celecoxib, Celebrex
Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation.

Takada Y, Bhardwaj A, Potdar P, Aggarwal BB.

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been shown to suppress transcription factor NF-kappaB, which controls the expression of genes such as cyclooxygenase (COX)-2 and cyclin D1, leading to inhibition of proliferation of tumor cells. There is no systematic study as to how these drugs differ in their ability to suppress NF-kappaB activation and NF-kappaB-regulated gene expression or cell proliferation. In the present study, we investigated the effect of almost a dozen different commonly used NSAIDs on tumor necrosis factor (TNF)-induced NF-kappaB activation and NF-kappaB-regulated gene products, and on cell proliferation. Dexamethasone, an anti-inflammatory steroid, was included for comparison with NSAIDs. As indicated by DNA binding, none of the drugs alone activated NF-kappaB. All compounds inhibited TNF-induced NF-kappaB activation, but with highly variable efficacy. The 50% inhibitory concentration required was 5.67, 3.49, 3.03, 1.25, 0.94, 0.60, 0.38, 0.084, 0.043, 0.027, 0.024, and 0.010 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. All drugs inhibited IkappaBalpha kinase and suppressed IkappaBalpha degradation and NF-kappaB-regulated reporter gene expression. They also suppressed NF-kappaB-regulated COX-2 and cyclin D1 protein expression in a dose-dependent manner. All compounds inhibited the proliferation of tumor cells, with 50% inhibitory concentrations of 6.09, 1.12, 0.65, 0.49, 1.01, 0.19, 0.36, 0.012, 0.016, 0.047, 0.013, and 0.008 mM for aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, resveratrol, curcumin, dexamethasone, celecoxib, and tamoxifen, respectively. Overall these results indicate that aspirin and ibuprofen are least potent, while resveratrol, curcumin, celecoxib, and tamoxifen are the most potent anti-inflammatory and antiproliferative agents of those we studied.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15489888&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Apoptosis protease activator protein-1 expression is dispensable for response of human melanoma cells to distinct proapoptotic agents.

Zanon M, Piris A, Bersani I, Vegetti C, Molla A, Scarito A, Anichini A.

Human Tumor Immunobiology Unit, Department of Experimental Oncology and Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Loss of expression of the apoptosis protease activator protein-1 (APAF-1) in human melanoma is thought to promote resistance to programmed cell death by preventing caspase-9 activation. However, the role of the APAF-1-dependent pathway in apoptosis activated by cellular stress and/or DNA damage has been recently questioned. We investigated APAF-1 expression in a large panel of human melanomas and assessed cellular response to several proapoptotic agents in tumors expressing or lacking APAF-1 protein. In two melanomas with wild-type p53 but with differential expression of APAF-1, treatment with camptothecin, celecoxib, or an nitric oxide synthase inhibitor (1400W) significantly modulated expression of 36 of 96 genes in an apoptosis-specific cDNA macroarray, but APAF-1 mRNA levels were not induced (in APAF-1(-) cells) nor up-regulated (in APAF-1(+) cells), a finding confirmed at the protein level. Treatment with cisplatin, camptothecin, etoposide, betulinic acid, celecoxib, 1400W, and staurosporine promoted enzymatic activity not only of caspases -2, -8, and -3 but also of caspase-9 in both APAF-1(+) and APAF-1(-) tumor cells. Moreover, drug-induced caspase-9 enzymatic activity could be not only partially but significantly reduced by caspase-2, -3, and -8 -specific inhibitors in both APAF-1(+) and APAF-1(-) tumor cells. In response to 1 to 100 micromol/L of cisplatin, camptothecin, or celecoxib, APAF-1(+) melanomas (n = 12) did not show significantly increased levels of apoptosis compared with APAF-1(-) tumors (n = 7), with the exception of enhanced apoptosis in response to a very high dose (100 micromol/L) of etoposide. These results suggest that the response of human melanoma cells to different proapoptotic agents may be independent of their APAF-1 phenotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15492260&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity.

Gierse JK, Zhang Y, Hood WF, Walker MC, Trigg JS, Maziasz TJ, Koboldt CM, Muhammad JL, Zweifel BS, Masferrer JL, Isakson PC, Seibert K.

Arthritis and Inflammation Pharmacology, Pfizer Research, 700 Chesterfield Parkway West, Chesterfield, MO 63017. james.k.gierse pfizer.com.

The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant COX-2, with an IC(50) of 0.005 muM; this compares with IC values of 0.05 muM for celecoxib, 0.5 muM for rofecoxib, and 5 muM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 muM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 muM; COX-1 IC(50) = 21.9 muM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15494548&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9.

Ding H, Han C, Zhu J, Chen CS, D'Ambrosio SM.

Department of Radiology, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.

