model of mammary carcinoma. 3-week-old, female C57BL/6 mice were housed in standard environment (SE) or EE cages for 9 weeks and transplanted orthotopically with syngeneic EO771 adenocarcinoma cells into the right inguinal mammary fat pad. EE housing influenced mammary gland development with a decrease in COX-2 expressing cells and enhanced side-branching and advanced development of alveolar structures of the mammary gland. Tumor volume and weight were decreased in EE housed mice and were associated with a reduction in COX-2 and Ki67 levels, and an increase in caspase-3 levels. In tumors of SE mice, high COX-2 expression correlated with enhanced leptin detection. Non-tumor-bearing EE mice showed a significant increase in adiponectin levels but no change in those of leptin, F2-isoprostanes, PGF2?, IL-6, TNF-?, PAI-1, and MCP-1 levels. Both tumor-bearing groups (SE and EE housing) had increased resistin, IL-6, TNF-?, PAI-1 and MCP-1 levels irrespective of the different housing environment demonstrating higher inflammatory response due to the presence of the tumor. This study demonstrates that EE housing influenced normal mammary gland development and inhibited mammary tumor growth resulting in a marked decrease in intratumoral COX-2 activity and an increase in the plasma ratio of adiponectin/leptin levels. PMID:23272114

  4. Effects of enriched environment on COX-2, leptin and eicosanoids in a mouse model of breast cancer.

    PubMed

    Nachat-Kappes, Rachida; Pinel, Alexandre; Combe, Kristell; Lamas, Bruno; Farges, Marie-Chantal; Rossary, Adrien; Goncalves-Mendes, Nicolas; Caldefie-Chezet, Florence; Vasson, Marie-Paule; Basu, Samar

    2012-01-01

    Cyclooxygenase-2 (COX-2) and adipokines have been implicated in breast cancer. This study investigated a possible link between COX-2 and adipokines in the development of mammary tumors. A model of environmental enrichment (EE), known to reduce tumor growth was used for a syngeneic murine model of mammary carcinoma. 3-week-old, female C57BL/6 mice were housed in standard environment (SE) or EE cages for 9 weeks and transplanted orthotopically with syngeneic EO771 adenocarcinoma cells into the right inguinal mammary fat pad. EE housing influenced mammary gland development with a decrease in COX-2 expressing cells and enhanced side-branching and advanced development of alveolar structures of the mammary gland. Tumor volume and weight were decreased in EE housed mice and were associated with a reduction in COX-2 and Ki67 levels, and an increase in caspase-3 levels. In tumors of SE mice, high COX-2 expression correlated with enhanced leptin detection. Non-tumor-bearing EE mice showed a significant increase in adiponectin levels but no change in those of leptin, F(2)-isoprostanes, PGF(2?), IL-6, TNF-?, PAI-1, and MCP-1 levels. Both tumor-bearing groups (SE and EE housing) had increased resistin, IL-6, TNF-?, PAI-1 and MCP-1 levels irrespective of the different housing environment demonstrating higher inflammatory response due to the presence of the tumor. This study demonstrates that EE housing influenced normal mammary gland development and inhibited mammary tumor growth resulting in a marked decrease in intratumoral COX-2 activity and an increase in the plasma ratio of adiponectin/leptin levels. PMID:23272114

  5. EGFR and COX2 protein expression in non-small cell lung cancer and the correlation with clinical features

    Microsoft Academic Search

    Feng Li; Yongmei Liu; Huijiao Chen; Dianying Liao; Yali Shen; Feng Xu; Jin Wang

    2011-01-01

    Background  To evaluate the expression of EGFR and COX-2 and their correlation with prognosis in NSCLC\\u000a \\u000a \\u000a \\u000a Methods  The paraffin embedded tumor samples of 50 NSCLC patients receiving radical resection were analyzed immunohistochemically for\\u000a EGFR and COX-2 expression and their prognostic values were explored.\\u000a \\u000a \\u000a \\u000a \\u000a Results  The positive rate of EGFR protein in NSCLC tumor cells was 46%, which was significantly higher than its expression

  6. Enhanced in vitro percutaneous absorption and in vivo anti-inflammatory effect of a selective cyclooxygenase inhibitor using microemulsion.

    PubMed

    Subramanian, N; Ghosal, Saroj K; Moulik, S P

    2005-05-01

    Celecoxib, a specific COX-2 inhibitor, was recently approved for the treatment of rheumatoid and osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. Oral administration of celecoxib is effective against ultraviolet B radiation (UVB)-induced skin carcinogenesis; however, its clinical use is restricted because of its failure to block the characteristic cutaneous inflammatory response and lower availability at the site of inflammation. Topical application of celecoxib has been effective compared with oral in certain clinical conditions. The present study was undertaken to develop and investigate the development of microemulsion system (isopropyl myristate/medium-chain glyceride/polysorbate 80/water) for topical delivery of celecoxib. The pseudoternary phase diagram was constructed with constant surfactant concentration, and several compositions were identified and characterized by using dynamic light scattering. The in vitro permeation rate of celecoxib through rat skin was determined for microemulsions, microemulsion gel, and cream by using the modified Franz-type diffusion cell. In all formulations tested, celecoxib permeated more quickly, and the microemulsions increased the permeation rate of celecoxib up to 5 and 11 times compared with those of microemulsion gel and cream, respectively. Increasing the concentration of medium-chain mono-/di-glyceride in microemulsion imparted increased droplet size and viscosity and decreased diffusion coefficient. In vivo anti-inflammatory study suggested that the developed microemulsion formulations might serve as potential drug vehicle for the prevention of UVB-induced skin cancer. PMID:16093206

  7. Piperazine and piperidine triazole ureas as ultrapotent and highly selective inhibitors of monoacylglycerol lipase.

    PubMed

    Aaltonen, Niina; Savinainen, Juha R; Ribas, Casandra Riera; Rönkkö, Jani; Kuusisto, Anne; Korhonen, Jani; Navia-Paldanius, Dina; Häyrinen, Jukka; Takabe, Piia; Käsnänen, Heikki; Pantsar, Tatu; Laitinen, Tuomo; Lehtonen, Marko; Pasonen-Seppänen, Sanna; Poso, Antti; Nevalainen, Tapio; Laitinen, Jarmo T

    2013-03-21

    Monoacylglycerol lipase (MAGL) terminates the signaling function of the endocannabinoid, 2-arachidonoylglycerol (2-AG). During 2-AG hydrolysis, MAGL liberates arachidonic acid, feeding the principal substrate for the neuroinflammatory prostaglandins. In cancer cells, MAGL redirects lipid stores toward protumorigenic signaling lipids. Thus MAGL inhibitors may have great therapeutic potential. Although potent and increasingly selective MAGL inhibitors have been described, their number is still limited. Here, we have characterized piperazine and piperidine triazole ureas that combine the high potency attributable to the triazole leaving group together with the bulky aromatic benzodioxolyl moiety required for selectivity, culminating in compound JJKK-048 that potently (IC50 < 0.4 nM) inhibited human and rodent MAGL. JJKK-048 displayed low cross-reactivity with other endocannabinoid targets. Activity-based protein profiling of mouse brain and human melanoma cell proteomes suggested high specificity also among the metabolic serine hydrolases. PMID:23521796

  8. Structural basis for the design of selective phosphodiesterase 4B inhibitors.

    PubMed

    Fox, David; Burgin, Alex B; Gurney, Mark E

    2014-03-01

    Phosphodiesterase-4B (PDE4B) regulates the pro-inflammatory Toll Receptor -Tumor Necrosis Factor ? (TNF?) pathway in monocytes, macrophages and microglial cells. As such, it is an important, although under-exploited molecular target for anti-inflammatory drugs. This is due in part to the difficulty of developing selective PDE4B inhibitors as the amino acid sequence of the PDE4 active site is identical in all PDE4 subtypes (PDE4A-D). We show that highly selective PDE4B inhibitors can be designed by exploiting sequence differences outside the active site. Specifically, PDE4B selectivity can be achieved by capture of a C-terminal regulatory helix, now termed CR3 (Control Region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D). The reciprocal mutations in PDE4B and PDE4D cause a 70-80 fold shift in selectivity. Our structural studies show that CR3 is flexible and can adopt multiple orientations and multiple registries in the closed conformation. The new co-crystal structure with bound ligand provides a guide map for the design of PDE4B selective anti-inflammatory drugs. PMID:24361374

  9. Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations

    PubMed Central

    Johnson, David K.; Karanicolas, John

    2015-01-01

    Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein-bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal structures. Next, we find that the ensembles generated using different members of this protein family are overlapping but distinct, and that the activity of a given compound against a particular family member (ligand selectivity) can be predicted from whether the corresponding ensemble samples a complementary surface pocket. Finally, we find that each ensemble includes certain surface pockets that are not shared by any other family member: while no inhibitors have yet been identified to take advantage of these pockets, we expect that chemical scaffolds complementing these “distinct” pockets will prove highly selective for their targets. The opportunity to achieve target selectivity within a protein family by exploiting differences in surface fluctuations represents a new paradigm that may facilitate design of family-selective small-molecule inhibitors of protein-protein interactions. PMID:25706586

  10. Selective Serotonin Reuptake Inhibitors and Cytochrome P-450 Mediated Drug-Drug Interactions: An Update

    Microsoft Academic Search

    Alex Hemeryck; Frans M. Belpaire

    2002-01-01

    The selective serotonin reuptake inhibitors (SSRIs) have become the most prescribed antidepressants in many countries. Although the SSRIs share a common mechanism of action, they differ substantially in their chemical structure, metabolism, and pharmacokinetics. Perhaps the most important difference between the SSRIs is their potential to cause drug-drug interactions through inhibition of cytochrome-P450 (CYP) isoforms. This paper provides an update

  11. Interactions of selective serotonin reuptake inhibitors with the serotonin 5HT 2C receptor

    Microsoft Academic Search

    E.-P. Pälvimäki; H. Majasuo; A. Laakso; M. Kuoppamäki; E. Syvälahti; B. L. Roth; J. Hietala

    1996-01-01

    Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic anti-depressant (TCA) imipramine with the rat serotonin 5-HT2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different

  12. Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn

    Microsoft Academic Search

    Christina D. Chambers; Sonia Hernandez-Diaz; Linda J. Van Marter; Martha M. Werler; Carol Louik; Kenneth Lyons Jones; Allen A. Mitchell

    2006-01-01

    ABSTRACT Background Persistent pulmonary,hypertension of the newborn,(PPHN) is associated with sub- stantial infant mortality and morbidity. A previous cohort study suggested a pos- sible association between maternal use of the selective serotonin-reuptake inhibitor (SSRI) fluoxetine late in the third trimester of pregnancy and the risk of PPHN in the infant. Weperformed,a case–control study to assess whether PPHN is associated with

