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COX-2
Terms modified by COX-2 Selected AbstractsOverexpression of cyclooxygenase-2 is associated with chemoradiotherapy resistance and prognosis in esophageal squamous cell carcinoma patientsDISEASES OF THE ESOPHAGUS, Issue 8 2008W.-Z. Huang SUMMARY Our objective was to investigate whether cyclooxygenase-2 (COX-2) expression can predict the patient's response to chemoradiotherapy (CRT) and ensuing prognosis in esophageal squamous cell carcinoma (ESCC). The clinicopathological and follow-up data of 112 patients with ESCC who underwent CRT from January 2001 to June 2006 were analyzed retrospectively. The immunohistochemical expression level of COX-2 was examined for all biopsy specimens of primary tumors, and the correlation of COX-2 expression with the patient's response to CRT and prognosis was examined. COX-2 positive immunostaining was detected in 111 (99.1%) of the patients, including overexpression in 54 (48.2%) patients and low expression in 58 (51.8%) of the patients. The response of tumors with a low level expression of COX-2 (70.7%, 41/58) was significantly higher than that of tumors with COX-2 overexpression (42.6%, 23/54; P = 0.003). Patients with a low level of COX-2 expression had a higher downstaged rate than those with a high level of COX-2 expression (9/13 vs 2/8), but the difference was not statistically significant (P = 0.08). In the definitive CRT group (91 cases), COX-2 overexpression was significantly associated with poor 3-year overall survival (P = 0.028). Multivariate analysis showed that only metastatic stage (nonregional node metastasis) was an independent prognosis factor. The assessment of COX-2 status may provide additional information to identify ESCC patients with poor chances of response to CRT and potential candidates for more individualized treatment. [source] COX-2 mRNA expression in esophageal squamous cell carcinoma (ESCC) and effect by NSAIDDISEASES OF THE ESOPHAGUS, Issue 1 2008X. Liu SUMMARY., To investigate cyclooxygenase-2 (COX-2) mRNA expression in human esophageal squamous cell carcinoma and the effect of a non-steroidal anti-inflammatory drug (NSAID) on it, in order to explore the mechanism of COX-2 in esophageal squamous cell carcinoma (ESCC) carcinogenesis and the ability of NSAID to prevent or treat ESCC. Frozen specimens of human ESCC and adjacent normal esophageal squamous epithelium pairs (n = 22) were examined for COX-2 mRNA expression by reverse-transcription polymerase chain reaction (RT-PCR). After incubation with aspirin (a non-selective COX inhibitor) or Nimesulide (a selective COX-2 inhibitor), the proliferation status of two human esophageal squamous cancer cell lines, EC-9706 and EC-109, was quantified by 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide assay. The expression of COX-2 mRNA in these cells was detected by RT-PCR. COX-2 mRNA was expressed in 12 of 22 (54.5%) ESCC tissue samples, but it was undetectable in all the specimens of adjacent normal esophageal squamous epithelium COX-2 mRNA expression. Both aspirin (5,20 mmol/L) and Nimesulide (0.1,0.8 mmol/L) inhibited EC-9706 cell line proliferation and suppressed its COX-2 mRNA expression dose-dependently. However, only aspirin (5,20 mmol/L) could inhibit proliferation in the EC-109 cell line and suppress COX-2 mRNA expression. Nimesulide (0.1,0.8 mmol/L) could neither inhibit EC-109 cell growth nor suppress COX-2 mRNA expression. COX-2 mRNA expression is a frequent phenomenon in human ESCC tissue samples and plays an important role in the carcinogenesis of ESCC. NSAID may be useful in the chemoprevention and therapy of human ESCC and its effects are likely to be mediated by modulating COX-2 activity. [source] Effect of celecoxib on cyclooxygenase-2 expression and possible variants in a patient with Barrett's esophagusDISEASES OF THE ESOPHAGUS, Issue 3 2007G. A. Jacobson SUMMARY., Cyclooxygenase-2 (COX-2) expression is increased in metaplastic and dysplastic Barrett's esophageal epithelium and it is thought that selective COX-2 inhibitors could offer hope as chemoprevention therapy. The aim of the study was to investigate the in vivo effect of celecoxib on COX-2 expression in patients with Barrett's esophagus and no recent history of non-steroidal anti-inflammatory drug use. Endoscopic mucosal biopsy specimens were collected at baseline and after 28 days of therapy in a patient treated with celecoxib 200 mg twice daily. Samples were analyzed for COX-2 expression by immunoblot analysis with chemiluminescence detection. COX-2 expression was found to decline 20% and 44% at two different biopsy sites compared to the baseline sample. Longer exposures revealed a number of previously unidentified proteins above and below the 67 kDa COX-2 protein including 38 kDa and 45 kDa proteins which were present only at study completion consistent with up-regulation after celecoxib therapy. Further investigations of the 38 kDa and 45 kDa proteins were undertaken using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) with immunoblot and MALDI-TOF (matrix assisted laser desorption ionization , time of flight) analysis but no matches were found and results were inconclusive. Unmatched masses from MALDI-TOF peptide mass fingerprinting were compared with human COX-2 (67 kDa) and COX-2b (39 kDa) using unspecific cleavage. Peptide sequence homology with COX-2 and COX-2b was found for a length of 19 amino acids. Based on immunodetection, molecular weight and equivical MALDI-TOF results, one of these up-regulated proteins may be COX-2b. [source] Protective effect of curcumin, a Curcuma longa constituent, in early colonic inflammation in rats,DRUG DEVELOPMENT RESEARCH, Issue 6 2009Juan Manuel Sánchez-Calvo Abstract Curcumin, a polyphenol derived from the plant, Curcuma longa, has a variety of pharmacological effects, including chemotherapeutic, anti-inflammatory, antiangiogenic, and antioxidant activities. To gain a better understanding of the effects and mechanisms of action of curcumin on the