celecoxib, Celebrex
[The effects of selective cyclooxygenase-2 inhibitors on the growth of gastric adenocarcinoma]

[Article in Chinese]

Liu C, Tang C, Wan X, Wang C, Zhou X.

Department of Gastroenterology, First Hospital of Chongqing Medical University, Chongqing 400016, China.

OBJECTIVE: This study was aimed to compare the effects of three kinds of selective cyclooxygenase-2 inhibitors (meloxicam, celecoxib, rofecoxib on the growth of gastric adenocarcinoma SGC7901 cell line, and to observe the effect of rofecoxib, on transplanted gastric cancer of nude mice in vivo. METHODS: The proliferation and apoptosis of SGC7901 cells were measured by 3H-thymidine incorporation into DNA and the TdT-mediated dUTP nick end-labeling assay (TUNEL) separately. The expression of PCNA and COX-2 of gastric adenocarcinoma cells were detected by immunocytochemistry. Human gastric adenocarcinoma SGC7901 cells were implanted orthotopically in the stomach of nude mice. Rofecoxib (30 mg.kg-1.d-1) was administrated i.g. for eight weeks. RESULTS: All the drugs potentially decreased 3H-thymidine incorporation into SGC7901 cells. The inhibition effects showed a dose-dependence manner. The median-response concentration was: 1.18 x 10(-7) mol/L (meloxicam), 1.68 x 10(-8) mol/L (celecoxib), 4.39 x 10(-9) mol/L (rofecoxib). After treatment with meloxicam, celecoxib, rofecoxib (1 x 10(-5) mol/L) for 24 hours, the apoptosis indices of SGC7901 cells were: 19.8% +/- 1.8%, 24.6% +/- 1.2% and 31.2% +/- 2.2%, respectively. The higher selective inhibition on COX-2, the higher apoptosis index (P < 0.01). Rofecoxib down-regulated the expression of COX-2 and PCNA of SGC7901 cell, both in vitro and in vivo. The inhibition rate for xenografts in situ in nude mice treated with rofecoxib was 93.9%. CONCLUSION: The higher selective inhibition on COX-2, the stronger inhibition on gastric adenocarcinoma cells. Rofecoxib may be one of the important medicines in the treatment of gastric adenocarcinoma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12910695&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Determination of celecoxib in human plasma using solid-phase extraction and high-performance liquid chromatography.

Chow HH, Anavy N, Salazar D, Frank DH, Alberts DS.

Arizona Cancer Center, The University of Arizona, 1515 N Campbell Avenue, Tucson, AZ 85724-5024, USA. schow zcc.arizona.edu

A simple reversed phase high-performance liquid chromatography (HPLC) method was developed for determination of celecoxib levels in human plasma. The procedure involves solid-phase extraction of celecoxib and the internal standard (SC-236) from plasma using C(18) extraction cartridges. The chromatographic separation of celecoxib and SC-236 was achieved with a Nova Pak C(8) column (3.8 mm x 150 mm) eluted with a mobile phase consisting of acetonitrile-tetrahydrofuran-sodium acetate buffer (pH 5.0) in the ratio of 30:8:62. An ultraviolet light detector with the wavelength set at 215 nm was employed for detection. Celecoxib was well resolved from the plasma constituents and the internal standard. The extraction recovery of celecoxib and SC-236 from human plasma was greater than 88%. Linear calibration curves were established over a concentration range of 40-4000 ng/ml when 0.25 ml aliquots of plasma were used. The inter- and intra-day R.S.D. for the assay was less than 12 and 5%, respectively. This assay has been applied to the analysis of celecoxib levels in plasma samples collected from healthy participants entered into a Phase II clinical study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14738931&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib.

White WB, Faich G, Borer JS, Makuch RW.

Division of Hypertension and Clinical Pharmacology, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut 06030-3940, USA. wwhite nso1.uchc.edu

To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of > or =4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were < or =1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12914871&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs celecoxib and nimesulide inhibit androgen receptor activity via induction of c-Jun in prostate cancer cells.

Pan Y, Zhang JS, Gazi MH, Young CY.

Departments of Urology and Biochemistry and Molecular Biology, Mayo Graduate School, Mayo Clinic/Foundation, Rochester, Minnesota 55905.

Nonsteroidal anti-inflammatory drugs (NSAIDs) play potential roles in cancer chemoprevention. In this study, we investigated the effects of NSAIDs on androgen receptor (AR)-mediated functions in prostate cancer cells. We found that two cyclooxygenase 2-specific NSAIDs, celecoxib and nimesulide, dramatically reduced the expression of androgen-inducible genes, such as prostate-specific antigen, hK2, and the FK506-binding protein 51 (FKBP51). We demonstrated that both NSAIDs repressed AR-mediated activation of prostate-specific antigen and hK2 promoter activity as well as AR protein expression. Finally, our findings suggested that overexpressed c-Jun by the NSAIDs not only inhibited the function of AR but also directly repressed AR expression at the transcription level. Our findings provide a strong rationale for celecoxib and nimesulide as potential agents for prostate cancer prevention and/or treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12917209&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis.