  13. Maternal Selective Serotonin Reuptake Inhibitor Use During Pregnancy and Newborn Neurobehavior

    Microsoft Academic Search

    Philip Sanford Zeskind; Laura E. Stephens

    2004-01-01

    ABSTRACT. Objective. This is a prospective study of the effects of maternal use of selective serotonin re- uptake inhibitors (SSRIs) during pregnancy on newborn neurobehavioral integrity, including systematic mea- sures of behavioral state, sleep organization, motor activ- ity, heart rate variability (HRV), tremulousness, and star- tles. Methods. The sample included 17 SSRI-exposed and 17 nonexposed, full-birth-weight newborn infants who had

  14. Is 5-HTTLPR linked to the response of selective serotonin reuptake inhibitors in MDD?

    Microsoft Academic Search

    Ari Illi; Outi Poutanen; Eija Setälä-Soikkeli; Olli Kampman; Merja Viikki; Heini Huhtala; Nina Mononen; Susann Haraldsson; Pasi A. Koivisto; Esa Leinonen; Terho Lehtimäki

    2011-01-01

    The role of a functional polymorphism in the transcriptional control region of serotonin transporter gene (5-HTTLPR, SERTPR)\\u000a has been studied intensively in major depression and in the response to selective serotonin inhibitors (SSRIs) in major depression.\\u000a The findings have been contradictory, although majority of the studies indicate that the short allele is associated with poor\\u000a response to SSRIs in major

  15. Catechol O-methyltransferase pharmacogenomics and selective serotonin reuptake inhibitor response

    Microsoft Academic Search

    Y Ji; J Biernacka; K Snyder; M Drews; L L Pelleymounter; C Colby; L Wang; D A Mrazek; R M Weinshilboum

    2012-01-01

    We applied a systematic pharmacogenetic approach to investigate the role of genetic variation in the gene encoding catechol O-methyltransferase (COMT) in individual variation in selective serotonin reuptake inhibitor (SSRI) response among depressed patients. In all, 23 single-nucleotide polymorphisms (SNPs) in COMT were genotyped using DNA from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (N=1914). One SNP, rs13306278, located

  16. UCN-01, an anti-tumor drug, is a selective inhibitor of the conventional PKC subfamily

    Microsoft Academic Search

    Keiko Mizuno; Kumi Noda; Yoshihiko Ueda; Hisao Hanaki; Takaomi C. Saido; Tohgo Ikuta; Toshio Kuroki; Tatsuya Tamaoki; Syu-ichi Hirai; Shin-ichi Osada; Shigeo Ohno

    1995-01-01

    A selective PKC inhibitor, UCN-01, was shown to exhibit anti-tumor activity in vitro and in vivo. We investigated UCN-01 with respect to isozyme-specific PKC inhibition using purified recombinant or rabbit brain PKC isozymes, cPKC?, ? and ?, nPKC?, ? and ?, and aPKC?. Of the PKC isozymes examined, cPKC? was inhibited by UCN-01 most effectively (Ki = 0.44 nM), suggesting

  17. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

    Microsoft Academic Search

    Kan He; Joseph M. Luettgen; Donglu Zhang; Bing He; James E. Grace; Baomin Xin; Donald J. P. Pinto; Pancras C. Wong; Robert M. Knabb; Patrick Y. S. Lam; Ruth R. Wexler; Scott J. Grossman

    Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention\\u000a and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low\\u000a systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute\\u000a oral bioavailability of approximately 50% or greater. The

  18. 2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes

    Microsoft Academic Search

    Maurice J. van Eis; Jean-Pierre Evenou; Philipp Floersheim; Christoph Gaul; Sandra W. Cowan-Jacob; Lauren Monovich; Gabriele Rummel; Walter Schuler; Wilhelm Stark; Andre Strauss; Anette von Matt; Eric Vangrevelinghe; Juergen Wagner; Nicolas Soldermann

    The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes ?, ?, ?, ? (in particular PKC?\\/?, and display a 10–100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKC?-dependent pathways in vitro and in vivo. In

  19. Directed mutagenesis confirms the functional importance of positively selected sites in polygalacturonase inhibitor protein.

    PubMed

    Bishop, John G

    2005-07-01

    Polygalacturonase inhibitor proteins (PGIPs) protect plants against invasion by diverse microbial and invertebrate enemies that use polygalacturonase (PG) to breach the plant cell wall. Directed mutagenesis has identified specific natural mutations conferring novel defensive capability in green bean PGIP against a specific fungal PG. These same sites are identified as positively selected by phylogenetic codon-substitution models, demonstrating the utility of such models for connecting retrospective comparative analyses with contemporary, ecologically relevant variation. PMID:15829620

  20. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability

    Microsoft Academic Search

    Ian M. Anderson

    2000-01-01

    Background: A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against tricyclic antidepressants (TCAs) in depressed patients was carried out. Methods: Efficacy data from 102 randomised controlled trials (10?706 patients) were pooled to provide a summary variance-weighted effect size. Tolerability data from 95 studies (10?553 patients) were combined to give variance-weighted relative risk of drop out

  1. N-Bridged 1-deoxynojirimycin dimers as selective insect trehalase inhibitors.

    PubMed

    Cipolla, Laura; Sgambato, Antonella; Forcella, Matilde; Fusi, Paola; Parenti, Paolo; Cardona, Francesca; Bini, Davide

    2014-05-01

    A small set of N-bridged 1-deoxynojirimycin dimers has been synthesized and evaluated as potential inhibitors of insect trehalase from midge larvae of Chironomus riparius, porcine trehalase as the mammalian counterpart and ?-amylase from human saliva. All the tested compounds (2-4) proved to be active (micromolar range activity) against insect trehalase, showing selectivity toward the insect glycosidase. No activity was observed against ?-amylase. PMID:24680508

  2. The discovery of RFI-641 as a potent and selective inhibitor of the respiratory syncytial virus.

    PubMed

    Nikitenko, A A; Raifeld, Y E; Wang, T Z

    2001-04-23

    The design and synthesis of a new potent and selective inhibitor of the respiratory syncytial virus are described. This compound, RFI-641, emerged from analysis of the structure-activity relationship in a series of biphenyl triazine anionic compounds possessing specific anti-RSV activity. The key synthetic step involves coupling of diaminobiphenyl 11 with two equivalents of chlorotriazine 10 under microwave conditions. RFI-641 inhibited RSV in vitro and in vivo models. PMID:11327584

  3. Combination therapy with selective serotonin reuptake inhibitors and phosphodiesterase-5 inhibitors in the treatment of premature ejaculation.

    PubMed

    Polat, E C; Ozbek, E; Otunctemur, A; Ozcan, L; Simsek, A

    2015-06-01

    We aimed to evaluate the effectiveness of paroxetine and tadalafil combination in the treatment of premature ejaculation (PE). A total of 150 primary (lifelong)PE patients were randomly distributed into three groups of 50 patients each. Group 1 received 20 mg paroxetine every day for 1 month, Group 2 received 20 mg tadalafil on demand 2 h before intercourse, and Group 3 received paroxetine and tadalafil on demand 2 h before intercourse. Intravaginal ejaculatory latency times (IELT) scores were evaluated at baseline, at the end of the first month of therapy and 1 month after discontinuation of the treatment, while International Index of Erectile Function (IIEF) questionnaire scores were evaluated both prior to and after the treatment. At the end of the first month of therapy, IELT scores were compared with the basal values and statistically significant changes were detected (60.6 ± 30.2-117.3 ± 67.3, 68.5 ± 21.4-110.2 ± 37.3, 71.56 ± 40.23-175.2 ± 60.2)(P < 0.01). IELT scores after discontinuation of treatment were found to be close to the baseline IELT scores (P > 0.05). IIEF scores were evaluated both prior to and after the treatment, and no statistically significant difference was detected (P > 0.05). It is concluded that utilisation of selective serotonin reuptake inhibitors (SSRI) and phosphodiesterase-5 inhibitors (PDE5i) combination before intercourse seems to provide significantly longer ejaculatory latency times as compared with SSRI alone for a long time in patients with PE. PMID:24811578

  4. Current limiting defects in Ba(Fe 1-x Cox)2As2 and YBa2Cu3O 7-x films.

    E-print Network

    Weston, Ken

    Current limiting defects in Ba(Fe 1-x Cox)2As2 and YBa2Cu3O 7-x films. D. Abraimov, Pei Li, J, Madison, WI 53706, USA Work at NHMFL was supported under by Department of Energy Office of Electricity;Current limiting defects in Ba(Fe 1-x Cox)2As2 films Description of Samples Ba(Fe 1-xCox)2As2 (x0.08) ab

  5. A potent and selective inhibitor for the UBLCP1 proteasome phosphatase.

    PubMed

    He, Yantao; Guo, Xing; Yu, Zhi-Hong; Wu, Li; Gunawan, Andrea M; Zhang, Yan; Dixon, Jack E; Zhang, Zhong-Yin

    2015-06-15

    The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) has been implicated as a negative regulator of the proteasome, a key mediator in the ubiquitin-dependent protein degradation. Small molecule inhibitors that block UBLCP1 activity would be valuable as research tools and potential therapeutics for human diseases caused by the cellular accumulation of misfold/damaged proteins. We report a salicylic acid fragment-based library approach aimed at targeting both the phosphatase active site and its adjacent binding pocket for enhanced affinity and selectivity. Screening of the focused libraries led to the identification of the first potent and selective UBLCP1 inhibitor 13. Compound 13 exhibits an IC50 of 1.0?M for UBLCP1 and greater than 5-fold selectivity against a large panel of protein phosphatases from several distinct families. Importantly, the inhibitor possesses efficacious cellular activity and is capable of inhibiting UBLCP1 function in cells, which in turn up-regulates nuclear proteasome activity. These studies set the groundwork for further developing compound 13 into chemical probes or potential therapeutic agents targeting the UBLCP1 phosphatase. PMID:25907364

  6. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.