acute injury caused by intra-colonic administration of acetic acid (AA) in rats, inflammation was assessed by histology and myeloperoxidase activity (MPO; an index of neutrophil infiltration in the mucosa); Th1 and Th2 cytokine production; histological and histochemical analysis of the lesions; nitrite production in colon mucosa; and the expression of iNOS, COX-1 and -2 using Western blotting and inmmunohistochemistry. We also studied the involvement of the p38 MAPK/JNK signalling pathway in the protective effect of curcumin in acute colonic inflammation. Curcumin (50,100,mg/kg/day) reduced the degree of colonic injury, the index of neutrophil infiltration and Th1 cytokine secretion, and increased IL-10 production, reduced colonic levels of nitrites, and reduced COX-2 and iNOS overexpression. A reduction in the activation of p38 and JNK MAPKs was also observed. Thus, we show that the widely used food additive, curcumin reduced the development of AA-induced colitis and alleviated the inflammatory response. Inhibition of MAPK signalling by curcumin could explain the changes on the cytokine Th1/Th2 profile, the reduction of COX-2 and iNOS signaling, as well as the decreased nitrite production in colonic mucosa, suggesting that curcumin may be useful in the treatment of ulcerative colitis. Drug Dev Res, 2009. © 2009 Wiley-Liss, Inc. [source] Determination of enantiomeric purity of a novel COX-2 anti-inflammatory drug by capillary electrophoresis using single and dual cyclodextrin systemsELECTROPHORESIS, Issue 9 2003Carlos Pérez-Maseda Abstract E-6087 is the most advanced compound among the cyclooxygenase-2 (COX-2) inhibitor drugs developed in our company. Its activity is mainly associated with the S(,)-enantiomer (E-6232), whereas the R(,)-enantiomer (E-6231) becomes an impurity whose content should be determined. Five main impurities and degradation products of E-6232 have been found (E-6144, E-6024, E-6072, E-6397 and E-6132), and some of them co-elute with the distomer when using a chiral high-performance liquid chromatography (HPLC) method. Consequently, we have optimized the separation of all the impurities from the two enantiomers of E-6087 by capillary electrophoresis (CE), in order to use the method for the enantiomeric purity determination of E-6232. The effect of the methanol (MeOH) content in the background electrolyte (BGE), the sulfobutyl ether-,-cyclodextrin (SBE-,-CD) and heptakis-(2,6-di- O -methyl)-,-cyclodextrin (DM-,-CD) concentration, and the capillary temperature have been studied. Separation of all compounds could be achieved in different systems, either in a single CD-system (with SBE-,-CD) or in a dual CD-system (with DM-,-CD as a neutral CD). By using the dual CD system a limit of detection (LOD) and a limit of quantitation (LOQ) of 0.03% and 0.1% of distomer, respectively, were achieved*. [source] Effect of intravenous lidocaine administration on laminar inflammation in the black walnut extract model of laminitisEQUINE VETERINARY JOURNAL, Issue 3 2010J. M. WILLIAMS Summary Reasons for performing study: Laminitis is a serious complication of horses suffering from sepsis/endotoxaemia-related events. Laminitis in horses and organ injury in human sepsis are both reported to involve inflammatory injury to the laminae/organs including early activation of endothelium and leucocytes leading to emigration of neutrophils into the tissue interstitium. In the black walnut extract (BWE) model, systemic inflammatory events coincide with marked increase in laminar mRNA concentrations of inflammatory genes including proinflammatory cytokines (i.e. IL-1,, IL-6), COX-2, chemokines (i.e. IL-8) and endothelial adhesion molecules (i.e. ICAM-1 and E-selectin). In models of human sepsis, i.v. lidocaine has been reported to decrease leucocyte and endothelial activation, and the expression of proinflammatory cytokines and chemokines. Objectives: To evaluate the effect of i.v. lidocaine therapy on the inflammatory processes documented to occur in the BWE model of laminitis. Methods: Twelve horses were administered BWE and treated immediately with either lidocaine (1.3 mg/kg bwt bolus, followed by 0.05 mg/kg bwt/min CRI, n = 6) or saline (n = 6) for 10 h. At 10 h post BWE administration, laminar samples were obtained under general anaesthesia for assessment of proinflammatory gene expression (using RT-qPCR) and leucocyte emigration (via CD13 immunohistochemistry). At 0, 3 and 10 h post BWE administration, skin samples were obtained for assessment of leucocyte emigration (via calprotectin immunohistochemistry). Results: No significant differences between groups were noted for inflammatory gene mRNA concentrations (IL-1,, IL-6, IL-8, COX-2) or for number of leucocytes present within the laminar interstitium or skin dermis. Increased (P<0.05) laminar E-selectin mRNA concentrations were present in the LD group (vs. SAL group). Conclusions: Continuous administration of i.v. lidocaine does not inhibit inflammatory events in either the laminae or skin in the horse administered black walnut extract. Potential relevance: This work questions the use of continuous i.v. administration of lidocaine as an effective anti-inflammatory therapy for systemic inflammation. [source] The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cellsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2002H.