celecoxib, Celebrex
Inhibition of ultraviolet light B-induced cutaneous inflammation by a specific cyclooxygenase-2 inhibitor.

Wilgus TA, Parrett ML, Ross MS, Tober KL, Robertson FM, Oberyszyn TM.

Ohio State University, Department of Molecular Virology, Immunology and Medical Genetics, 2058 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210, USA.

Ultraviolet B (UVB) radiation is responsible for the majority of cutaneous damage following both acute and long-term exposure, and is believed to be the most important etiologic agent in human skin cancer. UVB carcinogenesis initially induces an inflammatory response characterized by edema, dermal infiltration of leukocytes, as well as the production and release of prostaglandins, which may be critical to the observed damaging effects of UVB light on skin. Recently, a specific cyclooxygenase-2 (COX-2) inhibitor, Celecoxib, was developed, which inhibits COX-2-induced inflammation without inhibiting the cytoprotective function of cyclooxygenase-1 (COX-1). Studies have demonstrated that oral administration of Celecoxib decreased the incidence of skin and colon tumors. Recently, the process of inflammation has been linked to tumor formation. The present study examined the effects of a topical application of Celecoxib on the acute UVB-induced cutaneous inflammatory response. We show that topical Celecoxib treatment effectively reduced many parameters of UVB-mediated inflammation, including edema, dermal myeloperoxidase activity, neutrophil infiltration, and prostaglandin E2 (PGE2) levels. By inhibiting this inflammatory response, topical Celecoxib treatment could ultimately be effective in preventing tumor development and progression in the skin, which is known to result from long-term UV exposure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12664569&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

Ostrowski J, Wocial T, Skurzak H, Bartnik W.

Department of Gastroenterology, Medical Center for Postgraduate Education, Warsaw, Poland. jostrow warman.com.pl

Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12671717&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Differential effects of selective COX-2 inhibitors on cell cycle regulation and proliferation of glioblastoma cell lines.

Kardosh A, Blumenthal M, Wang WJ, Chen TC, Schonthal AH.

Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, USA.

It is well established that traditional NSAIDs, which inhibit cyclooxygenase (COX) 1 and COX-2, have the potential to reduce the risk of colorectal cancer. New generation COX inhibitors have been developed that selectively inhibit COX-2, which might cause less side effects while still retaining their therapeutic potential. As patients with brain tumors, such as glioblastoma, exhibit a very poor prognosis, we began to explore whether COX inhibitors could be useful for the treatment of this type of tumor. We found that celecoxib inhibited the proliferation of various glioblastoma cell lines in vitro much more potently than traditional NSAIDs. In addition, although several different selective COX-2 inhibitors potently reduced PGE2 levels in these cells, none of them exerted anti-proliferative effects that were comparable to celecoxib. The addition of external PGE2 to celecoxib-treated cells did not restore proliferation, indicating that growth inhibition by celecoxib was not mediated via the blockage of PGE2 production. In an effort to determine the underlying molecular processes that might mediate celecoxib's potent anti-proliferative effects, we found a loss of the activity of cyclin-dependent kinases, the essential regulators of cell proliferation, which was due to the transcriptional downregulation of cyclin A and cyclin B expression. Taken together, our results show that celecoxib exerts COX-2-independent anti-proliferative effects on glioblastoma cell growth, which are more potent than those of other selective COX-2 inhibitors or traditional NSAIDs, and which are mediated via the transcriptional inhibition of two essential components of the cell cycle machinery, cyclin A and cyclin B.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14726653&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effects of a selective cyclooxygenase-2 inhibitor on cancer cells in vitro.

Fife RS, Stott B, Carr RE.