    PubMed

    Yu, Wenyu; Chory, Emma J; Wernimont, Amy K; Tempel, Wolfram; Scopton, Alex; Federation, Alexander; Marineau, Jason J; Qi, Jun; Barsyte-Lovejoy, Dalia; Yi, Joanna; Marcellus, Richard; Iacob, Roxana E; Engen, John R; Griffin, Carly; Aman, Ahmed; Wienholds, Erno; Li, Fengling; Pineda, Javier; Estiu, Guillermina; Shatseva, Tatiana; Hajian, Taraneh; Al-Awar, Rima; Dick, John E; Vedadi, Masoud; Brown, Peter J; Arrowsmith, Cheryl H; Bradner, James E; Schapira, Matthieu

    2012-01-01

    Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy. PMID:23250418

  7. Development of Selective Inhibitors for Aldehyde Dehydrogenases Based on Substituted Indole-2,3-diones

    PubMed Central

    2015-01-01

    Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure–activity relationships for each ALDH isoenzyme. PMID:24444054

  8. Discovery of Potent and Selective Histone Deacetylase Inhibitors via Focused Combinatorial Libraries of Cyclic ?3?-Tetrapeptides

    PubMed Central

    Olsen, Christian A.; Ghadiri, M. Reza

    2009-01-01

    Histone deacetylase (HDAC) inhibitors are powerful tools in understanding epigenetic regulation and have proven especially promising for the treatment of various cancers, but the discovery of potent, isoform-selective HDAC inhibitors has been a major challenge. We recently developed a cyclic ?3?-tetrapeptide scaffold for the preparation of HDAC inhibitors with novel selectivity profiles [Montero, A.; Beierle, J. M.; Olsen, C. A.; Ghadiri, M. R. J. Am. Chem. Soc. 2009, 131, 3033]. In this study, we elaborate this scaffold with respect to side chain diversity by synthesizing one-bead–one-compound combinatorial libraries of cyclic tetrapeptide analogs and applying two generations of these focused libraries to the discovery of potent HDAC ligands using a convenient screening platform. Our studies led to the first HDAC6–selective cyclic tetrapeptide analog, which extends the use of cyclic tetrapeptides to the class-II HDAC isoforms. These findings highlight the persistent potential of cyclic tetrapeptides as epigenetic modulators and possible anticancer-drug lead compounds. PMID:19705846

  9. A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase?3 (PRMT3).

    PubMed

    Kaniskan, H Ümit; Szewczyk, Magdalena M; Yu, Zhengtian; Eram, Mohammad S; Yang, Xiaobao; Schmidt, Keith; Luo, Xiao; Dai, Miao; He, Feng; Zang, Irene; Lin, Ying; Kennedy, Steven; Li, Fengling; Dobrovetsky, Elena; Dong, Aiping; Smil, David; Min, Sun-Joon; Landon, Melissa; Lin-Jones, Jennifer; Huang, Xi-Ping; Roth, Bryan L; Schapira, Matthieu; Atadja, Peter; Barsyte-Lovejoy, Dalia; Arrowsmith, Cheryl H; Brown, Peter J; Zhao, Kehao; Jin, Jian; Vedadi, Masoud

    2015-04-20

    PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell-active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 =31±2?nM, KD =53±2?nM) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease. PMID:25728001

  10. Corrosion inhibitor testing and selection for exploration and production: A user`s perspective

    SciTech Connect

    Kapusta, S.D. [Shell Global Solutions, Amsterdam (Netherlands)

    1999-11-01

    The selection of corrosion inhibitors for field use is often based on laboratory and field testing of candidate products. At present, there are no universally accepted tests to compare the performance and other properties of candidate products. This paper describes a test protocol that can help inhibitor users with the testing and selection of inhibitors for use against CO{sub 2}/H{sub 2}S corrosion in oil and gas production, and that allows the screening of a large number of candidates, in a relatively cost-effective manner. The selection is based on two criteria: performance (effectiveness) against corrosion at the expected conditions, and compatibility with the injection and production systems, and with other chemicals. Performance is mostly affected by two factors: temperature, and to a lesser extent flow velocity. On that basis, three levels of increasing testing requirements have been defined: conditions green, yellow, and red. Under mild or well-established conditions (low pressure and temperature, existing operations) performance testing may not be required; however, compatibility testing is always recommended.

  11. Selective inhibitors of nuclear export for the treatment of non-Hodgkin’s lymphomas

    PubMed Central

    Azmi, Asfar S.; Al-Katib, Ayad; Aboukameel, Amro; McCauley, Dilara; Kauffman, Michael; Shacham, Sharon; Mohammad, Ramzi M.

    2013-01-01

    The nuclear export protein chromosome maintenance region 1, found to be elevated in non-Hodgkin’s lymphomas, controls localization of critical tumor suppressor proteins. Nuclear localization of tumor suppressor proteins is necessary for their cell surveillance function. However, their nuclear exclusion by chromosome maintenance region 1 renders them ineffective making this nuclear transporter an attractive therapeutic target. We have identified selective inhibitors of nuclear export that lock tumor suppressor proteins in the cell nucleus leading to apoptosis of lymphoid but not normal cells. Our inhibitors induce tumor suppressor protein nuclear retention-dependent growth inhibition and apoptosis in a panel of non-Hodgkin’s lymphoma cell lines. Western blot of nuclear protein fraction and confocal microscopy analysis demonstrated retention of major tumor suppressor proteins in the cell nucleus. Co-immunoprecipitation studies showed disruption of the tumor suppressor protein-chromosome maintenance region 1 interaction. Small inhibitor RNA knockdown of two major tumor suppressor proteins, p53 in wild-type protein-53 and protein 73 in mutant-protein-53, abrogated inhibitor activity. Oral administration of related inhibitor at 75 and 150 mg/kg resulted in 65 and 70% tumor reduction, respectively and subcutaneous injections of inhibitor (25 and 75 mg/kg) resulted in 70 and 74% suppression of non-Hodgkin’s lymphoma tumor growth with no toxicity; residual tumors showed activation of the protein 73 pathway. Our study verifies chromosome maintenance region 1 as a therapeutic target in non-Hodgkin’s lymphoma, indicating that this nuclear export protein warrants further clinical investigations. PMID:23403316

  12. A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore

    PubMed Central

    Miller, J. Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H. James; Huband, Michael D.; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y.; Mehrens, Shawn; Mueller, W. Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J. V. N. Vara; Shelly, John A.; Skerlos, Laura; Sulavik, Mark; Thomas, V. Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C. Kendall

    2009-01-01

    As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity. PMID:19164768

  13. A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.

    PubMed

    Miller, J Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H James; Huband, Michael D; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y; Mehrens, Shawn; Mueller, W Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J V N Vara; Shelly, John A; Skerlos, Laura; Sulavik, Mark; Thomas, V Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C Kendall

    2009-02-10

    As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity. PMID:19164768

  14. A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore

    SciTech Connect

    Miller, J. Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H. James; Huband, Michael D.; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y.; Mehrens, Shawn; Mueller, W. Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J.V.N. Vara; Shelly, John A.; Skerlos, Laura; Sulavik, Mark; Thomas, V. Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C. Kendall; (Pfizer)

    2009-06-25

    As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

  15. Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review.

    PubMed

    Yokouchi, Hiroshi; Kanazawa, Kenya; Ishida, Takashi; Oizumi, Satoshi; Shinagawa, Naofumi; Sukoh, Noriaki; Harada, Masao; Ogura, Shigeaki; Munakata, Mitsuru; Dosaka-Akita, Hirotoshi; Isobe, Hiroshi; Nishimura, Masaharu

    2014-09-01

    Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg/ml × min on day 1) and docetaxel (60 mg/m(2) on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6-6.7] and 13.7 months (95% CI: 11.4-15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high- and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration. PMID:25054040

  16. Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: A phase II trial and literature review

    PubMed Central

    YOKOUCHI, HIROSHI; KANAZAWA, KENYA; ISHIDA, TAKASHI; OIZUMI, SATOSHI; SHINAGAWA, NAOFUMI; SUKOH, NORIAKI; HARADA, MASAO; OGURA, SHIGEAKI; MUNAKATA, MITSURU; DOSAKA-AKITA, HIROTOSHI; ISOBE, HIROSHI; NISHIMURA, MASAHARU

    2014-01-01

    Several preclinical and clinical studies have demonstrated that cyclooxygenase-2 (COX-2) inhibitors are efficient for the treatment of non-small-cell lung cancer (NSCLC). However, two recent phase III clinical trials using COX-2 inhibitors in combination with platinum-based chemotherapy failed to demonstrate a survival benefit. Thus, validation and discussion regarding the usefulness of COX-2 inhibitors for patients with NSCLC are required. We conducted a prospective trial using COX-2 inhibitors for the treatment of 50 NSCLC patients accrued between April, 2005 and July, 2006. Patients with untreated advanced NSCLC received oral meloxicam (150 mg daily), carboplatin (area under the curve = 5 mg/ml × min on day 1) and docetaxel (60 mg/m2 on day 1) every 3 weeks. The primary endpoint was response rate. The response and disease control rates were 36.0 and 76.0%, respectively. The time-to-progression (TTP) and overall survival (OS) were 5.7 months [95% confidence interval (CI): 4.6–6.7] and 13.7 months (95% CI: 11.4–15.9), respectively. The 1-year survival ratio was 56.0%. Grade 3 neuropathy was observed in only 1 patient. We performed tumor immunohistochemistry for COX-2 and p27 and investigated the correlation between their expression and clinical outcome. COX-2 expression in the tumor tended to correlate with a higher response rate (50.0% in the high- and 18.2% in the low-COX-2 group; P=0.092). Based on our results and previous reports, various trial designs, such as the prospective use of COX-2 inhibitors only for patients with COX-2-positive NSCLC, including the exploratory analysis of biomarkers associated with the COX-2 pathway, may be worth further consideration. PMID:25054040

  17. Overexpression of COX-2 but not indoleamine 2,3-dioxygenase-1 enhances the immunosuppressive ability of human umbilical cord-derived mesenchymal stem cells.

