celecoxib, Celebrex
Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines.

El-Rayes BF, Ali S, Sarkar FH, Philip PA.

Department of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John R. Street, Detroit, MI 48201, USA.

Cyclooxygenase-2 (COX-2) is involved in inhibition of apoptosis, potentiation of cell growth, and angiogenesis and as such is a target for drug development. The COX-2 enzyme is frequently overexpressed in pancreatic cancer. The aim of this study was to determine the effects of celecoxib on the growth inhibition and induction of apoptosis by gemcitabine in pancreatic cancer cell lines. Baseline expression of COX-2 enzyme was determined by Western blot analysis in five human pancreatic cancer cell lines. Cells were treated with gemcitabine (100 nmol/L), celecoxib (1, 10, and 50 micromol/L), and the combination. No potentiation in growth inhibition was observed in MIAPaCa cells (low COX-2 expression). However, growth inhibition and apoptosis were significantly increased with celecoxib in the BxPC-3 cells that have a high COX-2 expression. Significant down-regulation of nuclear factor-kappaB activation was observed in BxPC-3 cells treated with celecoxib and gemcitabine. Moreover, down-regulation of COX-2 mRNA and protein expression was also observed in the BxPC-3 cells treated with the combination as compared with the untreated and the celecoxib-treated and gemcitabine-treated cell lines. We conclude that celecoxib potentiates gemcitabine-induced growth inhibition and apoptosis in pancreatic cell lines. In addition to inhibition of the COX-2 enzyme, the celecoxib and gemcitabine combination down-regulated nuclear factor-kappaB activation, which in turn may have contributed to the induction of apoptosis and the down-regulation of transcription of the COX-2 enzyme.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15542781&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration.

Ayalasomayajula SP, Kompella UB.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.

PURPOSE: We have previously demonstrated that celecoxib, a selective COX-2 inhibitor, reaches the retina following repeated oral administrations and inhibits diabetes-induced vascular endothelial growth factor (VEGF) mRNA expression and vascular leakage in a rat model. The aim of this study was to quantify the relative retinal bioavailability of celecoxib from the subconjunctival route compared to a systemic route. METHODS: The plasma and ocular tissue distribution of celecoxib was determined in male Sprague-Dawley rats following subconjunctival and intraperitoneal administrations of drug suspension at a dose of 3 mg/rat. The animals were sacrificed at 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing, the blood was collected, and the eyes were enucleated and frozen. The plasma, sclera, retina, vitreous, lens, and the cornea were isolated and celecoxib levels were determined using an HPLC method. The tissue exposure of the drug was measured as the area under the curve (AUC(0-infinity)) of the concentration vs. time profiles. The relative bioavailability was estimated as the AUC(0-infinity) ratio between subconjunctival and intraperitoneal groups. RESULTS: For the subconjunctivally dosed (ipsilateral) eye, the AUC(0-infinity) ratios between subconjunctival and intraperitoneal groups were 0.8 +/- 0.1, 53 +/- 4, 54 +/- 8, 145 +/- 21, 61 +/- 16, and 52 +/- 6 for plasma, sclera, retina, vitreous, lens, and cornea, respectively. For the contralateral ocular tissues, the AUC0-infinity ratios were 1.2 +/- 03, 11 +/- 0.3, 1.1 +/- 0.4, 1.0 +/- 0.3, and 1.2 +/- 0.3 in the sclera, retina, vitreous, lens, and the cornea, respectively, between the subconjunctival and the intraperitoneal groups. Assuming that the drug AUCs in contralateral eye were equal to the systemic pathway contribution to AUCs in the ipsilateral eye, the percent contribution of local pathways as opposed to systemic circulation for celecoxib delivery to the ipsilateral eye tissues was estimated to be 98% or greater. CONCLUSIONS: The retinal delivery of celecoxib was substantially higher following subconjunctival administration compared to the intraperitoneal route. The transscleral pathway almost completely accounts for the retinal celecoxib delivery following subconjunctival administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15553225&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Control of pulmonary metastases of rat mammary cancer by inhibition of uPA and COX-2, singly and in combination.

Evans DM, Sloan Stakleff KD.

Akron General Medical Systems, Kenneth Calhoun Research Laboratory, Akron, Ohio 44307, USA.