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

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Cyclooxygenase-2 (COX-2)-controlled prostaglandin (PG) metabolism recently has been implicated in the pathogenesis of hepatocellular carcinoma (HCC). However, the biologic role and molecular mechanism of COX-2-mediated PGs in the control of liver cancer growth have not been established. This study was designed to examine the direct effect of COX-2 and its inhibitor celecoxib on the growth control of liver cancer cells. Human HCC cell lines Hep3B and HepG2 transfected with COX-2 expression vector showed increased cell growth and enhanced phosphorylation of serine/threonine protein kinase B (Akt). The level of COX-2 expression and Akt phosphorylation is correlated positively in cultured HCC cells and human liver cancer tissues. Inhibition of Akt activation by phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 significantly decreased the viability of Hep3B and HepG2 cells (P <.01). These results reveal a novel role of Akt activation in COX-2-induced HCC cell survival. Furthermore, HCC cells treated with the COX-2 inhibitor celecoxib showed significant reduction of Akt phosphorylation and marked morphologic and biochemical characteristics of apoptosis. Overexpression of COX-2 or addition of exogenous PGE(2) partially prevented celecoxib-induced apoptosis (P <.01). In conclusion, our results suggest the involvement of COX-2-dependent and -independent mechanisms in celecoxib-mediated HCC cell apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12939602&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Chemotherapeutic efficacy of topical celecoxib in a murine model of ultraviolet light B-induced skin cancer.

Wilgus TA, Koki AT, Zweifel BS, Rubal PA, Oberyszyn TM.

Department of Pathology, The Ohio State University, Columbus, Ohio, USA.

Over a million nonmelanoma skin cancer cases will be reported in the United States this year alone. Currently the primary form of treatment for these types of skin tumors is excision. However, excision of the initial lesion may not be curative because almost 50% of patients with one nonmelanoma skin cancer lesion develop another tumor within the next 5 yr at the site or adjacent to the site of excision. As with other types of epithelial based cancers, there is mounting evidence for the role of cyclooxygenase-2 (COX-2) and its products, particularly prostaglandin E(2) (PGE(2)), in the development of nonmelanoma skin cancer. To avoid the excision process, the present study was designed to evaluate the possible chemotherapeutic effect of directly treating established tumors with a topical formulation of the specific COX-2 inhibitor celecoxib. Skh/hr hairless mice were irradiated three times per wk for 16 wk to induce tumor formation. The mice were then divided into two groups and treated topically with either 500 microg celecoxib or the vehicle for 6 wk. Our results demonstrated that although topical treatment with celecoxib was not able to induce regression of established tumors, it did prevent new tumor formation after the onset of photocarcinogenesis. Although further studies are warranted, these data suggest that topical celecoxib treatment may prove to be effective in preventing the recurrence of tumors at the site of nonmelanoma skin cancer excision. Copyright 2003 Wiley-Liss, Inc.

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celecoxib, Celebrex
Suppression of N-methyl-N-nitrosourea/testosterone-induced rat prostate cancer growth by celecoxib: effects on cyclooxygenase-2, cell cycle regulation, and apoptosis mechanism(s).

Narayanan BA, Condon MS, Bosland MC, Narayanan NK, Reddy BS.

Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595, USA. bnarayan ifcp.us

PURPOSE: This study was aimed at examining the mechanisms underlying the chemopreventive effect of celecoxib against prostate cancer. We focused our attention on events at the cellular level to show the ability of celecoxib to inhibit prostate cancer growth, by inducing cell cycle arrest and apoptosis. Moreover, we attempted to demonstrate the expression of genes involved in the downstream events related to cyclooxygenase-2 (COX-2) regulation and apoptosis. EXPERIMENTAL DESIGN: To determine the level of COX-2 expression, we used paraffin-embedded tumor tissue sections and cancer cells (I-26) derived from N-methyl-N-nitroso-urea/testosterone-induced rat dorsolateral prostate, and we used immunofluorescence detection and Western blot analyses with anti-COX-2 monoclonal antibodies. We conducted clonogenic cell survival assays to demonstrate cell growth inhibition at very low doses of celecoxib. Flow cytometric analysis demonstrated the effects on the cell cycle. Reverse transcription-PCR and Western blot analyses were performed to show the effect of celecoxib on the downstream events of COX-2 and apoptosis-related targets. RESULTS: The summary of our findings indicates that (a). these cells from chemically induced rat prostate tumors express COX-2 at both the mRNA and the protein level; (b). celecoxib significantly reduces COX-2 expression in these cancer cells; and (c). celecoxib induces cell cycle arrest at the G(1)-S phase transition point and modifies cell cycle regulatory proteins such as cyclin D1, retinoblastoma (Rb), and phosphorylated Rb, cyclin E, p27(KIP1), and p21(WAF1/CIP1). Furthermore, celecoxib inhibits DNA synthesis and induces apoptosis. Most importantly, celecoxib-induced apoptosis was associated with down-regulation of COX-2, nuclear factor kappaBp65, and with activation of peroxisome proliferator-activated receptor gamma, apoptosis activating factor-1, and caspase-3. CONCLUSION: Results from the present study clearly indicate that celecoxib exerts its anticancer effect partly through COX-2-independent mechanisms in addition to the known primary function of COX-2 inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12960143&dopt=Abstract celecoxib, Celebrex