    PubMed

    Li, Dong; Han, Yan; Zhuang, Yong; Fu, Jinqiu; Liu, Huan; Shi, Qing; Ju, Xiuli

    2015-05-01

    Owing to their immunosuppressive properties mesenchymal stem cells (MSCs) are widely applicable in the treatment of autoimmune disease. The aim of this study was to investigate whether the indoleamine 2,3-dioxygenase-1 (IDO-1) and cyclooxygenase-2 (COX-2) genes enhanced the immunosuppressive functional ability of MSCs following stable transfection. To strengthen the immunomodulatory ability of MSCs, IDO-1 and COX-2 were overexpressed in umbilical cord progenitor cell-derived MSCs using recombinant plasmids and electroporation. RT-qPCR analysis and western blotting confirmed the expression of IDO-1 and COX-2 in transfected MSCs. Further functional assays in co-culture experiments, including lymphocyte proliferation and cyto-toxicity assays showed that COX-2-transfected MSCs possessed more potent immunomodulatory cells than the untreated MSCs, or MSCs transfected with IDO-1. Additionally, synthesis of interferon-? and tumor necrosis factor-? (TNF-?) was significantly inhibited in lymphocytes co-cultured with COX-2-transfected MSCs, which was consistent with changes in immune-related genes in MSCs. An enhanced expression of IDO-1, COX-2, heme-oxygenase-1, inducible nitric-oxide synthase, TNF-?-stimulated gene/protein-6, transforming growth factor-? (TGF-?), human leukocyte antigen molecule 5 (HLA-G5) and interleukin-10 (IL-10) was identified following COX-2 transfection. We showed that the overexpression of COX-2 enhanced the immunosuppressive function of MSCs. COX-2-modified MSCs more potently inhibited the activation and proliferation of peripheral blood mononuclear cells. PMID:25777747

  18. Study on the association of COX2 genetic polymorphisms with risk of gastric cancer in high incidence Hexi area of Gansu province in China

    Microsoft Academic Search

    Zhu Ke-Xiang; Li Yu-Min; Li Xun; Zhou Wen-Ce; Shan Yong; Liu Tao

    2011-01-01

    To investigate the possible association of polymorphisms, cyclooxygenase-2 (COX-2) promoter region ?899G>C, COX-2 codon 587G>A,\\u000a with risk of gastric cancer in the high incidence Hexi area of Gansu province in China. Blood samples from 140 patients with\\u000a gastric carcinoma and 125 normal persons were collected in Hexi area of Gansu province in China. Polymorphisms of COX-2 ?899G>A\\u000a and COX-2 587G>A

  19. Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: SAR, structural biology and cellular activity

    PubMed Central

    Innocenti, Paolo; Cheung, Kwai-Ming J.; Solanki, Savade; Mas-Droux, Corine; Rowan, Fiona; Yeoh, Sharon; Boxall, Kathy; Westlake, Maura; Pickard, Lisa; Hardy, Tara; Baxter, Joanne E.; Aherne, G. Wynne; Bayliss, Richard; Fry, Andrew M.; Hoelder, Swen

    2013-01-01

    We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R )-21, a potent and selective inhibitor able to modulate Nek2 activity in cells. PMID:22404346

  20. In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor

    Microsoft Academic Search

    Caterina Trozzi; Linda Bartholomew; Alessandra Ceccacci; Gabriella Biasiol; Laura Pacini; Sergio Altamura; Frank Narjes; Ester Muraglia; Giacomo Paonessa; Uwe Koch; Raffaele De Francesco; Christian Steinkuhler; Giovanni Migliaccio

    2003-01-01

    The hepatitis C virus (HCV) serine protease is necessary for viral replication and represents a valid target for developing new therapies for HCV infection. Potent and selective inhibitors of this enzyme have been identified and shown to inhibit HCV replication in tissue culture. The optimization of these inhibitors for clinical development would greatly benefit from in vitro systems for the

  1. SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in ?-catenin-mutated tumors

    PubMed Central

    Kiga, Masaki; Nakayama, Ayako; Shikata, Yuki; Sasazawa, Yukiko; Murakami, Ryo; Nakanishi, Toshiyuki; Tashiro, Etsu; Imoto, Masaya

    2015-01-01

    Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that ?-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring ?-catenin mutations at its effective concentration. To confirm that ?-catenin mutations and mutant ?-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated ?-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated ?-catenin accelerated it. Our findings show that ?-catenin mutations are an important responder biomarker for MEK1/2 inhibitors. PMID:25640451

  2. Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors.

    PubMed

    Schwarz, S; Csuk, R; Rauter, A P

    2014-04-21

    Alzheimer's disease (AD), the most common form of senile dementia, is characterized by high butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this enzyme in disease progression, we present now microwave-assisted synthesis and anticholinesterase activity of a new nucleoside series embodying 6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of sugar stereochemistry, purine structure and linkage to the sugar for cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The ?-anomers were the most active compounds, while selectivity for BChE or acetylcholinesterase (AChE) inhibition could be tuned by the purine base, by the glycosyl moiety and by N(7)-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-?-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE. PMID:24604285

  3. Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity

    PubMed Central

    2015-01-01

    Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of ?-amino functionalized aminopyridine derivatives (3–8) were designed to probe the structure–activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. PMID:24758147

  4. Response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) differs in mouse strains and reveals a divergence in JNK signaling and COX-2 induction prior to loss of neurons in the substantia nigra pars compacta.

    PubMed

    Boyd, Justin D; Jang, Haeman; Shepherd, Kennie R; Faherty, Ciaran; Slack, Sally; Jiao, Yun; Smeyne, Richard J

    2007-10-17

    Parkinson's disease (PD) is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Recent studies have described the activation of a stress-induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK-mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice. However, mice exhibit a strain-dependent susceptibility to MPTP. Identifying the point(s) of molecular divergence in the MPTP-induced response may provide insight into the cause of PD or a means to identify susceptibility to PD in humans. Here we examined JNK signaling and COX-2 induction in two strains of mice, the MPTP-sensitive C57BL/6J and the MPTP-resistant Swiss Webster (SW). We show that C57BL/6J and SW strains differ in JNK and c-Jun activation in response to MPTP. In addition, the MPTP-induced COX-2 response occurs exclusively in C57BL/6J mice. Furthermore, strain-specific responses to MPTP are not due to differences in MPP(+) levels and are not secondary to cell death. These results provide evidence toward a mechanism of strain-dependent sensitivity to MPTP. PMID:17884023

  5. Discovery and characterization of novel, potent, and selective cytochrome P450 2J2 inhibitors.

    PubMed

    Ren, Shuang; Zeng, Juan; Mei, Ye; Zhang, John Z H; Yan, S Frank; Fei, Jian; Chen, Li

    2013-01-01

    Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues, including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, and the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first-pass intestinal metabolism and involvement in drug-drug interaction. To fully characterize its role in drug metabolism, selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs were screened for the inhibition of CYP2J2, and we discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC(50) values of 0.42 ?M and 0.94 ?M, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrates of CYP2J2 and show no time-dependent inhibition toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed-type inhibitor, and flunarizine competitively inhibits CYP2J2. The K(i) for telmisartan is 0.19 ?M, with an ? value, an indicator of the type of inhibition mechanism, of 2.80, and flunarizine has a K(i) value of 0.13 ?M. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting. PMID:23033255

  6. AS2077715 is a selective inhibitor of fungal mitochondrial cytochrome bc? complex.

    PubMed

    Ohsumi, Keisuke; Watanabe, Masato; Fujie, Akihiko

    2014-10-01

    AS2077715 is a novel antifungal metabolite produced by the newly isolated fungal strain Capnodium sp. 339855. This compound has an analogous structure to funiculosin, an inhibitor of mitochondrial cytochrome bc1 complex (complex III). AS2077715 inhibited ubiquinol-cytochrome c reductase activity of Trichophyton mentagrophytes complex III with an IC50 of 0.9?ng?ml(-1), while 6000-20,000?ng?ml(-1) AS2077715 was required to obtain comparable inhibition of mammalian complex III. This inhibitor also suppressed the growth of T. mentagrophytes with a MIC of 0.08??g?ml(-1), while cytotoxicity for mammalian cells was >6??g?ml(-1). These results indicate that AS2077715 is a selective inhibitor of fungal mitochondrial complex III. AS2077715 in doses of 1??g?ml(-1) or greater showed fungicidal activity against T. mentagrophytes within 2?h of incubation. This early-onset effect of fungicidal activity was also exhibited by other complex III inhibitors. These results suggest that inhibition of complex III is a promising strategy for designing anti-Trichophyton agents and that AS2077715 can be a potential drug candidate for treating Trichophyton infections. PMID:24865866

  7. A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity.

    PubMed

    Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia; Osipiuk, Jerzy; Gu, Minyi; Zhang, Minjia; Mandapati, Kavitha; Gollapalli, Deviprasad R; Gorla, Suresh Kumar; Hedstrom, Lizbeth; Joachimiak, Andrzej

    2015-02-27

    The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5'-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD(+), which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD(+) and XMP/NAD(+). In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD(+) adenosine moiety. More importantly, this new NAD(+)-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD(+)-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. These findings offer a potential strategy for further ligand optimization. PMID:25572472

  8. The Cox-2 -1195 G > A polymorphism and cancer risk: a meta-analysis of 25 case-control studies.

    PubMed

    Tang, Zhipeng; Nie, Zhen-Lin; Pan, Yuqin; Zhang, Lirong; Gao, Lei; Zhang, Qian; Qu, Lili; He, Bangshun; Song, Guoqi; Zhang, Ying; Shukui Wang

    2011-11-01

    Cyclooxygenase 2 (Cox-2, a rate-limiting enzyme in the conversion of arachidonic acid to prostanoids) has been implicated in several physiological and pathological processes, and it has been reported that polymorphisms in the regulatory region of Cox-2 might influence its expression, contributing to the interindividual susceptibility to cancer. However, results from published studies on the association between the Cox-2 -1195G > A polymorphism and the risk of cancer are conflicting. We performed a meta-analysis based on 25 case-control studies, including a total of 9482 cancer cases and 12?206 controls to derive a more precise estimation of the association and its possible influence on cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall results indicated that the variant genotypes moderately increased risk of cancer (AA/AG versus GG, OR = 1.15, 95% CI: 1.02-1.31). In the stratified analysis for the -1195G > A polymorphism, a proximate association was observed in Asian populations (AA/AG versus GG, OR = 1.28, 95% CI: 1.12-1.46), but no significant association except for oesophageal cancer and 'others' was found when stratified by cancer type. In conclusion, our meta-analysis indicates that -1195G > A of Cox-2 is a low penetration risk factor for cancer. PMID:21734230

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

    ERIC Educational Resources Information Center

    Albrecht, Doris

    2007-01-01

    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…

  10. Probing the skin permeation of fish oil\\/EPA and ketoprofen3. Effects on epidermal COX2 and LOX

    Microsoft Academic Search

    Christopher P. Thomas; Zoe Davison; Charles M. Heard

    2007-01-01

    This work employed immunocytochemistry (ICC) techniques to study the effect of topically applied fish oil and ketoprofen on cyclooxygenase (COX-2) and lipoxygenase (LOX) within freshly excised porcine ear skin. Maintained in Hanks buffer immediately post excision, full thickness membranes were mounted in Franz diffusion cells and dosed with 1ml of individual formulations containing ketoprofen, fish oil or both. At different

  11. Hydroxytyrosol inhibits pro-inflammatory cytokines, iNOS, and COX-2 expression in human monocytic cells.

    PubMed

    Zhang, Xiaomei; Cao, Jun; Zhong, Laifu

    2009-06-01

    Hydroxytyrosol (HT), isolated from extra-virgin olive oil, possesses a marked antioxidant activity and is a good radical scavenger. In this study, our aim was to examine the anti-inflammatory mechanism of HT through measuring the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression, TNF-alpha formation, and nitric oxide (NO) release in lipopolysaccharide (LPS)-induced human monocytic (THP-1) cells. Results showed that HT remarkably suppressed the LPS (1 microg/ml) induction of NO release. It also significantly attenuated the LPS-induced transcription of TNF-alpha, iNOS, and COX-2 in a dose-dependent manner. Furthermore, it was also found that HT in a concentration-dependent manner inhibited the expression of iNOS and COX-2 in THP-1 cells treated with 1 microg/ml LPS using Western Blot. Taken together, these results suggest that HT exerts anti-inflammatory effects probably through the suppression of COX-2 and iNOS expression. PMID:19198806

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

    PubMed Central

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

    2013-01-01

    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

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

    PubMed

    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

    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

  14. Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.