-G. Yu Summary Background Acetylsalicylic acid (ASA, aspirin), the most common nonsteroidal anti-inflammatory drug (NSAID), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the mechanism of its anticancer function remains unclear. The aim of this study was to determine the effects of acetylsalicylic acid on proliferation, apoptosis, and invasion in human cyclooxygenase-2 (COX-2) negative colorectal cancer cell lines. Materials and Methods After treatment with various concentrations of ASA, cell proliferation was measured in the human colon cancer cell line SW480. Apoptotic cells were identified by transmission electron microscopy, acridine orange staining, and flow cytometry. The invasive potential of SW480 cells was detected using an in vitro invasion assay. The production of carcinoembryonic antigen was measured by microparticle enzyme immunoassay. Expression of Bcl2, Bax, CD44v6, and nm23 were evaluated by immunocytochemistry. Results ASA significantly inhibited the proliferation of SW480 cells and stimulated apoptosis. Production of carcinoembryonic antigen and the invasive potential of SW480 cells were also inhibited by ASA. After treatment with ASA, down-regulation of Bcl2 and CD44v6 expression and up-regulation of nm23 expression were observed in SW480 cells. No obvious effect of ASA was found on Bax expression. Conclusion Our findings reveal that ASA inhibits the proliferation and promotes apoptosis in the human colon cancer cell line SW480. Down-regulation of Bcl2 expression might represent a potential mechanism by which ASA induces apoptosis in this COX-2 negative colon cancer cell line. Our results also suggest that ASA decreases the invasive potential of these colon cancer cells. Decreased CEA content and CD44v6 expression and elevated nm23 expression may contribute to the effect of ASA on invasive potential of SW480 colon cancer cells. [source] AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase-2 mRNA by inhibiting mitogen-activated protein kinase p38EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2004Pilar Alcaide Abstract Secretion of proinflammatory mediators by activated macrophages plays an important role in the immune response to Trypanosoma cruzi. We have previously reported that AgC10, a glycosylphosphatidylinositol-anchored mucin from T. cruzi, inhibits TNF secretion by activated macrophages (de Diego, J., Punzon, C., Duarte, M. and Fresno, M., Alteration of macrophage function bya Trypanosoma cruzi membrane mucin. J. Immunol. 1997. 159: 4983,4989). In this report we have further investigated the molecular mechanisms underlying this inhibition. AgC10 inhibited TNF, IL-10 and cyclooxygenase-2 (COX-2) synthesis by macrophages activated with LPS or LPS plus IFN-, in a dose-dependent manner. AgC10 did not affect other aspects of macrophage activation induced by LPS, such as inducible nitric oxide synthase (iNOS) expression. AgC10 also had no effect on TNF or COX-2 transcription or the induction of their promoters but inhibited the stability of TNF and COX-2 mRNA, which are regulated post-transcriptionally by the mitogen-activated protein kinase (MAPK) p38 pathway. AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited. This led to TNF and COX-2 mRNA destabilization. In contrast, AgC10 did not affect p38 activation induced by TNF. Furthermore, AgC10 inhibition must lie upstream in the MAPK activation pathway by LPS, since this mucin also inhibited extracellularly regulated kinase (ERK) and Jun kinase (JNK)activation. [source] COX-2, but not COX-1, activity is necessary for the induction of perforant path long-term potentiation and spatial learning in vivoEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2008T. R. Cowley Abstract The objectives of this research were to investigate the role played by the enzyme cyclooxygenase (COX) in learning and memory, synaptic plasticity and synaptic transmission in the rat brain in vivo. Male Wistar rats were treated with isoform-selective inhibitors for COX-1 and COX-2, either chronically and tested in the watermaze or acutely before electrophysiological recordings were made. We found a significant impairment in acquisition of the watermaze with inhibition of COX-2. Furthermore, we found COX-2 but not COX-1 inhibition significantly blocked long-term potentiation (LTP) induction but had no effect on already established LTP. Moreover, exogenous replacement of the main metabolite of COX-2 activity, PGE2, was sufficient to restore LTP induction and for normal downstream signalling to ensue, namely extracellular signalling-regulated kinase (ERK)-phosphorylation and c-FOS expression. We conclude that endogenous basal levels of PGE2 resulting from COX-2 but not COX-1 activity are necessary for synaptic plasticity and memory acquisition. [source] Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2001Chunyu Cao Abstract Peripheral immunological insults induce interleukin (IL)-1, and IL-6 in the brain. To elucidate the mechanism(s) of fever evoked by these brain-derived cytokines, and possible interactions between them, we examined in rats: (i) whether cyclooxygenase-2 is responsible for fever evoked by central injection of these cytokines; (ii) if so, where in the brain cyclooxygenase-2 is induced; (iii) where the receptors for these cytokines are located; and (iv) how the expression of these receptors is influenced by the cytokines. Intracerebroventricular injection of these cytokines evoked fever that was suppressed by a cyclooxygenase-2 inhibitor. Brain endothelium was the site of cyclooxygenase-2 induction by these cytokines. IL-1 receptor (IL-1R) was constitutively expressed in brain endothelium, and its mRNA was further upregulated by either cytokine. IL-6R mRNA was constitutively expressed in the cerebral cortex, and was newly induced in as yet unidentified cells in brain blood vessels by either cytokine. Messenger RNAs for cyclooxygenase-2, IL-1R, and IL-6R were often observed in the same blood vessels. These results suggest that COX-2 induced in brain endothelium is, at least in part, involved in the fever evoked by these cytokines, and that one possible interaction between these two cytokines is mutual upregulation of their receptors in the endothelium or perivascular cells, resulting in augmentation of their actions. [source] An active triple-catalytic hybrid enzyme engineered by linking cyclo-oxygenase isoform-1 to prostacyclin synthase that can constantly biosynthesize prostacyclin, the vascular protectorFEBS JOURNAL, Issue 23 2008Ke-He Ruan It remains a challenge to achieve the stable and long-term expression (in human cell lines) of a previously engineered hybrid enzyme [triple-catalytic (Trip-cat) enzyme-2; Ruan KH, Deng H & So SP (2006) Biochemistry45, 14003,14011], which links cyclo-oxygenase isoform-2 (COX-2) to prostacyclin (PGI2) synthase (PGIS) for the direct conversion of arachidonic acid into PGI2 through the enzyme's Trip-cat functions. The stable upregulation of the biosynthesis of the vascular protector, PGI2, in cells is an ideal model for the prevention and treatment of thromboxane A2 (TXA2)-mediated thrombosis and vasoconstriction, both of which cause stroke, myocardial infarction, and hypertension. Here, we report another case of engineering of the Trip-cat enzyme, in which human cyclo-oxygenase isoform-1, which has a different C-terminal sequence from COX-2, was linked to PGI2 synthase and called Trip-cat enzyme-1. Transient expression of recombinant Trip-cat enzyme-1 in HEK293 cells led to 3,5-fold higher expression capacity and better PGI2 -synthesizing activity as compared to that of the previously engineered Trip-cat enzyme-2. Furthermore, an HEK293 cell line that can stably express the active new Trip-cat enzyme-1 and constantly synthesize the bioactive PGI2 was established by a screening approach. In addition, the stable HEK293 cell line, with constant production of PGI2, revealed strong antiplatelet aggregation properties through its unique dual functions (increasing PGI2 production while decreasing TXA2 production) in TXA2 synthase-rich plasma. This study has optimized engineering of the active Trip-cat enzyme, allowing it to become the first to stably upregulate PGI2 biosynthesis in a human cell line, which provides a basis for developing a PGI2 -producing therapeutic cell line for use against vascular diseases. [source] Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: Synergy with interleukin-1,, tumor necrosis factor-,, and bacterial lipopolysaccharideGLIA, Issue 4 2003Pavle Repovic Abstract Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E2 (PGE2), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE2 production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1,, tumor necrosis factor-,, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE2 production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE2 production by OSM and IL-1, treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE2 synthesis. Of the enzymes involved in PGE2 biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1,. Nuclear run-on assays demonstrate that OSM and IL-1, synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1,. To effect synergy on the PGE2 level, OSM signals in part through its gp130/OSMR, receptor, since neutralizing antibodies against gp130 and OSMR,, but not LIFR,, decrease PGE2 production in response to OSM plus IL-1,. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1, and OSM upregulation of COX-2 and PGE2, indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE2 amplification may be active in brain pathologies where both OSM and IL-1, are present, such as glioblastomas and multiple sclerosis. GLIA 42:433,446, 2003. © 2003 Wiley-Liss, Inc. [source] COX-2 polymorphisms and the risk for head and neck cancer in white patientsHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 7 2009Wilbert H. M. Peters PhD Abstract Background. Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether functional genetic polymorphisms in COX-2 may have a risk-modifying effect on head and neck carcinogenesis. Methods. Blood from 431 white patients with oral, pharyngeal, or laryngeal carcinoma and 438 white healthy controls was investigated for the presence of 2 functional promoter region polymorphisms (,1195A,G and ,765G,C) in COX-2. Results. Logistic regression analysis did not show differences in COX-2 genotype distributions between patients and controls. Also no differences were found when stratified according to tumor localization, sex, or tobacco consumption. Conclusion. In contrast to earlier reports on the role of these COX-2 polymorphisms in mediating susceptibility to squamous esophageal carcinoma in a Chinese population, we could not demonstrate a risk-modifying effect in head and neck carcinogenesis in whites. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [source] Prediction of poor survival by cyclooxygenase-2 in patients with T4 nasopharyngeal cancer treated by radiation therapy: Clinical and in vitro studiesHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 6 2005Wen-Cheng Chen MD Abstract Background. This study was undertaken to determine the status of cyclooxygenase-2 (COX-2) in nasopharyngeal cancer (NPC) in Taiwanese patients and its relationship to survival after radiotherapy (RT). In addition, the effect of NS-398, a potent selective COX-2 inhibitor, was tested in vitro alone and in combination with radiation on NPC-BM1 human NPC cells as a prelude to using this drug along with RT in the treatment of patients with NPC. Methods. Thirty-seven patients diagnosed with T4N0,3M0 NPC were enrolled into this study. COX-2 expression was determined by immunohistochemical staining of formalin-fixed, paraffin-embedded tumor tissue. Patient survival was the clinical end point. The effects of COX-2 expression on cell survival and radioresistance was tested in vitro using the selective COX-2 inhibitor NS-398 in conjunction with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) and clonogenic assays. Results. COX-2 immunoreactivity was detected in 62% of NPC tumors, and expression levels were high in 43%. Survival analysis showed the 5-year overall survival rates for patients who had high COX-2 expression was 27% compared with 60% for those with low/absent expression (p = .047). Pattern of failure analysis showed no significant difference between high and low COX-2 expression in locoregional failure (27% vs 25%, p = .91). However, patients with N0 to N1 disease and high COX-2 expression had a significantly higher incidence of distant metastasis compared with patients with stage N0 to N1 disease and low COX-2 expression (83% vs 15%, p = .004). This difference was not observed in patients with N2 to N3 disease. This difference contributed to worse survival of patients whose tumors had high COX-2 expression levels. The selective COX-2 inhibitor NS-398 was directly cytotoxic to NPC-BM1 cells in vitro, as judged in an MTT assay (viable cells decreased from 92% to 76%, 52%, and 22%, with increases of NS-398 from 20 to 40, 60, and 80 ,M, respectively). Radiation-induced cell death was also increased by treatment with NS-398. At a 10% survival level, 40 ,M NS-398 increased radiation cytotoxicity by a factor of 1.37, whereas 60 ,M increased it by a factor of 4.9. Conclusions. COX-2 overexpression is a predictor for poor survival for advanced stage NPC. In vitro, NS-398 radiosensitizes the NPC-BM1 cell line, providing a basis for testing the combination of COX-2 inhibitors with radiation in the treatment of patients with NPC. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX,XXX, 2005 [source] The Effects of Cyclooxygenase2,ProstaglandinE2 Pathway on Helicobacter pylori -Induced Urokinase-Type Plasminogen Activator System in the Gastric Cancer CellsHELICOBACTER, Issue 3 2008Junichi Iwamoto Abstract Background:, Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in the destruction of the extracellular matrix and basement membrane. The induction of uPA and uPAR in the gastric cancer cells with H. pylori has been demonstrated previously. The involvement of COX-2-PGE2 pathway in the uPA system (uPA and uPAR) expression is unclear. Methods:, Gastric cancer cells (MKN45) were co-cultured with H. pylori standard strain (NCTC11637). The specific inductions of uPA and uPAR mRNA were examined by reverse transcription-polymerase chain reaction amplification. The secreted uPA antigen was measured by ELISA. To evaluate the involvement of COX-2 and PGE2 pathway in H. pylori -induced uPA and uPAR expressions, we examined the effects of COX-2 inhibitor and PGE2 receptor antagonist on H. pylori -induced uPA and uPAR expression in the gastric cancer cells. Results:, The expressions of both uPA and uPAR mRNAs in the gastric cancer cells increased obviously (12-fold and 3-fold, respectively) with H. pylori stimulation. The amount of uPA antigen into the culture medium increased dramatically with H. pylori stimulation. The COX-2 expression level in the gastric cancer cells increased remarkably with H. pylori stimulation. H. pylori -induced uPA and uPAR expression levels were suppressed with COX2 inhibitor treatment. The amount of PGE2 antigen into the culture medium increased dramatically 24 hours after H. pylori stimulation. The gastric cancer cells expressed EP2 and EP4 subtypes. EP2 receptor antagonist suppressed the H. pylori -induced uPA and uPAR expressions in the gastric cancer cells. Conclusions:, Our results indicated that COX2-PGE2 pathway may be involved in H. pylori- associated uPA and uPAR induction, and that COX-2 inhibitor or EP2 receptor antagonist may inhibit angiogenesis and tumor invasion via suppression of the uPA system. [source] Enhanced Activation of Cyclooxygenase-2 Downregulates Th1 Signaling Pathway in Helicobacter pylori -infected Human Gastric MucosaHELICOBACTER, Issue 3 2007Antonia Pellicanň Abstract Background:, Evidence suggests that an impaired T-cell response against Helicobacter pylori plays a role in the pathogenesis of H. pylori -related diseases. Cyclooxygenase (COX) 2 has been shown to inhibit the production of T-helper (Th) 1 cytokines. This study aimed to ascertain whether COX-2 downregulates Th1 signaling pathway in human gastric mucosa colonized by H. pylori. Methods:, COX-2 expression and prostaglandin E2 (PGE2) production were determined in total proteins extracted from freshly obtained gastric biopsies of H. pylori -infected and uninfected patients by Western blotting and enzyme-linked immunosorbent assay (ELISA). Phosphorylated (p)STAT4, pSTAT1, T-bet, and pSTAT6 expression and interleukin (IL)-12, interferon (IFN)-,, and IL-4 production were also determined by Western blotting and ELISA, respectively, in total protein extracts from gastric biopsy cultures of H. pylori -infected patients treated without and with COX-2 inhibitor NS-398. Results:, Enhanced expression of COX-2 and production of PGE2 was found in H. pylori -infected compared to uninfected patients. COX-2 inhibition significantly increased expression of Th1 transcription factors along with production of IL-12 and IFN-,. By contrast, no changes in the expression of STAT6 and production of IL-4 were found. Conclusion:, This study provides a mechanism by which H. pylori may actually interfere with normal T-cell activation in human gastric mucosa, possibly enhancing its pathogenicity. The use of COX-2 selective inhibitors as immunomodulators in the course of H. pylori infection deserves investigations. [source] The Effect of Ascorbic Acid on Helicobacter pylori Induced Cyclooxygenase 2 Expression and Prostaglandin E2 Production by Gastric Epithelial Cells in vitroHELICOBACTER, Issue 1 2005Geoff V. Smith ABSTRACT Background., Cyclooxygenase 2 (COX-2) is induced by the presence of Helicobacter pylori (H. pylori) on the gastric mucosa as part of the inflammatory response; this results in the synthesis of prostaglandins that amplify the local inflammatory response. The presence of H. pylori inhibits the secretion of ascorbate into the gastric lumen. Interestingly, ascorbate inhibits the growth of H. pylori and low dietary levels are associated with an increased risk of gastric adenocarcinoma. We therefore investigated the effect of ascorbate on H. pylori mediated COX-2 induction and prostaglandin production in vitro. Methods.,H. pylori was cocultured with gastric epithelial cells in the presence of ascorbate at physiological concentrations. The expression of COX-2 was assessed by Western blotting and prostaglandin E2 (PGE2) was assessed by ELISA. Results., Ascorbate inhibited gastric cell PGE2 synthesis but not in COX-2 expression in response to H. pylori. In the absence of the organism, ascorbate also reduced PGE2 expression in cells that constitutively express COX-2, again with no reduction of COX-2 protein