Tumor cell metastasis can be suppressed by the attenuation of proteolytic and angiogenic events that are mediated by tumor and endothelial cells. Combinations of specific inhibitors directed to separate stages of the metastatic cascade may improve the potential for adjuvant therapies. Amiloride is an effective plasminogen activator inhibitor, while celecoxib is a cylcooxygenase-2 inhibitor. In vitro invasion assays were used to assess the effect of each inhibitor on the cellular invasion of MATB rat mammary carcinoma cells. Individually, both amiloride and celecoxib impeded cellular invasion in a dose-dependent manner. Combinations consistently exerted a significant inhibitory response (91 to 99%). These inhibitors were administered alone and in combination to evaluate their efficacy in the prevention of pulmonary metastases from a primary rat mammary carcinoma. Amiloride and celecoxib, alone and in combination, consistently showed no effect on the growth of primary tumors. The combined inhibitors were able to reduce significantly the growth of local recurrences following primary tumor excision and metastatic incidence rates. Numbers of pulmonary metastases were reproducibly and significantly decreased with the administration of amiloride and celecoxib, alone and in combination. Celecoxib alone was most effective with a reduction in 98% of the metastases, yet distinctions were observed in the results with respect to the local recurrences, blood levels for the inhibitors and tissue production of prostaglandin E2. These data demonstrate the potential use for celecoxib, alone and in combination with amiloride, in the suppression of metastases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15554390&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer.

Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, Mukherjee P.

Mayo Clinic College of Medicine, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.

Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15561779&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
THE EARLY VASODILATOR RESPONSE TO ANODAL CURRENT APPLICATION IN HUMAN IS NOT IMPAIRED BY CYCLOOXYGENASE-2 BLOCKADE.

Tartas M, Gallois Y, Koitka A, Durand S, Bouye P, Saumet JL, Abraham P.

Laboratory for Vascular Investigations, University Hospital, Angers, France.

It is generally acknowledged that the cutaneous vasodilatation to monopolar galvanic current application would result from an axon reflex in primary afferent fibres and to the neurogenic inflammation resulting from neuropeptide release. Previous papers have suggested a participation of prostaglandin (PG) in anodal current-induced cutaneous vasodilatation. Thus, the inducible cyclooxygenase isoform (COX-2), assumed to play a key role in inflammation, should be involved in the synthesis of the PG released. Skin blood flow (SkBF) variations induced by 5-min, 0.1-mA monopolar anodal current application was evaluated with laser-Doppler flowmetry on the forearm of healthy volunteers under indomethacin (COX-1&2 inhibitor), celecoxib (COX-2 inhibitor) or placebo treatment. SkBF was indexed as cutaneous vascular conductance (CVC) expressed as percent of heatinduced maximal CVC (%MVC). Urinalyses were performed to test celecoxib treatment efficiency. No difference was found in CVC values at rest: 14.3 +/- 4.0, 11.9 +/- 3.2, 10.9 +/- 2.0 %MVC after indomethacin, celecoxib or placebo treatment, respectively. At 10-min following the onset of anodal current application, CVC values were 22.2 +/- 4.9 %MVC, (non-significant from rest) under indomethacin, 85.7 +/- 15.3 %MVC (p<0.001 from rest) under celecoxib and 70.4 +/- 13.1 %MVC (p<0.001 from rest) under placebo. Celecoxib treatment significantly depressed the urinary prostacyclin metabolite 6-keto PGF1alpha (p<0.05 from placebo). Indomethacin but not celecoxib treatment significantly inhibited the anodal current-induced vasodilatation. Thus, although assumed to result from an axon reflex in primary afferent fibres and neurogenic inflammation, these results suggest that the early anodal current-induced vasodilatation is mainly dependent on COX-1 prostaglandin synthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15563538&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
A COX-2 inhibitor prevents the esophageal inflammation-metaplasia-adenocarcinoma sequence in rats.

Oyama K, Fujimura T, Ninomiya I, Miyashita T, Kinami S, Fushida S, Ohta T, Koichi M.

Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Barrett's esophagus (BE) and esophageal adenocarcinoma (ADC) is associated with reflux of duodenal contents. Cyclooxygenase (COX)-2 is over-expressed in BE and ADC, and supposedly contributes to esophageal carcinogenesis. The aim of this study is to investigate what effect a COX-2 inhibitor has on esophageal adenocarcinogenesis in rats. A series of 90 rats underwent a duodenoesophageal reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing celecoxib (celecoxib group). The animals were sacrificed sequentially, at the 10th, 20th, 30th and, finally, 40th week after surgery, and their esophagi were examined. In the control group, esophagitis, columnar-lined epithelium (CLE) and ADC were first observed at the 10th week, 20th week and 30th week, respectively. Their incidences sequentially increased and at the 40th week reached 100, 89 and 47%, respectively. In the celecoxib group, the esophagitis was mild and the incidence of CLE was significantly lower at each week (P < 0.001), compared with the control group, and ADC was not observed throughout the experiment (P < 0.05). COX-2 expression was observed predominantly in the stroma of inflamed esophageal epithelia, and up-regulated at the 10th and 20th week (P < 0.05, respectively). PGE2 level and proliferative activity were also up-regulated in both groups, but they were lower in the celecoxib group than in the control group (P < 0.05). Apoptosis was observed to increase with celecoxib treatment (P < 0.05). Celecoxib is effective in preventing CLE and ADC by suppressing esophagitis in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15564290&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model.

Narayanan BA, Narayanan NK, Pittman B, Reddy BS.

Cancer Genomics Laboratory, Chemoprevention and Nutritional Carcinogenesis Program, and Statistics and Data Management, Institute for Cancer Prevention, Valhalla, New York 10987, USA.

PURPOSE: Epidemiologic studies have revealed a decreased risk of colon cancer among people who have regularly taken cyclooxygenase (COX)-2 inhibitors such as aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas the selective COX-2 inhibitor celecoxib and exisulind, a metabolic product of sulindac, have gained increasing attention as efficacious chemopreventive agents against colon and prostate cancer, not much is known about the underlying molecular targets and mechanisms. Moreover, the side effects of NSAIDs are a major obstacle for large-scale application to the prevention of cancer in humans; for example, in the United States in 1998, there were 16,550 deaths from NSAID-induced gastrointestinal complications. The toxicity associated with these compounds is raising concerns, and more needs to be known about their mode of action and molecular targets. EXPERIMENTAL DESIGN: We used the transgenic mouse prostate (TRAMP) model, which exhibits similarities with human prostate cancer, including epithelial origin, progression from the PIN stage to adenocarcinoma, and metastasis by a transgene that is hormonally regulated by androgens. In addition to histologically analyzing the PIN lesions of the dorsolateral prostate from TRAMP mice, we delineated the molecular targets and mechanisms of celecoxib and exisulind against mouse PIN lesions. We performed Western blot analysis of the total protein lysate from the tissues of mouse PIN lesions to measure the level of expression of androgen receptor, vascular endothelial growth factor, nuclear factor-kappaB p65, BclII, AKT (total and phosphorylated Ser473), p53, cyclin-dependent kinase inhibitor p21WAF1/CIP1, p27, BAX, and caspase-3 to demonstrate the COX-2-independent mechanism involved in the inhibition of PIN lesions of the dorsolateral prostate by both celecoxib and exisulind. RESULTS: We found for the first time that (a) both celecoxib and exisulind as dietary supplements induce strong inhibitory effects against prostate cancer at doses of 800 and 500 ppm, respectively, after 16 weeks; (b) the histologic analysis of the dorsolateral prostate after 2 weeks of treatment indicated a reduction of PIN lesions from 75% to 19% with celecoxib and to 16% with exisulind; (c) more importantly, those few PINs and adenocarcinomas in the groups treated with celecoxib or exisulind showed more apoptotic cells, lower levels of proliferating cell nuclear antigen, and a lower number of mitotic cells. To understand the molecular mechanisms involved in the inhibition of PIN lesions, first, we examined the expression of molecular targets involved in angiogenesis and inflammatory processes. It was clearly evident from Western blot analysis of the total protein lysate derived from the dorsolateral prostate tissues with PIN lesions that expression of androgen receptor, vascular endothelial growth factor, nuclear factor-kappaB p65, and BclII is down-regulated more effectively by celecoxib. Down-regulation of AKT protein (total and phosphorylated at Ser473) signaling by celecoxib clearly indicates an inhibition of the survival gene and the pathological process that could otherwise lead to adenocarcinoma. CONCLUSIONS: Overall, the findings from this study clearly show the effectiveness of celecoxib and exisulind in reducing the PIN lesions by modulating a cascade of molecular targets involved in COX-2-dependent and -independent mechanisms. Whereas these agents are already in clinical trial or in use as chemopreventive agents, findings from this study demonstrate the difference in their mode of action, thus helping us to understand the side effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15570007&dopt=Abstract celecoxib, Celebrex