    PubMed

    Crawford, James J; Lee, Wendy; Aliagas, Ignacio; Mathieu, Simon; Hoeflich, Klaus P; Zhou, Wei; Wang, Weiru; Rouge, Lionel; Murray, Lesley; La, Hank; Liu, Ning; Fan, Peter W; Cheong, Jonathan; Heise, Christopher E; Ramaswamy, Sreemathy; Mintzer, Robert; Liu, Yanzhou; Chao, Qi; Rudolph, Joachim

    2015-06-25

    The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity. PMID:26030457

  15. Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases.

    PubMed

    Altmeyer, Markus; Amtmann, Eberhard; Heyl, Carina; Marschner, Aline; Scheidig, Axel J; Klein, Christian D

    2014-11-15

    We identified and characterized ?-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. ?-Aminoketones with certain structural features form ?,?-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP. PMID:25293447

  16. Structural Bioinformatics-Based Prediction of Exceptional Selectivity of p38 MAP Kinase Inhibitor PH-797804

    SciTech Connect

    Xing, Li; Shieh, Huey S.; Selness, Shaun R.; Devraj, Rajesh V.; Walker, John K.; Devadas, Balekudru; Hope, Heidi R.; Compton, Robert P.; Schindler, John F.; Hirsch, Jeffrey L.; Benson, Alan G.; Kurumbail, Ravi G.; Stegeman, Roderick A.; Williams, Jennifer M.; Broadus, Richard M.; Walden, Zara; Monahan, Joseph B.; Pfizer

    2009-07-24

    PH-797804 is a diarylpyridinone inhibitor of p38{alpha} mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38{alpha} inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38{alpha} kinase hinge: (i) Thr106 that serves as the gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180{sup o} rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38{alpha} kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38{alpha} kinase inhibitors.

  17. LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor**

    PubMed Central

    Clark, Peter G K; Vieira, Lucas C C; Tallant, Cynthia; Fedorov, Oleg; Singleton, Dean C; Rogers, Catherine M; Monteiro, Octovia P; Bennett, James M; Baronio, Roberta; Müller, Susanne; Daniels, Danette L; Méndez, Jacqui; Knapp, Stefan; Brennan, Paul E; Dixon, Darren J

    2015-01-01

    The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in?vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion. PMID:25864491

  18. Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

    PubMed Central

    2015-01-01

    A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke. PMID:24684213

  19. Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor

    PubMed Central

    2013-01-01

    The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 Å DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the ‘DFG-out’ conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction. PMID:23899692

  20. ARTICLES Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine

    Microsoft Academic Search

    Vered Stearns; Michael D. Johnson; James M. Rae; Alan Morocho; Antonella Novielli; Pankaj Bhargava; Daniel F. Hayes; Zeruesenay Desta; David A. Flockhart

    Background: Tamoxifen, a selective estrogen receptor mod- ulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) en- zymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of

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

    PubMed

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

    2014-01-01

    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

  2. Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression.

    PubMed

    Raisch, Jennifer; Rolhion, Nathalie; Dubois, Anaëlle; Darfeuille-Michaud, Arlette; Bringer, Marie-Agnès

    2015-03-01

    Intestinal dysbiosis has been reported in patients with colorectal cancer, and there is a high prevalence of Escherichia coli belonging to B2 phylogroup and producing a genotoxin, termed colibactin. Macrophages are one of the predominant tumor-infiltrating immune cells supporting key processes in tumor progression by producing protumoral factors such as cyclooxygenase-2 (COX-2). Here, we investigated whether B2 E. coli colonizing colon tumors could influence protumoral activities of macrophages. In contrast to commensal or nonpathogenic E. coli strains that were efficiently and rapidly degraded by macrophages at 24?h after infection, colon cancer-associated E. coli were able to resist killing by human THP-1 macrophages, to replicate intracellularly, and to persist inside host cells until at least 72?h after infection. Significant increases in COX-2 expression were observed in macrophages infected with colon cancer E. coli compared with macrophages infected with commensal and nonpathogenic E. coli strains or uninfected cells at 72?h after infection. Induction of COX-2 expression required live bacteria and was not due to colibactin production, as similar COX-2 levels were observed in macrophages infected with the wild-type colon cancer-associated E. coli 11G5 strain or a clbQ mutant unable to produce colibactin. Treatment of macrophages with ofloxacin, an antibiotic with intracellular tropism, efficiently decreased the number of intracellular bacteria and suppressed bacteria-induced COX-2 expression. This study provides new insights into the understanding of how tumor- infiltrating bacteria could influence cancer progression through their interaction with immune cells. Manipulation of microbes associated with tumors could have a deep influence on the secretion of protumoral molecules by infiltrating macrophages. PMID:25545478

  3. The synthetic cannabinoid WIN 55,212-2 increases COX-2 expression and PGE2 release in murine brain-derived endothelial cells following Theiler's virus infection.

    PubMed

    Mestre, Leyre; Correa, Fernando; Docagne, Fabian; Clemente, Diego; Guaza, Carmen

    2006-09-28

    Brain endothelial cells infection represents one of the first events in the pathogenesis of TMEV-induced demyelination disease (TMEV-IDD), a model of multiple sclerosis (MS). The fact that cyclooxygenase-2 (COX-2) expression in brain endothelium mediates a wide variety of actions during CNS inflammatory diseases such as MS, and that cannabinoids ameliorate the progression of TMEV-IDD, lead us to investigate the role of cannabinoids on COX-2 expression on murine brain endothelial cell cultures subjected or not to TMEV infection. Murine brain endothelial cells (b.end5) express both cannabinoid receptors CB1 and CB2. However, treatment of b.end5 with the cannabinoid agonist WIN 55,212-2 resulted in up-regulation COX-2 protein and PGE2 release by a mechanism independent on activation of these receptors. Other cannabinoids such as 2-arachidonoyl glycerol (2-AG) or the abnormal cannabidiol (Abn-CBD) failed to affect COX-2 in our conditions. TMEV infection of murine brain endothelial cell cultures induced a significant increase of COX-2 expression at 8h, which was maintained even increased, at 20 and 32h post-infection. The combination of TMEV infection and Win 55,212-2 treatment increased COX-2 expression to a greater amount than was seen with either treatment alone. 2-AG and Abn-CBD did not modify COX-2 expression after TMEV. COX-2 synthesis involved different signaling pathways when was induced by WIN 55,212-2 and/or by TMEV infection. WIN 55,212-2-induced COX-2 up-regulation involves the PI(3)K pathway, whereas COX-2 induction by TMEV needs p38 MAPK activation too. Overexpression of COX-2 and the subsequent increase of PGE2 could be affecting flow blood and/or immune reactivity. PMID:16914119

  4. Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors.

    PubMed

    Tong, Xu; Chen, Rui; Zhang, Tong-Tian; Han, Yan; Tang, Wen-Jian; Liu, Xin-Hua

    2015-02-01

    Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds 7h (IC50=2.40 ?M) and 12c (IC50=2.00 ?M) exhibited best inhibitory activity and selectivity against hMAO-A, surpassing that of the positive control Clorgyline (IC50=2.76 ?M). Based on selective activity of hMAO-A, SAR analysis showed that the order of N1 substituent contribution was bromo (3)>piperidinyl (4)>morpholinyl (5)>imidazolyl (6), and compounds with electron-withdrawing substituents (-F, -Cl) at C3 or C5 phenyl ring of 2-pyrazoline nucleus dedicated stronger MAO-A inhibitory activity. Molecular docking showed that compounds 7h and 12c were nicely bound to hMAO-A via two hydrogen bonds (SER209, GLU216), one Pi-Pi interaction and three hydrogen bonds (SER209, GLU216, TYR69), one Sigma-Pi interaction, respectively. In addition, the substituent at C3 position of 2-pyrazoline with the N1 acetyl has little effect on MAO-A inhibitory activity. These data support further studies to assess rational design of more efficiently selective hMAO inhibitors in the future. PMID:25541201

  5. Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines.

    PubMed

    Baldini, Enke; Tuccilli, Chiara; Prinzi, Natalie; Sorrenti, Salvatore; Antonelli, Alessandro; Gnessi, Lucio; Morrone, Stefania; Moretti, Costanzo; Bononi, Marco; Arlot-Bonnemains, Yannick; D'Armiento, Massimino; Ulisse, Salvatore

    2014-10-01

    Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities, resulting in either cell death or aneuploidy. Overexpression of Aurora kinases is often found in several malignancies, among which is anaplastic thyroid carcinoma (ATC). We have previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In this study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) on four human ATC cell lines (CAL-62, BHT-101, 8305C, and 8505C) were analysed. Both inhibitors reduced cell proliferation in a time- and dose-dependent manner, with IC50 ranges of 44.3-134.2?nM for MLN8237 and of 9.2-461.3?nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy yielded evidence that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152-treated cells, and in two out of four cell lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C, and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable of blocking anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but inhibition of Aurora-A appears more effective for suppressing ATC cell proliferation and for inducing the apoptotic pathway. PMID:25074669

  6. 2-Arylthiomorpholine derivatives as potent and selective monoamine oxidase B inhibitors.

    PubMed

    Lühr, Susan; Vilches-Herrera, Marcelo; Fierro, Angélica; Ramsay, Rona R; Edmondson, Dale E; Reyes-Parada, Miguel; Cassels, Bruce K; Iturriaga-Vásquez, Patricio

    2010-02-15

    2-Arylthiomorpholine and 2-arylthiomorpholin-5-one derivatives, designed as rigid and/or non-basic phenylethylamine analogues, were evaluated as rat and human monoamine oxidase inhibitors. Molecular docking provided insight into the binding mode of these inhibitors and rationalized their different potencies. Making the phenylethylamine scaffold rigid by fixing the amine chain in an extended six-membered ring conformation increased MAO-B (but not MAO-A) inhibitory activity relative to the more flexible alpha-methylated derivative. The presence of a basic nitrogen atom is not a prerequisite in either MAO-A or MAO-B. The best K(i) values were in the 10(-8)M range, with selectivities towards human MAO-B exceeding 2000-fold. PMID:20123154

  7. Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans.

