celecoxib, Celebrex
The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells.

Wu T, Leng J, Han C, Demetris AJ.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. wut msx.upmc.edu

The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcinoma tissues showed increased levels of COX-2 as well as phospho-Akt (Thr (308)), a protein kinase activated by COX-2-mediated prostaglandins, in human cholangiocarcinoma cells. Treatment of cultured human cholangiocarcinoma cells (HuCCT1, SG231, and CCLP1) with celecoxib resulted in a dose- and time-dependent reduction of cell viability. Fluorescence microscopy, Western blot, and caspase activity assays demonstrated that celecoxib induced morphological features of apoptosis, activation of caspase-9 and caspase-3, and release of cytochrome c. The celecoxib-induced cell death was significantly blocked by N-benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone, a wide-spectrum caspase inhibitor. Furthermore, cholangiocarcinoma cells treated with celecoxib showed significant reduction of Akt phosphorylation, whereas the levels of Bcl-2 and Bax were not altered. Inhibition of Akt activation by LY294002 significantly decreased the viability of human cholangiocarcinoma cells. These findings suggest that celecoxib inhibits cholangiocarcinoma growth partly through induction of apoptosis and inhibition of Akt phosphorylation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15026550&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells.

Maier TJ, Schilling K, Schmidt R, Geisslinger G, Grosch S.

Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universitat Frankfurt, Theodor Stern Kai 7, Frankfurt/Main 60590, Germany. tmaier stud.uni-frankfurt.de

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anticarcinogenic effects of celecoxib is still not fully understood. To investigate the extent to which the anticarcinogenic effect of celecoxib depends on COX-2 expression, we transfected human colon carcinoma cells (Caco-2) with the human COX-2 cDNA, in both sense and in antisense orientation, to generate cells which either overexpress COX-2 (human COX-2-sense, hCOX-2-s), express no COX-2 (human COX-2-antisense, hCOX-2-as) or express only very small amounts of COX-2 (control cells). Treatment of these cells with celecoxib dose-dependently (0-100microM) reduced cell survival which was accompanied by an induction of a G(0)/G(1) phase block and apoptosis. The effect of celecoxib treatment on both, cell survival and induction of apoptosis in hCOX-2-as cells was less marked than in the COX-2-expressing cells. Apoptosis was accompanied by an activation of caspase-3 and caspase-9 and cytochrome c release. In contrast, we observed no difference in sensitivity with regard to the induction of a cell cycle block between the different cell clones. The G(0)/G(1) phase block caused by celecoxib correlated with a decrease in expression levels of cyclin A and cyclin B1 and an increase in the expression of the cell cycle inhibitory proteins p21(Waf1) and p27(Kip1) irrespective of the type of cell used. These data indicate that apoptosis-inducing effects of celecoxib partly depend on COX-2 expression of the cells, whereas induction of a cell cycle block occurred COX-2 independently. Thus, the anticarinogenic effects of celecoxib can be explained by both COX-2-dependent and -independent mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15041464&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation.

Zhang Z, Lai GH, Sirica AE.

Division of Cellular and Molecular Pathogenesis, Department of Pathology, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, VA, USA.