expression. Conclusions., Physiological concentrations of ascorbate inhibit PGE2 but not COX-2 expression in response to H. pylori in gastric epithelial cells. [source] Insulin Secretagogues from Moringa oleifera with Cyclooxygenase Enzyme and Lipid Peroxidation Inhibitory ActivitiesHELVETICA CHIMICA ACTA, Issue 2 2004Jayaraj Bioassay-directed isolation and purification of the methanol extract of Moringa oleifera fruits yielded bioactive N -benzyl thiocarbamates, N -benzyl carbamates, benzyl nitriles, and a benzyl ester. Among these, methyl 2-[4-(, - L -rhamnopyranosyl)phenyl]acetate (2), N -[4-(, - L -rhamnopyranosyl)benzyl]-1- O - , - D -glucopyranosylthiocarboxamide (3), 1- O -phenyl- , - L -rhamnopyranoside (5), and 4-[(, - D -glucopyranosyl)-(1,3)-(, - L -rhamnopyranosyl)]phenylacetonitrile (6) are novel, and their structures were determined by spectroscopic methods. The known compounds isolated and characterized from the MeOH extract were niazirin (=4-(, - L -rhamnopyranosyl)phenylacetonitrile; 1), niazicin A (=methyl N -{4-[(4,- O -acetyl- , - L -rhamnopyranosyl)benzyl]}thiocarbamate; 4), methyl N -{4-[(, - L -rhamnopyranosyl)benzyl]}carbamate (7), and methyl N -{4-[(4,- O -acetyl- , - L -rhamnopyranosyl)benzyl]}carbamate (8). The combined yield of these compounds from dried M. oleifera fruits was 1.63%. In rodent pancreatic , -cells (INS-1), compounds 4, 5, 6, 7, and 8 at 100,ppm significantly stimulated insulin release. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibition assays revealed that 5 and 6 were most active at 83,ppm. Compound 6, however, demonstrated greater specificity for inhibition of COX-2 enzyme (46%) than COX-1 enzyme. Lipid peroxidation assays revealed that 4 and 6 at 50,ppm inhibited peroxidation reactions by 80 and 95%, respectively, while 3 and 8 inhibited lipid peroxidation by 35%. These compounds did not inhibit the cell growth when tested with human breast (MCF-7), central nervous system (CNS, SF-268), lung (NCI-H460), or colon (HCT-116) cancer cell lines. Moreover, these compounds were not cytotoxic at the concentrations tested. [source] Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes,HEPATOLOGY, Issue 3 2007Marta Casado Cyclooxygenase-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE2 found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals. However, Tg animals were resistant to Fas-mediated liver injury, as demonstrated by low levels of plasmatic aminotransferases, a lesser caspase-3 activation, and Bax levels and an increase in Bcl-2, Mcl-1, and xIAP proteins, when compared with the Wt animals. Moreover, the resistance to Fas-mediated apoptosis is suppressed in the presence of COX-2,selective inhibitors, which prevented prostaglandin accumulation in the liver of Tg mice. Conclusion: These results demonstrate that expression of COX-2,dependent prostaglandins exerted a protection against liver apoptosis. (HEPATOLOGY 2007;45:631,638.) [source] COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cellsHEPATOLOGY, Issue 3 2002Ugochukwu C. Nzeako Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptor,mediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-,, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells. [source] Lipoxin A4 inhibited hepatocyte growth factor-induced invasion of human hepatoma cellsHEPATOLOGY RESEARCH, Issue 9 2009Xiao-Yan Zhou Aim:, Inflammation is a critical component of tumor progression. Lipoxin A4 (LXA4) has been approved for potent anti-inflammatory properties. Recently, it was reported that LXA4 repressed the expression and activity of cyclooxygenase-2 (COX-2), which is essential for invasion. However, there are few reports dealing with its effects on cancer. To explore whether LXA4 regulate invasion, the effects of LXA4 and its receptor agonist BML-111 on hepatocyte growth factor (HGF)-induced invasion of hepatoma cells and the possible mechanisms were researched. Methods:, Lipoxin A4 receptor (ALX) expression in HepG2 cells were measured through reverse transcription polymerase chain reaction and western blot. Cytotoxicity of LXA4 and BML-111 to HepG2 cells was detected by MTT and (3H)-TdR incorporation assay. Cell migration and invasion assays were performed using a Boyden chemotaxis chamber. COX-2 expression was detected by real-time polymerase chain reaction and western blot, respectively. Moreover, the expressions of matrix metalloproteinases (MMP)-2, MMP-9, I,B, and nuclear factor-,B (NF-,B) p65 were observed via western blot, and NF-,B transcriptional activity was tested by transfections and luciferase activities assay. Results:, ALX expression was detected in HepG2 cells, and suitable concentrations of LXA4 and BML-111 had no cytotoxicity to cells. LXA4 and BML-111 inhibited HGF-induced migration and invasion; downregulated COX-2, MMP-2 and -9; restrained HGF-induced I,B, degradation, NF-,B translocation and the transcriptional activity of NF-,B in HepG2 cells. Furthermore, exogenous PGE2 could reverse the inhibitory effects of LXA4 also BML-111 on HGF-induced invasion and migration partially. Conclusion:, LXA4 inhibited HGF-induced invasion of HepG2 cells through NF-,B/COX-2 signaling pathway partially. [source] Cyclooxygenase-2 expression correlates with phaeochromocytoma malignancy: evidence for a Bcl-2-dependent mechanismHISTOPATHOLOGY, Issue 6 2007I S Cadden Aims:, Phaeochromocytomas are rare but potentially life-threatening neuroendocrine tumours of the adrenal medulla or sympathetic nervous system ganglia. There are no histological features which reliably differentiate benign from malignant phaeochromocytomas. The aim of the study was to evaluate cyclooxygenase (COX)-2 and Bcl-2 as tissue-based biomarkers of phaeochromocytoma prognosis. Methods and results:, COX-2 and Bcl-2 expression were examined immunohistochemically in tissue from 41 sporadic phaeochromocytoma patients followed up for a minimum of 5 years after diagnosis. There was a statistically significant association between COX-2 histoscore (intensity × proportion) and the development