    PubMed

    Hui, Raymond; El Bakkouri, Majida; Sibley, L David

    2015-07-01

    Apicomplexan parasites cause some of the most severe human diseases, including malaria (caused by Plasmodium), toxoplasmosis, and cryptosporidiosis. Treatments are limited by the lack of effective drugs and development of resistance to available agents. By exploiting novel features of protein kinases in these parasites, it may be possible to develop new treatments. We summarize here recent advances in identifying small molecule inhibitors against a novel family of plant-like, calcium-dependent kinases that are uniquely expanded in apicomplexan parasites. Analysis of the 3D structure, activation mechanism, and sensitivity to small molecules had identified several attractive chemical scaffolds that are potent and selective inhibitors of these parasite kinases. Further optimization of these leads may yield promising new drugs for treatment of these parasitic infections. PMID:26002073

  8. Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.

    PubMed

    Peterson, Emily A; Teffera, Yohannes; Albrecht, Brian K; Bauer, David; Bellon, Steven F; Boezio, Alessandro; Boezio, Christiane; Broome, Martin A; Choquette, Deborah; Copeland, Katrina W; Dussault, Isabelle; Lewis, Richard; Lin, Min-Hwa Jasmine; Lohman, Julia; Liu, Jingzhou; Potashman, Michele; Rex, Karen; Shimanovich, Roman; Whittington, Douglas A; Vaida, Karina R; Harmange, Jean-Christophe

    2015-03-12

    The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model. PMID:25699405

  9. Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.

    PubMed

    Menet, Christel J; Fletcher, Stephen R; Van Lommen, Guy; Geney, Raphael; Blanc, Javier; Smits, Koen; Jouannigot, Nolwenn; Deprez, Pierre; van der Aar, Ellen M; Clement-Lacroix, Philippe; Lepescheux, Liên; Galien, René; Vayssiere, Béatrice; Nelles, Luc; Christophe, Thierry; Brys, Reginald; Uhring, Muriel; Ciesielski, Fabrice; Van Rompaey, Luc

    2014-11-26

    Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD). PMID:25369270

  10. Relation between flexibility and positively selected HIV-1 protease mutants against inhibitors.

    PubMed

    Braz, Antônio S K; Tufanetto, Patrícia; Perahia, David; Scott, Luis P B

    2012-12-01

    The antiretroviral chemotherapy helps to reduce the mortality of HIVs infected patients. However, RNA dependant virus replication has a high mutation rate. Human immunodeficiency virus Type 1 protease plays an essential role in viral replication cycle. This protein is an important target for therapy with viral protein inhibitors. There are few works using normal mode analysis to investigate this problem from the structural changes viewpoint. The investigation of protein flexibility may be important for the study of processes associated with conformational changes and state transitions. The normal mode analysis allowed us to investigate structural changes in the protease (such as flexibility) in a straightforward way and try to associate these changes with the increase of fitness for each positively selected HIV-1 mutant protease of patients treated with several protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir, and tripanavir) in combination or separately. These positively selected mutations introduce significant flexibility in important regions such as the active site cavity and flaps. These mutations were also able to cause changes in accessible solvent area. This study showed that the majority of HIV-1 protease mutants can be grouped into two main classes of protein flexibility behavior. We presented a new approach to study structural changes caused by positively selected mutations in a pathogen protein, for instance the HIV-1 protease and their relationship with their resistance mechanism against known inhibitors. The method can be applied to any pharmaceutically relevant pathogen proteins and could be very useful to understand the effects of positively selected mutations in the context of structural changes. PMID:22821809

  11. Triple-Helical Transition State Analogs: A New Class of Selective Matrix Metalloproteinase Inhibitors

    PubMed Central

    Lauer-Fields, Janelle; Brew, Keith; Whitehead, John K.; Li, Shunzi; Hammer, Robert P.; Fields, Gregg B.

    2008-01-01

    Alterations in activities of one family of proteases, the matrix metalloproteinases (MMPs), have been implicated in primary and metastatic tumor growth, angiogenesis, and pathological degradation of extracellular matrix (ECM) components, such as collagen and laminin. Since hydrolysis of the collagen triple-helix is one of the committed steps in ECM turnover, we envisioned modulation of collagenolytic activity as a strategy for creating selective MMP inhibitors. In the present study, a phosphinate transition state analog has been incorporated within a triple-helical peptide template. The template sequence was based on the ?1(V)436-450 collagen region, which is hydrolyzed at the Gly439~Val440 bond selectively by MMP-2 and MMP-9. The phosphinate acts as a tetrahedral transition state analog, which mimics the water-bound peptide bond of a protein substrate during hydrolysis. The phosphinate replaced the amide bond between Gly-Val in the P1-P1? subsites of the triple-helical peptide. Inhibition studies revealed Ki values in the low nanomolar range for MMP-2 and MMP-9 and low to middle micromolar range for MMP-8 and MMP-13. MMP-1, MMP-3, and MT1-MMP/MMP-14 were not inhibited effectively. Melting of the triple-helix resulted in a decrease in inhibitor affinity for MMP-2. The phosphinate triple-helical transition state analog has high affinity and selectivity for the gelatinases (MMP-2 and MMP-9), and represents a new class of protease inhibitors that maximizes potential selectivity via interactions with both prime and non-prime active site subsites as well as with secondary binding sites (exosites). PMID:17672455

  12. Cyclooxygenase2 (COX2) G-765C is a protective factor for coronary artery disease but not for ischemic stroke: A meta-analysis

    Microsoft Academic Search

    Wenlong Li; Jing Xu; Xiaojian Wang; Jingzhou Chen; Channa Zhang; Kai Sun; Rutai Hui

    2009-01-01

    ObjectivePrevious case–control studies suggested the single nucleotide polymorphism of cyclooxygenase-2 (COX-2) gene (G-765C) is associated with coronary artery disease (CAD) and ischemic stroke. However, other studies did not confirm this relationship. The objective was to assess the relationship of COX-2 G-765C and CAD and ischemic stroke, using a meta-analysis.

  13. Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

    SciTech Connect

    Medina, Jesus R.; Becker, Christopher J.; Blackledge, Charles W.; Duquenne, Celine; Feng, Yanhong; Grant, Seth W.; Heerding, Dirk; Li, William H.; Miller, William H.; Romeril, Stuart P.; Scherzer, Daryl; Shu, Arthur; Bobko, Mark A.; Chadderton, Antony R.; Dumble, Melissa; Gardiner, Christine M.; Gilbert, Seth; Liu, Qi; Rabindran, Sridhar K.; Sudakin, Valery; Xiang, Hong; Brady, Pat G.; Campobasso, Nino; Ward, Paris; Axten, Jeffrey M. (GSKPA)

    2014-10-02

    Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

  14. Identification of the molecular basis of inhibitor selectivity between the human and streptococcal type I methionine aminopeptidases.

    PubMed

    Arya, Tarun; Reddi, Ravikumar; Kishor, Chandan; Ganji, Roopa Jones; Bhukya, Supriya; Gumpena, Rajesh; McGowan, Sheena; Drag, Marcin; Addlagatta, Anthony

    2015-03-12

    The methionine aminopeptidase (MetAP) family is responsible for the cleavage of the initiator methionine from newly synthesized proteins. Currently, there are no small molecule inhibitors that show selectivity toward the bacterial MetAPs compared to the human enzyme. In our current study, we have screened 20 ?-aminophosphonate derivatives and identified a molecule (compound 15) that selectively inhibits the S. pneumonia MetAP in low micromolar range but not the human enzyme. Further bioinformatics, biochemical, and structural analyses suggested that phenylalanine (F309) in the human enzyme and methionine (M205) in the S. pneumonia MetAP at the analogous position render them with different susceptibilities against the identified inhibitor. X-ray crystal structures of various inhibitors in complex with wild type and F309M enzyme further established the molecular basis for the inhibitor selectivity. PMID:25699713

  15. Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping

    PubMed Central

    Ji, Haitao; Li, Huiying; Martásek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.

    2009-01-01

    Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity, but more drug-like properties can be achieved by fragment hopping. Based on the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better drug-like properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure-based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known drug-like small-molecule modulators are still limited. PMID:19125620

  16. Nanomolar Inhibitors of the Transcription Factor STAT5b with High Selectivity over STAT5a**

    PubMed Central

    Elumalai, Nagarajan; Berg, Angela; Natarajan, Kalaiselvi; Scharow, Andrej; Berg, Thorsten

    2015-01-01

    Src homology?2 (SH2) domains play a central role in signal transduction. Although many SH2 domains have been validated as drug targets, their structural similarity makes development of specific inhibitors difficult. The cancer-relevant transcription factors STAT5a and STAT5b are particularly challenging small-molecule targets because their SH2 domains are 93?% identical on the amino acid level. Here we present the natural product-inspired development of the low-nanomolar inhibitor Stafib-1, as the first small molecule which inhibits the STAT5b SH2 domain (Ki=44?nm) with more than 50-fold selectivity over STAT5a. The binding site of the core moiety of Stafib-1 was validated by functional analysis of point mutants. A prodrug of Stafib-1 was shown to inhibit STAT5b with high selectivity over STAT5a in tumor cells. Stafib-1 provides the first demonstration that naturally occurring SH2 domains with more than 90?% sequence identity can be selectively targeted with small organic molecules. PMID:25702814

  17. Use of Selective Inhibitors and Chromogenic Substrates to Differentiate Bacteria Based on Toluene Oxygenase Activity

    SciTech Connect

    Keener, William Kelvin; Schaller, Kastli Dianne; Walton, Michelle Rene; Partin, Judy Kaye; Watwood, Mary Elizabeth; Smith, William Aaron; Chingenpeel, S. R.

    2001-09-01

    In whole-cell studies, two alkynes, 1-pentyne and phenylacetylene, were selective, irreversible inhibitors of monooxygenase enzymes in catabolic pathways that permit growth of bacteria on toluene. 1-Pentyne selectively inhibited growth of Burkholderia cepacia G4 (toluene 2-monooxygenase [T2MO] pathway) and B. pickettii PKO1 (toluene 3-monooxygenase [T3MO] pathway) on toluene, but did not inhibit growth of bacteria expressing other pathways. In further studies with strain G4, chromogenic transformation of a,a,a-Trifluoro-m-cresol (TFC) was irreversibly inhibited by 1-pentyne, but the presence of phenol prevented this inhibition. Transformation of catechol by G4 was unaffected by 1-pentyne. With respect to the various pathways and bacteria tested, phenylacetylene selectively inhibited growth of Pseudomonas mendocina KR1 (toluene 4-monooxygenase [T4MO] pathway) on toluene, but not on p-cresol. An Escherichia coli transformant expressing T4MO transformed indole or naphthalene in chromogenic reactions, but not after exposure to phenylacetylene. The naphthalene reaction remained diminished in phenylacetylene-treated cells relative to untreated cells after phenylacetylene was removed, indicating irreversible inhibition. These techniques were used to differentiate toluene-degrading isolates from an aquifer. Based on data generated with these indicators and inhibitors, along with results from Biolog analysis for sole carbon source oxidation, the groundwater isolates were assigned to eight separate groups, some of which apparently differ in their mode of toluene catabolism.