Recently, we demonstrated that the cyclooxygenase-2 (COX-2) inhibitor celecoxib acts to significantly suppress the growth of rat C611B cholangiocarcinoma (ChC) cells in vitro. To establish a molecular mechanism for this growth suppression, we investigated the effects of celecoxib on apoptotic signaling pathways in cultured rat C611B ChC cells. Celecoxib and another COX-2 inhibitor, rofecoxib, at 5 microM were almost equally effective in inhibiting prostaglandin E(2) (PGE(2)) production by these cells, but at this low concentration, neither inhibitor suppressed growth or induced apoptosis. Celecoxib at 50 microM induced prominent apoptosis in these cells, whereas rofecoxib at 50 microM was without effect in either suppressing growth or inducing apoptosis. Celecoxib (50 microM) did not alter Bcl-2, Bcl-x(L), or COX-2 protein levels, nor did it inhibit p42/44 mitogen-activated protein kinase (MAPK) phosphorylation; however, it significantly suppressed serine/threonine kinase Akt/PKB (Akt) phosphorylation and kinase activity in cultured C611B cells. This effect, in turn, directly correlated with Bax translocation to mitochondria, cytochrome c release into cytosol, activation of caspase-9 and caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Addition of 25 microM PGE(2) to C611B cell cultures blocked the apoptotic actions of celecoxib. Rofecoxib (50 microM) was without effect in suppressing Akt phosphorylation and caspase-3 activation. In vivo, celecoxib partially suppressed tumorigenic growth of C611B ChC cells. In conclusion, our results indicate that celecoxib preferentially acts in vitro to induce apoptosis in ChC cells through a mechanism involving Akt inactivation, Bax translocation, and cytochrome c release. Our in vivo results further suggest celecoxib might have potential therapeutic or chemopreventive value against ChC.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15057907&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Post-treatment, but not pre-treatment, with the selective cyclooxygenase-2 inhibitor celecoxib markedly enhances functional recovery from kainic acid-induced neurodegeneration.

Gobbo OL, O'Mara SM.

Department of Psychology and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.

We have investigated the role of inflammation in the excitotoxicity induced by overstimulation of glutamate receptors using kainic acid, an important tool for studying functions related to excitatory amino acid transmission and for producing neuronal death, especially in areas CA1 and CA3 of the hippocampus. We hypothesised that by inhibiting one of the major components of the neuroinflammation response, after kainic acid injection, that there would be less inflammation and therefore a reduction in cell loss, an enhancement of cognitive function (using spatial learning and object exploration tasks) or both. We examined brain-derived neurotrophic factor levels, expecting that there would be a correlation between its level and subsequent recovery. Our results confirmed our hypothesis: the kainic acid injected-rats treated with celecoxib (after kainic injection) performed better in the spatial and non-spatial tasks than the kainic acid-treated group. However, there was not any improvement if celecoxib was given before kainic acid treatment, underlining also the importance of the production of prostaglandin at the beginning of inflammation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15062975&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Uptake of COX-2 selective inhibitors and influence on NSAID prescribing in Northern Ireland.

Girvin B, Rafferty T, Stevenson MR, Johnston GD.

Regional Prescribing Information Unit, Department of Therapeutics and Pharmacology, Queen's University of Belfast, Belfast, UK. b.girvin qub.ac.uk

PURPOSE: Rofecoxib and celecoxib have been recently introduced and promoted as 'safer' non-steroidal anti-inflammatory drugs (NSAIDs) regarding gastric toxicity. The primary aim was to measure their uptake and any impact on conventional NSAID prescribing. A secondary aim was to assess any change in proton pump inhibitor (PPI) prescribing. METHODS: Prescribing data in terms of defined daily doses (DDDs) were pooled from 1997 onwards. Linear trends in the data were tested for using regression analyses. Direct comparisons were made between the April-June quarter of the year 1999 (i.e. before the introduction of rofecoxib and celecoxib) and the same quarter 3 years later. RESULTS: Overall NSAID prescribing in Northern Ireland was found to be increasing linearly at an estimated rate of 154,000 DDDs per quarter since the introduction of celecoxib and rofecoxib. The rate of increase in the volume of prescribing of the two new drugs was found to be four times the rate of decrease in prescribing of the 'older' NSAIDs. Overall prescribing of anti-inflammatory agents had increased from 37.8 to 47.7 DDDs/1000 patients/day over 3 years with no effect on the upward trend in PPI prescribing. CONCLUSIONS: The introduction of rofecoxib and celecoxib has increased prescribing volume of anti-inflammatory agents by 26% in Northern Ireland over the 3-year period. This could pose safety problems in the future as more people are being prescribed anti-inflammatory agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15072114&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice.