Department of Medicine, University School of Medicine, Indianapolis, Indiana, USA. rfife iupui.edu

The cyclooxygenase (COX) family of enzymes has been implicated in cell proliferation and angiogenesis in many tumors, including colon cancer. Indeed, cyclooxygenase-2 (COX-2) inhibitors recently have been approved for use for prophylaxis in individuals with familial adenomatous polyposis. We now report on the effects of a selective COX-2 inhibitor, celecoxib, on cell proliferation, matrix metalloproteinase (MMP) concentration, angiogenesis using an in vitro assay, and apoptosis in several human cancer cell lines. We demonstrate that celecoxib modestly reduces proliferation in some cell lines and does not affect MMP concentrations. However, celecoxib significantly decreases microtubule formation in stimulated human umbilical vein endothelial cells (HUVECs) exposed to cancer cell supernatants, an in vitro angiogenesis model, when compared to controls incubated with supernatants from untreated cells. Celecoxib does not consistently induce apoptosis in these cell lines, as determined by DNA laddering in agarose gels and by a caspase assay. Thus, it appears that COX-2 inhibitors have beneficial effects in reducing malignant cell behavior in vitro and warrant further study to elucidate their mechanisms of action and to examine their mechanisms of action in this role and their utility in vivo in a variety of animal and human tumors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14726667&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Anticonvulsant action of celecoxib (alone and in combination with sub-threshold dose of phenytoin) in electroshock induced convulsion.

Shafiq N, Malhotra S, Pandhi P.

Department of Pharmacology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, COX-2 has been shown to be upregulated by convulsive nerve activity. Various earlier studies have given conflicting reports on the effect of COX inhibitors on seizures. This study investigates the effect of pretreatment with celecoxib alone, or in combination with phenytoin, on electroshock-induced convulsions. Both percentage protection (i.e., the percentage of animals not showing Tonic Hind Limb Extension [THLE] when a fixed dose of current is administered) and CC50 (i.e., the threshold current inducing THLE in 50%) was determined using a technoconvulsometer. Celecoxib and phenytoin were administered 1 and 2 h, respectively, prior to the experiments. When administered alone, celecoxib showed an increase in percentage protection at increasing doses, with maximum percentage protection (66.6%) occurring at a 30 mg/kg-1 dose. The ED25 value of celecoxib was calculated to be 8.03 mg/kg-1. The CC50 values for the treatment groups were significantly increased compared with the control group (CC50 values for control, celecoxib 10 mg/kg-1, celecoxib 20 mg/kg-1 and celecoxib 30 mg/kg-1, respectively, were 36.3, 49.12, 100.3 and 125.02 mA). An increase in percentage protection was noted when celecoxib 8.03 mg/kg-1 was coadministered with phenytoin 6 mg/kg-1 (66.6% with the combination vs. 16.6% when administered individually). A significant increase was noted in the CC50 value in a combination regimen (CC50 = 79.06) compared with either drug administered alone (CC50 = 49.12 with celecoxib 8.03 mg/kg-1 and 62.06 with phenytoin 6 mg/kg-1). This study may stimulate further interest in the role of COX-2 inhibitors in the modulation of seizure activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12731453&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
A model analysis of costs of blood pressure destabilization and edema associated with rofecoxib and celecoxib among older patients with osteoarthritis and hypertension in a Medicare Choice population.

Becker RV, Burke TA, McCoy MA, Trotter JP.

Ovation Research Group, Highland Park, Illinois, USA.

BACKGROUND: Economic analyses consider all costs relevant to the use of a particular treatment or treatments. Recently, head-to-head, randomized, controlled trials have shown a significantly higher incidence of blood pressure (BP) destabilization and clinically significant edema with rofecoxib than with celecoxib among older, hypertensive patients with osteoarthritis (OA). OBJECTIVE: The objective of this analysis was to estimate the COX-2 specific inhibitor medication costs, in addition to the costs of drugs and physicians' fees, for BP destabilization and clinically significant edema associated with the use of rofecoxib 25 mg QD and celecoxib 200 mg QD in patients with OA and hypertension in a Medicare Choice population (aged > or = 65 years). METHODS: A decision analysis model was constructed to determine the costs (from the payer's perspective) of treating patients in this population with either of the 2 regimens for 6 weeks. The analysis used pooled data from 2 recent, independently conducted, multicenter, double-blind, randomized, controlled trials of OA patients aged > or = 65 years with treated hypertension who received either celecoxib 200 mg QD or rofecoxib 25 mg QD for 6 weeks. In the individual trials, rofecoxib was associated with significantly higher rates of destabilized BP (P < 0.032 and P < 0.001) and edema (P < 0.01 and P = 0.045) than celecoxib. RESULTS: For a 100,000-member Medicare Choice population, an estimated 25,630 persons would have OA and hypertension (stages I-III), and an estimated 5126 of these patients would use celecoxib or rofecoxib. The estimated costs were 33,938 dollars (6.2%) higher if all hypertensive patients with OA were treated with rofecoxib rather than celecoxib for 6 weeks. The cost per day of use was 0.16 dollars less with celecoxib, and per-patient, per-month costs were 4.79 dollars lower. CONCLUSION: Celecoxib was a less costly treatment option than rofecoxib among OA patients with hypertension aged > or = 65 years, based on our model of the direct costs of COX-2 specific inhibitor therapy combined with those associated with physician monitoring and treatment of edema and BP destabilization.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12749519&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib simulates respiratory burst through pertussis toxin-sensitive G-protein, a possible signal for beta 2-integrin expression on human neutrophils.