  18. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.

    PubMed

    Souers, Andrew J; Leverson, Joel D; Boghaert, Erwin R; Ackler, Scott L; Catron, Nathaniel D; Chen, Jun; Dayton, Brian D; Ding, Hong; Enschede, Sari H; Fairbrother, Wayne J; Huang, David C S; Hymowitz, Sarah G; Jin, Sha; Khaw, Seong Lin; Kovar, Peter J; Lam, Lloyd T; Lee, Jackie; Maecker, Heather L; Marsh, Kennan C; Mason, Kylie D; Mitten, Michael J; Nimmer, Paul M; Oleksijew, Anatol; Park, Chang H; Park, Cheol-Min; Phillips, Darren C; Roberts, Andrew W; Sampath, Deepak; Seymour, John F; Smith, Morey L; Sullivan, Gerard M; Tahir, Stephen K; Tse, Chris; Wendt, Michael D; Xiao, Yu; Xue, John C; Zhang, Haichao; Humerickhouse, Rod A; Rosenberg, Saul H; Elmore, Steven W

    2013-02-01

    Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers. PMID:23291630

  19. Selectivity and Anti-Parkinson's Potential of Thiadiazolidinone RGS4 Inhibitors.

    PubMed

    Blazer, Levi L; Storaska, Andrew J; Jutkiewicz, Emily M; Turner, Emma M; Calcagno, Mariangela; Wade, Susan M; Wang, Qin; Huang, Xi-Ping; Traynor, John R; Husbands, Stephen M; Morari, Michele; Neubig, Richard R

    2015-06-17

    Many current therapies target G protein coupled receptors (GPCR), transporters, or ion channels. In addition to directly targeting these proteins, disrupting the protein-protein interactions that localize or regulate their function could enhance selectivity and provide unique pharmacologic actions. Regulators of G protein signaling (RGS) proteins, especially RGS4, play significant roles in epilepsy and Parkinson's disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3?, another target of this class of chemical scaffolds. It does not inhibit the cysteine protease papain at 100 ?M. CCG-203769 enhances G?q-dependent cellular Ca(2+) signaling in an RGS4-dependent manner. TDZD inhibitors also enhance G?i-dependent ?-OR inhibition of cAMP production in SH-SY-5Y cells, which express endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 mechanism of G?i-dependent muscarinic bradycardia in vivo. Furthermore, it reverses raclopride-induced akinesia and bradykinesia in mice, a model of some aspects of the movement disorder in Parkinson's disease. A broad assessment of compound effects revealed minimal off-target effects at concentrations necessary for cellular RGS4 inhibition. These results expand our understanding of the mechanism and specificity of TDZD RGS inhibitors and support the potential for therapeutic targeting of RGS proteins in Parkinson's disease and other neural disorders. PMID:25844489

  20. 2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes.

    PubMed

    van Eis, Maurice J; Evenou, Jean-Pierre; Floersheim, Philipp; Gaul, Christoph; Cowan-Jacob, Sandra W; Monovich, Lauren; Rummel, Gabriele; Schuler, Walter; Stark, Wilhelm; Strauss, Andre; von Matt, Anette; Vangrevelinghe, Eric; Wagner, Juergen; Soldermann, Nicolas

    2011-12-15

    The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes ?, ?, ?, ? (in particular PKC?/?, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKC?-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing. PMID:22078216

  1. Effects of selective serotonin reuptake inhibitors on sperm and male fertility

    PubMed Central

    Riggin, Lauren; Koren, Gideon

    2015-01-01

    Abstract Question Some of my male patients who are taking antidepressants are planning to become fathers. Do selective serotonin reuptake inhibitors (SSRIs) affect sperm, causing either decreased fertility or increased risk of congenital anomalies? Answer There is limited evidence regarding paternal SSRI use before conception and its effects on reproductive outcomes; however, there might be some increased risk of subfertility based on animal studies and sperm-quality studies. There are insufficient data at this time to change prescribing practices of SSRIs in men who are hoping to become fathers.

  2. Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2

    PubMed Central

    2012-01-01

    The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2. PMID:24900432

  3. Syntheses of Mycobactin Analogs as Potent and Selective Inhibitors of Mycobacterium tuberculosis

    PubMed Central

    Juárez-Hernández, Raúl E.; Franzblau, Scott G.

    2012-01-01

    Three analogs of mycobactin T, the siderophore secreted by Mycobacterium tuberculosis (Mtb) were synthesized and screened for their antibiotic activity against Mtb H37Rv and a broad panel of Gram-positive and Gram-negative bacteria. The synthetic mycobactins were potent (MIC90 0.02–0.88 ?M in 7H12 media) and selective Mtb inhibitors, with no inhibitory activity observed against any other of the microorganisms tested. The maleimide-containing analog 40 represents a versatile platform for the development of mycobactin-drug conjugates, as well as other applications. PMID:22895786

  4. Synthesis and biological evaluation of novel azole derivatives as selective potent inhibitors of brassinosteroid biosynthesis.

    PubMed

    Yamada, Kazuhiro; Yajima, Osamu; Yoshizawa, Yuko; Oh, Keimei

    2013-05-01

    Brassinosteroids (BRs) are phytohormones that control several important agronomic traits, such as flowering, plant architecture, seed yield, and stress tolerance. To manipulate the BR levels in plant tissues using specific inhibitors of BR biosynthesis, a series of novel azole derivatives were synthesized and their inhibitory activity on BR biosynthesis was investigated. Structure-activity relationship studies revealed that 2RS, 4RS-1-[4-(2-allyloxyphenoxymethyl)-2-(4-chlorophenyl)-[1,3]dioxolan-2-ylmethyl]-1H-[1,2,4]triazole (G(2)) is a highly selective inhibitor of BR biosynthesis, with an IC(50) value of approximately 46 ± 2 nM, which is the most potent BR biosynthesis inhibitor observed to date. Use of gibberellin (GA) biosynthesis mutants and BR signaling mutants to analyze the mechanism of action of this synthetic series indicated that the primary site of action is BR biosynthesis. Experiments feeding BR biosynthesis intermediates to chemically treated Arabidopsis seedlings suggested that the target sites of this synthetic series are CYP90s, which are responsible for the C-22 and/or C-23 hydroxylation of campesterol. PMID:23541834

  5. CGX1037 is a novel PKC isoform delta selective inhibitor in platelets.

    PubMed

    Bhavanasi, Dheeraj; Kostyak, John C; Swindle, John; Kilpatrick, Laurie E; Kunapuli, Satya P

    2015-01-01

    Platelets upon activation change their shape, aggregate and secrete alpha and dense granule contents among which ADP acts as a feedback activator. Different Protein Kinase C (PKC) isoforms have specific non-redundant roles in mediating platelet responses including secretion and thrombus formation. Murine platelets lacking specific PKC isoforms have been used to evaluate the isoform specific functions. Novel PKC isoform ? has been shown to play an important role in some pathological processes. Lack of specific inhibitors for PKC? has restricted analysis of its role in various cells. The current study was carried out to evaluate a novel small molecule PKC? inhibitor, CGX1037 in platelets. Platelet aggregation, dense granule secretion and western blotting experiments were performed to evaluate CGX1037. In human platelets, CGX1037 inhibited PAR4-mediated phosphorylation on PKD2, a PKC?-specific substrate. Pre-treatment of human or murine platelets with CGX1037 inhibited PAR4-mediated dense granule secretion whereas it potentiated GPVI-mediated dense granule secretion similar to the responses observed in murine platelets lacking PKC?· Furthermore, pre-treatment of platelets from PKC?(-/-) mice with CGX1037 had no significant additive effect on platelet responses suggesting the specificity of CGX1037. Hence, we show that CGX1037 is a selective small molecule inhibitor of PKC? in platelets. PMID:24433221

  6. Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors

    PubMed Central

    Feng, Li; Geisselbrecht, Yann; Blanck, Sebastian; Wilbuer, Alexander; Atilla-Gokcumen, G. Ekin; Filippakopoulos, Panagis; Kräling, Katja; Celik, Mehmet Ali; Harms, Klaus; Maksimoska, Jasna; Marmorstein, Ronen; Frenking, Gernot; Knapp, Stefan; Essen, Lars-Oliver; Meggers, Eric

    2011-01-01

    The generation of synthetic compounds with exclusive target specificity is an extraordinary challenge of molecular recognition and demands novel design strategies, in particular for large and homologous protein families such as protein kinases with more than 500 members. Simple organic molecules often do not reach the necessary sophistication to fulfill this task. Here, we present six carefully tailored, stable metal-containing compounds in which unique and defined molecular geometries with natural-product-like structural complexity are constructed around octahedral ruthenium(II) or iridium(III) metal centers. Each of the six reported metal compounds displays high selectivity for an individual protein kinase, namely GSK3?, PAK1, PIM1, DAPK1, MLCK, and FLT4. Although being conventional ATP-competitive inhibitors, the combination of the unusual globular shape and rigidity characteristics, of these compounds facilitates the design of highly selective protein kinase inhibitors. Unique structural features of the octahedral coordination geometry allow novel interactions with the glycine-rich loop, which contribute significantly to binding potencies and selectivities. The sensitive correlation between metal coordination sphere and inhibition properties suggests that in this design, the metal is located at a “hot spot” with the ATP binding pocket, not too close to the hinge region where globular space is unavailable, and at the same time not too far out towards the solvent where the octahedral coordination sphere would not have a significant impact on potency and selectivity. This study thus demonstrates that inert (stable) octahedral metal complexes are sophisticated structural scaffolds for the design of highly selective chemical probes. PMID:21446733

  7. Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines

    PubMed Central

    Garofalo, Cecilia; Capristo, Mariantonietta; Mancarella, Caterina; Reunevi, Hadas; Picci, Piero; Scotlandi, Katia

    2015-01-01

    Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Several studies have confirmed the involvement of the insulin-like growth factor (IGF) system in the regulation of OS cell proliferation and differentiation as well as in the protection of cells from chemotherapy. Insulin receptor substrate (IRS)-1 is a critical mediator of IGF-1R signaling, and we recently reported that its overexpression in OS cells increases proliferation, migration, and metastasis both in vitro and in vivo. In this study, we evaluated the efficacy of NT157, a selective inhibitor of IRS-1/2, in a panel of OS cells. A strong dose-dependent inhibition of growth was observed in the MG-63, OS-19, and U-2OS OS cell lines, displaying IC50 values at sub-micromolar doses after 72?h of treatment. Exposure to NT157 elicited dose- and time-dependent decreases in IRS-1 levels. Moreover, a protein analysis showed that the degradation of IRS-1 inhibited the activation of principal downstream mediators of the IGF pathway. NT157 significantly affected the cells’ migratory ability, as confirmed by a wound-healing assay. The inhibitor induced cytostatic effects, as evidenced by G2/M cell cycle arrest, and did not affect apoptosis. Consequently, NT157 was combined with drugs used to treat OS in order to capitalize on its therapeutic potential. Simultaneous treatments were made in association with chemotherapeutic agents in a fixed ratio for 72?h and cell proliferation was determined by MTT assay. Synergistic or addictive effects with respect to single agents are expressed as the combination index. Significant synergistic effects were obtained with several targeted drugs, such as Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and NVP-BEZ235, a dual inhibitor of PI-3K/mTOR. Overall, these findings provide evidence for the effectiveness of a selected inhibitor of IRS-1/2 NT157 in OS cells, displaying a promising approach based on the targeting of IRS-1 combined with other therapies for the treatment of this pediatric solid tumor. PMID:26029165

  8. Interaction between selective cyclooxygenase inhibitors and capsaicin-sensitive afferent sensory nerves in pathogenesis of stress-induced gastric lesions. Role of oxidative stress.