of tumour recurrence or metastases (P = 0.006). A significant relationship was observed between coexpression of COX-2 and Bcl-2 in the primary tumour and the presence of recurrent disease (P = 0.034). A highly significant association was observed between (i) tumour-associated expression of these two oncoproteins (P = 0.001) and (ii) COX-2 histoscore and the presence of Bcl-2 expression (P = 0.002). COX regression analysis demonstrated no significant relationship between (i) the presence or absence of either COX-2 or Bcl-2 and patient survival or (ii) COX-2 histoscore and patient survival. Conclusions:, COX-2 and Bcl-2 may promote phaeochromocytoma malignancy, and these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype. [source] Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancerHISTOPATHOLOGY, Issue 4 2007M Yuri Aims:, Two different pathways of linoleic acid (LA) metabolism have opposite effects on the development of colonic cancer: a protumoral prostaglandin cascade metabolized by cyclooxygenase (COX)-2, and an antitumoral peroxisome proliferator-activated receptor (PPAR)-, ligands metabolized by 15-lipooxygenase (LOX)-1. The aim was to examine the switching of the two LA metabolic pathways in colonic adenomas and carcinomas. Materials and methods:, The expression of 15LOX-1 mRNA and COX-2 protein was examined in 54 adenomas, 21 pTis carcinoma-in-adenoma lesions and 36 pT3/p Stage II carcinomas of the colon by in-situ hybridization and immunohistochemistry, respectively. Results:, 15LOX-1 expression was found in 89% (48 of 54) of adenomas, 43% (nine of 21) of adenomas and 10% (two of 21) of carcinomas in carcinoma-in-adenoma lesions, but not in pT3 carcinomas (P < 0.0001). In contrast, COX-2 production was found in 11% (six of 54) of adenomas, 52% (11 of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Concurrence of 15LOX-1 down-regulation and COX-2 up-regulation was found in 6% (three of 54) of adenomas, 33% (seven of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Conclusions:, These results suggest that switching of LA metabolism by reversal of the expression of 15LOX-1 and COX-2 is associated with acquisition of malignant potential in colonic neoplasia. [source] Pak1 and Pak2 are activated in recurrent respiratory papillomas, contributing to one pathway of Rac1-mediated COX-2 expressionINTERNATIONAL JOURNAL OF CANCER, Issue 9 2010Rong Wu Abstract Recurrent respiratory papillomas are premalignant tumors of the airway caused by human papillomaviruses (HPVs), primarily Types 6 and 11. We had reported that respiratory papillomas overexpress the epidermal growth factor receptor (EGFR), the small GTPase Rac1 and cyclooxygenase-2 (COX-2), and have enhanced nuclear factor-,B (NF,B) activation with decreased levels of I,B-, but not I,B-,. We also showed that EGFR-activated Rac1 mediates expression of COX-2 through activation of p38 mitogen-activated protein kinase. We have now asked whether the p21-activated kinases Pak1 or Pak2 mediate activation of p38 by Rac1 in papilloma cells. Pak1 and Pak2 were constitutively activated in vivo in papilloma tissue compared with normal epithelium, and Rac1 siRNA reduced the level of both phospho-Pak1 and phospho-Pak2 in cultured papilloma cells. Reduction in Pak1 and Pak2 with siRNA decreased the COX-2 expression in papilloma cells, increased the levels of I,B-, and reduced the nuclear localization of NF-,B, but had no effect on p38 phosphorylation. Our studies suggest that Rac1 , Pak1/Pak2 , NF,B is a separate pathway that contributes to the expression of COX-2 in HPV-induced papillomas, independently of the previously described Rac1 , p38 , COX-2 pathway. [source] Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancerINTERNATIONAL JOURNAL OF CANCER, Issue 2 2010Shahab Uddin Abstract Cyclooxygenase-2 (COX-2) expression contributes to tumor growth and invasion in epithelial ovarian cancer (EOC). COX-2 inhibitors exhibit important anticarcinogenic potential against EOC, but the molecular mechanisms underlying this effect and relation with PI3-kinase/AKT signaling remain the subject of intense investigations. Therefore, the role of COX-2 in EOC and its cross talk with PI3-kinase/AKT pathway were investigated using a large series of EOC tissues in a tissue micro array (TMA) format followed by in vitro and in vivo studies using EOC cell lines and NUDE mice. Clinically, COX-2 was overexpressed in 60.3% of EOC and was significantly associated with activated AKT (p < 0.0001). Cox-1 expression was seen in 59.9% but did not associate with AKT. Our in vitro data using EOC cell line showed that inhibition of COX-2 by aspirin, selective inhibitor NS398 and gene silencing by COX-2 specific siRNA impaired phosphorylation of AKT resulting decreased downstream signaling leading to cell growth inhibition and induction of apoptosis. Finally, treatment of MDAH2774 cell line xenografts with aspirin resulted in growth inhibition of tumors in NUDE mice via down-regulation of COX-2 and AKT activity. These data identify COX-2 as a potential biomarker and therapeutic target in distinct molecular subtypes of ovarian cancer. [source] Prostaglandin E2 promotes cell proliferation via protein kinase C/extracellular signal regulated kinase pathway-dependent induction of c-Myc expression in human esophageal squamous cell carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Le Yu Abstract Overexpression of cyclooxygenase-2 (COX-2) and elevation of its derivative prostaglandin E2 (PGE2) are implicated in human esophageal squamous cell carcinoma. The expression of c-Myc, an oncogenic transcription factor, is also upregulated in this malignant disease. This study sought to elucidate whether a functional connection exists between COX-2/PGE2 and c-Myc in esophageal squamous cell carcinoma. Results showed that PGE2 substantially increased the proliferation of cultured esophageal squamous cell carcinoma cells. In this regard, PGE2 substantially increased the mRNA and protein expression of c-Myc and its association with the