Schilling G, Savonenko AV, Coonfield ML, Morton JL, Vorovich E, Gale A, Neslon C, Chan N, Eaton M, Fromholt D, Ross CA, Borchelt DR.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. gschill1 jhem.jhmi.edu

The HD-N171-82Q (line 81) mouse model of Huntington's disease (HD), expresses an N-terminal fragment of mutant huntingtin (htt), loses motor function, displays HD-related pathological features, and dies prematurely. In the present study, we compare the efficacy with which environmental, pharmacological, and genetic interventions ameliorate these abnormalities. As previously reported for the R6/2 mouse model of HD, housing mice in enriched environments improved the motor skills of N171-82Q mice. However, life expectancy was not prolonged. Significant improvements in motor function, without prolonging survival, were also observed in N171-82Q mice treated with Coenzyme Q10 (CoQ10, an energy metabolism enhancer). Several compounds were not effective in either improving motor skills or prolonging life, including Remacemide (a glutamate antagonist), Celecoxib (a COX-2 inhibitor), and Chlorpromazine (a prion inhibitor); Celecoxib dramatically shortened life expectancy. We also tested whether raising cellular antioxidant capacity by co-expressing high levels of wild-type human Cu/Zn superoxide dismutase 1 (SOD1) was beneficial. However, no improvement in motor performance or life expectancy was observed. Although we would argue that positive outcomes in mice carry far greater weight than negative outcomes, we suggest that caution may be warranted in testing Celecoxib in HD patients. The positive outcomes achieved by CoQ10 therapy and environmental stimuli point toward two potentially therapeutic approaches that should be readily accessible to HD patients and at-risk family members.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15081595&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Modulation of intracellular calcium signaling and mitochondrial function in cultured osteoblastic cells by dexamethasone and celecoxib during mechanical stimulation.

Schuchmann S, Wiontzek M, Burmester GR, Buttgereit F.

Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Universitatsklinikum Charite, Humboldt Universitat Berlin, Germany. sebastian.schuchmann uni-greifswald.de

OBJECTIVE: Evaluation of potentially therapeutically relevant effects of dexamethasone and celecoxib on crucial parameters of bone physiology during and following mechanical stimulation in cultured osteoblasts. METHODS: An in vitro mechanical stimulation model based on the rat osteogenic cell line UMR-106 was developed to investigate glucocorticoid (dexamethasone) and selective COX-2 inhibitor (celecoxib) induced changes in the intracellular calcium concentration ([Ca2+]i) and mitochondrial membrane potential (deltapsi(m)). Microfluorometric techniques were applied to monitor [Ca2+]i (Fura-2 AM) and deltapsi(m) (rhodamine 123) online as the main parameters of the actual cellular metabolism. RESULTS: Basal [Ca2+] was found to be 92.2 +/- 3.7 nM and increased tip to 711 +/- 27 nM during mechanical stimulation under controlled conditions. Addition of 100 nM dexamethasone or 10 microM celecoxib for 24 h suppressed the increase in [Ca2+]i significantly to 530 +/- 33 nM and 546 +/- 39 nM, respectively. Dexamethasone significantly reduced, but celecoxib significantly increased the spread velocity of the mechanically induced intracellular calcium wave. Furthermore, the effects induced by dexamethasone were amplified during the inhibition of gap junction coupling and diminished following enlarged gap junction coupling. In contrast, the modulation of gap junction coupling exerted only a minor influence on the celecoxib-induced effects. Short-term application of dexamethasone (5 min) caused significantly reduced mechanically induced depolarization of the mitochondrial membrane, but long-term application (24 h) did not. In contrast, only the long-term application (24 h) of celecoxib caused such depolarization. CONCLUSION: The observed effects of dexamethasone and celecoxib on mechanically induced changes in [Ca2+] and deltapsi(m) are suggested to result from short-term changes in membrane characteristics and long-term changes in protein synthesis. This indicates an influence of these drugs on cell-to-cell communication and metabolism that may be therapeutically relevant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15083886&dopt=Abstract celecoxib, Celebrex