    PubMed

    Kwiecien, S; Konturek, P C; Sliwowski, Z; Mitis-Musiol, M; Pawlik, M W; Brzozowski, B; Jasnos, K; Magierowski, M; Konturek, S J; Brzozowski, T

    2012-04-01

    Gastric microcirculation plays an important role in the maintenance of the mucosal gastric integrity and the mechanism of injury as well as providing protection to the gastric mucosa. Disturbances in the blood perfusion, through the microcapillaries within the gastric mucosa may result in the formation of mucosal damage. Acute gastric mucosal lesions constitute an important clinical problem. Originally, one of the essential component of maintaining the gastric mucosal integrity was the biosynthesis of prostaglandins (PGs), an issue that has captured the attention of numerous investigations. PGs form due to the activity of cyclooxygenase (COX), an enzyme which is divided into 2 isoforms: constitutive (COX-1) and inducible (COX-2) ones. The inhibition of COX-1 by SC-560, or COX-2 by rofecoxib, reduces gastric blood flow (GBF) and impairs gastric mucosal integrity. Another detrimental effect on the gastric mucosal barrier results from the ablation of sensory afferent nerves by neurotoxic doses of capsaicin. Functional ablation of the sensory afferent nerves by capsaicin attenuates GBF and also renders the gastric mucosa more susceptible to gastric mucosal damage induced by ethanol, aspirin and stress. However, the role of reactive oxygen species (ROS) in the interaction between COX specific inhibitors and afferent sensory nerves has not been extensively studied. The aim of our present study was to determine the participation of ROS in pathogenesis of stress-induced gastric lesions in rats administered with SC-560 or rofecoxib, with or without ablation of the sensory afferent nerves. ROS were estimated by measuring the gastric mucosal tissue level of MDA and 4-HNE, the products of lipid peroxidation by ROS as well as the SOD activity and reduced glutathione (GSH) levels, both considered to be scavengers of ROS. It was demonstrated that exposure to 3.5 h of WRS resulted in gastric lesions, causing a significant increase of MDA and 4-HNE in the gastric mucosa, accompanied by a decrease of SOD activity and mucosal GSH level. Pretreatment with COX-1 and COX-2 inhibitors (SC-560 and rofecoxib, respectively) aggravated the number of gastric lesions, decreased GBF, attenuated GSH level without further significant changes in MDA and 4-HNE tissue levels and SOD activity. Furthermore, the capsaicin--nactivation of sensory nerves resulted in exaggeration of gastric mucosal damage induced by WRS and this was further augmented by rofecoxib. We conclude that oxidative stress, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), as well as decrease of SOD activity and the fall in GSH tissue level, may play an important role in the mechanism of interaction between the inhibition of COX activity and afferent sensory nerves releasing vasoactive neuropeptides. This is supported by the fact that the addition of specific COX-1 or COX-2 inhibitors to animals with capsaicin denervation led to exacerbation of gastric lesions, and further fall in the antioxidizing status of gastric mucosa exposed to stress. PMID:22653901

  9. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

    PubMed Central

    Rasmussen, B B; Maënpää, J; Pelkonen, O; Loft, S; Poulsen, H E; Lykkesfeldt, J; Brøsen, K

    1995-01-01

    1. Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2. None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only potent inhibitor of CYP3A having IC50 values of 11 microM and 19 microM for testosterone 6 beta-hydroxylase and cortisol 6 beta-hydroxylase, respectively. 3. Norfluoxetine, sertraline and fluvoxamine inhibited CYP1A1 (7-ethoxyresorufin O-deethylase) in microsomes from human placenta (IC50 values 29 microM, 35 microM and 80 microM, respectively). Fluvoxamine was a potent inhibitor of CYP1A2-mediated 7-ethoxyresorufin O-deethylase activity (IC50 = 0.3 microM) in human liver. 4. In microsomes from three human livers fluvoxamine potently inhibited all pathways of theophylline biotransformation, the apparent inhibitor constant, Ki, was 0.07-0.13 microM, 0.05-0.10 microM and 0.16-0.29 microM for inhibition of 1-methylxanthine, 3-methylxanthine and 1,3-dimethyluric acid formation, respectively. Seven other SSRIs showed either weak or no inhibition of theophylline metabolism. 5. Ethanol inhibited the formation of 1,3-dimethyluric acid with K(i) value of 300 microM, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8-hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3-dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8-hydroxylation of theophylline. 6. It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2. PMID:7742153

  10. A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase

    PubMed Central

    Sharma, Amit; Slaughter, Alison; Jena, Nivedita; Feng, Lei; Kessl, Jacques J.; Fadel, Hind J.; Malani, Nirav; Male, Frances; Wu, Li; Poeschla, Eric; Bushman, Frederic D.; Fuchs, James R.; Kvaratskhelia, Mamuka

    2014-01-01

    The quinoline-based allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are promising candidates for clinically useful antiviral agents. Studies using these compounds have highlighted the role of IN in both early and late stages of virus replication. However, dissecting the exact mechanism of action of the quinoline-based ALLINIs has been complicated by the multifunctional nature of these inhibitors because they both inhibit IN binding with its cofactor LEDGF/p75 and promote aberrant IN multimerization with similar potencies in vitro. Here we report design of small molecules that allowed us to probe the role of HIV-1 IN multimerization independently from IN-LEDGF/p75 interactions in infected cells. We altered the rigid quinoline moiety in ALLINIs and designed pyridine-based molecules with a rotatable single bond to allow these compounds to bridge between interacting IN subunits optimally and promote oligomerization. The most potent pyridine-based inhibitor, KF116, potently (EC50 of 0.024 µM) blocked HIV-1 replication by inducing aberrant IN multimerization in virus particles, whereas it was not effective when added to target cells. Furthermore, KF116 inhibited the HIV-1 IN variant with the A128T substitution, which confers resistance to the majority of quinoline-based ALLINIs. A genome-wide HIV-1 integration site analysis demonstrated that addition of KF116 to target or producer cells did not affect LEDGF/p75-dependent HIV-1 integration in host chromosomes, indicating that this compound is not detectably inhibiting IN-LEDGF/p75 binding. These findings delineate the significance of correctly ordered IN structure for HIV-1 particle morphogenesis and demonstrate feasibility of exploiting IN multimerization as a therapeutic target. Furthermore, pyridine-based compounds present a novel class of multimerization selective IN inhibitors as investigational probes for HIV-1 molecular biology. PMID:24874515

  11. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.

    PubMed

    Leverson, Joel D; Phillips, Darren C; Mitten, Michael J; Boghaert, Erwin R; Diaz, Dolores; Tahir, Stephen K; Belmont, Lisa D; Nimmer, Paul; Xiao, Yu; Ma, Xiaoju Max; Lowes, Kym N; Kovar, Peter; Chen, Jun; Jin, Sha; Smith, Morey; Xue, John; Zhang, Haichao; Oleksijew, Anatol; Magoc, Terrance J; Vaidya, Kedar S; Albert, Daniel H; Tarrant, Jacqueline M; La, Nghi; Wang, Le; Tao, Zhi-Fu; Wendt, Michael D; Sampath, Deepak; Rosenberg, Saul H; Tse, Chris; Huang, David C S; Fairbrother, Wayne J; Elmore, Steven W; Souers, Andrew J

    2015-03-18

    The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics. PMID:25787766

  12. COX2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer

    Microsoft Academic Search

    Huidong Liu; Jianbing Xiao; Yanmei Yang; Yan Liu; Ruijin Ma; Yuhang Li; Fengchun Deng; Yafang Zhang

    Lymphangiogenesis has been shown to promote lymph node metastasis in cancers, making it an important target in cancer therapy. Vascular endothelial growth factor (VEGF)-C is upregulated in various tumors\\/cancers and is one of the most potent growth factors for inducing lymphangiogenesis and promoting lymph node metastasis (LNM). Likewise, cyclooxygenase (COX)-2 plays major roles in carcinogenesis, tumor growth and metastasis via

  13. Piceatannol Inhibits Phorbol Ester-Induced NF-? B Activation and COX2 Expression in Cultured Human Mammary Epithelial Cells

    Microsoft Academic Search

    Dan Liu; Do-Hee Kim; Jong-Min Park; Hye-Kyung Na; Young-Joon Surh

    2009-01-01

    There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3?,5?-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and antioxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking

  14. Current evidence on the relationship between polymorphisms in the COX2 gene and breast cancer risk: a meta-analysis

    Microsoft Academic Search

    Ke-Da Yu; Ao-Xiang Chen; Chen Yang; Li-Xin Qiu; Lei Fan; Wen-Huan Xu; Zhi-Ming Shao

    2010-01-01

    The association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene and breast cancer risk is still ambiguous.\\u000a We here try to derive a more precise estimation of the relationship by performing a meta-analysis based on currently available\\u000a evidence from literature. More than 15 SNPs have been studied, and the most studied genetic variants were rs5275, rs5277,\\u000a and rs20417. Crude odds

  15. Hydroxytyrosol inhibits pro-inflammatory cytokines, iNOS, and COX2 expression in human monocytic cells

    Microsoft Academic Search

    Xiaomei Zhang; Jun Cao; Laifu Zhong

    2009-01-01

    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

  16. Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1

    PubMed Central

    2011-01-01