binding partner Max. Knockdown of c-Myc by RNA interference also significantly attenuated PGE2 -induced cell proliferation. Further, mechanistic study revealed that PGE2 increased the protein stability and nuclear accumulation of c-Myc via phosphorylation on serine 62 in an extracellular signal regulated kinase (ERK)-dependent manner. To this end, ERK activation by PGE2 was completely abolished by protein kinase C (PKC) inhibitors. Moreover, the effect of PGE2 on c-Myc expression was mimicked by EP2 receptor agonist. In addition, knockdown of EP2 receptor by EP2 siRNA attenuated PGE2 -induced c-Myc expression. Collectively, our findings suggest that PGE2 upregulates c-Myc via the EP2/PKC/ERK pathway. This study sheds new light on the carcinogenic mechanism of PGE2 in esophageal squamous cell carcinoma. © 2009 UICC [source] Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patientsINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Srilatha Swami Abstract Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE2 by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment. © 2008 Wiley-Liss, Inc. [source] Somatic mutations of adenomatous polyposis coli gene and nuclear b-catenin accumulation have prognostic significance in invasive urothelial carcinomas: Evidence for Wnt pathway implicationINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Efstathios Kastritis Abstract Wnt pathway signaling is crucial in many cancers and data indicate crosstalk with other key cancer pathways, however in urothelial carcinogenesis it has not been extensively studied. We searched for mutations in adenomatous polyposis coli (APC), a key regulator of the pathway, and studied b-catenin expression and interactions with the expression of other markers of apoptosis, angiogenesis, and proliferation in patients with invasive urothelial cancer. The mutation cluster region of APC was directly sequenced in 70 patients with muscle invasive disease who were treated with surgery and adjuvant chemotherapy. COX-2, p53, Ki67, and b-catenin were studied immunohistochemically and micro vessel density was quantified by CD105 expression. Single somatic amino-acid substitutions (missense) were found in 9 (13%) and frameshift deletions in 2 (3%) tumors, all located in regions adjacent to b-catenin binding sites. Patients having either APC missense mutations or b-catenin nuclear accumulation had less frequent COX-2 overexpression (24% vs. 76%, p = 0.043) and more frequent lymph node involvement (75% vs. 38%, p = 0.023). Patients with either APC mutations or b-catenin accumulation had shorter disease-free interval (13.4 vs. 28 months, p = 0.07), whereas in multivariate analysis they had shorter disease-specific survival (60.5 vs. 20.6 months, p = 0.048). Somatic APC missense mutations are not rare in advanced urothelial neoplasms. Either APC mutations and/or aberrant expression of b-catenin are associated with worse outcome. Further study of the role of the Wnt pathway, potential crosstalk with other pathways and potential candidate therapeutic targets in urothelial cancer is needed. © 2008 Wiley-Liss, Inc. [source] A specific inducible nitric oxide inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male ApcMin/+ miceINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Hiroyuki Kohno Abstract It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the ApcMin/+ mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the ApcMin/+ mouse treated with DSS. Male C57BL/6J ApcMin/+ and Apc+/+ mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-, and interleukin (IL)-1,. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the ApcMin/+ mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNF, and IL-1, of colonic mucosa in the DSS-treated ApcMin/+ mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc+/+ mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the ApcMin/+ mice. © 2007 Wiley-Liss, Inc. [source] Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial,mesenchymal interactions of growth in scirrhous gastric carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Masakazu Yashiro Abstract The importance of cancer-mesenchymal interactions in the aggressive behavior of scirrhous gastric cancer is supported by experimental and clinical evidences. We have previously reported that gastric fibroblasts secretion of keratinocyte growth factor (KGF) underline the remarkable proliferation of scirrhous gastric cancer cells. Cyclooxygenase-2 (COX-2) is not only expressed in cancer cells, but also in interstitial fibroblasts in gastric carcinoma. To clarify the mechanisms responsible for the antiproliferation effect of COX-2 inhibitors, effect of COX-2 inhibitor on the paracrine epithelial,mesenchymal interactions of growth was examined. Scirrhous gastric cancer cell line, OCUM-2M, gastric fibroblasts, NF-21, and COX-2 inhibitor, JTE-522, were used. Growth-interaction was examined by calculating the number of cancer cells or by measuring [3H] thymidine incorporation of cancer cells. Effect of JTE-522 on KGF expression from NF-21 cells and OCUM-2M cells was analyzed by ELISA and RT-PCR. The conditioned medium from gastric fibroblasts significantly stimulated the growth of scirrhous gastric cancer cells. JTE-522 at the concentrations of 10,5 and 10,6 M significantly decreased the growth-stimulating activity of gastric fibroblasts. JTE-522 reduced the expression of KGF mRNA and the production of KGF from gastric fibroblasts. Oral administration of JTE-522 significantly decreased the size of xenografted tumor coinoculated with OCUM-2M cells and NF-21 cells in nude mice. JTE-522 decreased COX-2 expression and Ki67 labeling index within the coinoculated tumor. These findings suggested that a selective COX-2 inhibitor, JTE-522, downregulates KGF production from gastric fibroblasts, resulting in the inhibition of paracrine epithelial,mesenchymal interactions of proliferation between scirrhous gastric cancer cells and gastric fibroblasts. © 2006 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||||||||