Chang-Hui L, Yen-Ju H, Yin-Chou L.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, No. 259 Wen-Hwa 1st Road, Kwei-Shan, 333, Tao-Yuan, Taiwan, ROC. liaoch mail.cgu.edu.tw

The superoxide anion-generating effect of celecoxib (4-[5-(4-methylpheny)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide); SC58633), a selective cyclooxygenase-2 inhibitor, on human neutrophils was evaluated in this study. Celecoxib induced superoxide anion generation in a concentration-dependent manner in human neutrophils. The EC50 value of celecoxib on superoxide anion generation was 15.5+/-2.5 microM. A NADPH oxidase inhibitor, diphenyliodonium (20 microM), and superoxide dismutase (150 U/ml) completely inhibited the free radical generation caused by celecoxib, indicating that the respiratory burst was activated by celecoxib. 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM;10 microM) and staurosporine (200 nM) completely inhibited the superoxide anion release caused by celecoxib, respectively. These data indicated that celecoxib increased superoxide anion release by increasing intracellular calcium and protein kinase C activation. Moreover, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-C)-carbazole (Go-6976; 1 microM) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide, methane sulfate (Ro-31-8220; 0.5 microM), specific inhibitors of conventional protein kinase C isotypes (alpha, beta(I) and beta(II)), significantly inhibited superoxide anion release caused by celecoxib. Rottlerin (5 microM), a protein kinase C delta inhibitor, did not affect the free radical generation caused by celecoxib. Celecoxib caused translocation of protein kinase C alpha, beta(I) and beta(II) from the cytosol to the cellular membrane. 2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one (PD98059; 20 microM) and wortmannin (100 nM) did not decrease the superoxide anion generation caused by celecoxib, indicating that Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3 kinase) were not involved in the respiratory burst induced by celecoxib. Pertussis toxin (2 microg/ml), a Gi-protein sensitive inhibitor, significantly inhibited superoxide anion release. Moreover, pertussis toxin significantly inhibited intracellular calcium mobilization and protein kinase C alpha, beta(I) and beta(II) translocation from the cytosol to the membrane. Celecoxib increased beta(2)-integrin expression on human neutrophils and this effect was inhibited by BAPTA/AM (10 microM), superoxide dismutase (150 U/ml), genistein (25 microM) and PD98059 (20 microM). This information indicated that intracellular calcium, superoxide anion, tyrosine kinase and MAP kinase are involved in beta(2)-integrin expression. Furthermore, BAPTA/AM, superoxide dismutase and genistein inhibited celecoxib-increased MAP kinase activity, indicating that MAP kinase is a downstream signal for beta(2)-integrin expression. In conclusion, celecoxib stimulates superoxide anion release from human neutrophils by activating pertussis toxin sensitive G-protein. An increase in intracellular calcium and protein kinase C alpha, beta(I) and beta(II) is involved in this process. Celecoxib also regulates beta(2)-integrin expression through superoxide anion release, tyrosine kinase and p42/p44 MAP kinase on human neutrophils.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14729379&dopt=Abstract celecoxib, Celebrex