Celecoxib is a potent nonsteroid antiinflammatory drug (NSAID) that has shown great promise in cancer chemoprevention and treatment. The tumor suppression activity of celecoxib and other NSAIDs have been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is a specific inhibitor of cyclooxygenase (COX)-2, recent data indicate that its apoptotic properties may also be mediated through COX-independent pathways. In our study, we evaluated second generation celecoxib derivatives, lacking COX-2 inhibitory activity, in a premalignant and malignant human oral cell culture model to determine their potential anticancer effect and mechanisms responsible for the COX-independent apoptotic activity. Celecoxib and its derivatives delayed the progression of cells through the G(2)/M phase and induced apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced apoptosis and cell cycle delay. Apoptosis and cell cycle arrest appeared to be independent of derivative induced inhibition of PDK1 and phosphorylation of Akt and Erk1/2. Derivatives induced apoptosis was mediated by the cleavage and activation of caspase-9 and caspase-3, but not caspase 8, implicating the mitochondrial pathway for apoptosis induction. Inhibitors of caspase-3 and caspase-9 and cyclosporin A, a mitochondrial membrane potential stabilizer, attenuated derivative induced apoptosis. Inhibition of caspase-3 prevented the activation of caspase 8, while the inhibition of caspase-9 inhibitor blocked activation of both caspase 3 and 8 by the derivatives. Apoptosis was independent of Bcl-2. These results indicate that the second generation celecoxib derivatives induce apoptosis in human oral cancer lines by the disruption of mitochondrial membrane potential activating caspase 9 and downstream caspase 3 and 8. This suggests that the modification of the celecoxib structure can lead to highly effective COX-independent growth inhibitory and apoptotic agents in chemoprevention and therapy. (c) 2004 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15499625&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Modulation of pulmonary leukotriene B4 production by cyclooxygenase-2 inhibitors and lipopolysaccharide.

Mao JT, Tsu IH, Dubinett SM, Adams B, Sarafian T, Baratelli F, Roth MD, Serio KJ.

Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-1690, USA. jmao mednet.ucla.edu

PURPOSE: Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways. We therefore evaluated the effects of cyclooxygenase (COX)-2 inhibition on leukotriene (LT) B(4) synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor. EXPERIMENTAL DESIGN: Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from ex-smoker control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation. RESULTS: Treatment with oral celecoxib only modestly increased LTB(4) levels in bronchoalveolar lavage, without increasing the mRNA transcription of 5-lipoxygenase (5-LOX) or 5-LOX-activating protein in AMs, whereas the acute calcium ionophore-stimulated LTB(4) production from smokers' AMs was markedly increased by 10.6-fold. In addition, smokers' AMs were twice as responsive in producing LTB(4) when exposed to lipopolysaccharide compared with ex-smokers' AMs. Concomitant COX-2 inhibition with SC58236, however, did not significantly impact these changes, whereas the 5-LOX inhibitor Zileuton blocked the generation of LTB(4) in a dose-responsive manner. Finally, cycloheximide increased the production of LTB(4) under all conditions, suggesting a shunting phenomenon and/or the presence of pathway inhibitors. CONCLUSIONS: Our findings suggest that whereas oral celecoxib is capable of modulating LTB(4) production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15501964&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effects of a prior-authorization policy for celecoxib on medical service and prescription drug use in a managed care Medicaid population.

Hartung DM, Touchette DR, Ketchum KL, Haxby DG, Goldberg BW.

Oregon State University College of Pharmacy, Portland, USA.

BACKGROUND: Prior authorization (PA) is a poorly studied but commonly employed policy used by health care payers to manage the rising costs of pharmacy benefits. OBJECTIVE: The aim of this study was to evaluate the intended and unintended effects of a PA policy for celecoxib on pharmacy and medical-service utilization in a Medicaid managed-care organization. METHODS: This was a retrospective, interrupted time-series analysis of 22 monthly health-related utilization rates from January 1, 1999, to October 31, 2000. All Medicaid claims for CareOregon (a managed-care organization) and a fee-for-service program were reviewed. A model was constructed to evaluate changes in utilization of therapeutically related drug classes (eg, conventional nonsteroidal anti-inflammatory drugs [NSAIDs], gastrointestinal agents), office and emergency-department encounters, and hospitalizations before and after the PA policy was implemented on November 16, 1999. A secondary analysis evaluated these changes among a sample of prior NSAID users. RESULTS: After the PA policy was implemented, use of celecoxib was immediately reduced from 1.07 to 0.53 days' supply per person-year (58.9%; 95% CI, 50.0%-67.9%). The monthly rate of increase was also reduced (P < 0.001). Utilization changes were not observed in other drug classes. Similar changes were observed in the secondary analysis. An 18% (95% CI, 2.2%-33.9%) nonsignificant increase in emergency-department visits was observed in the entire sample after the PA policy was implemented. However, a similar change was not observed in the secondary analysis of prior NSAID users. No other changes in medical service encounters were noted after the PA policy was activated. CONCLUSIONS: This observational study found that celecoxib use was substantially reduced after the implementation of a PA policy. No important changes in use of other drug classes were detected. The overall increase in emergency-department visits--although not observed among previous NSAID users--should be explored on the individual level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15531015&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats.

Fabricio AS, Veiga FH, Cristofoletti R, Navarra P, Souza GE.

Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1, 00168 Rome, Italy. alinefabricio hotmail.com

It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET(B) receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 mug/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE(2) and PGF(2alpha) in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15539607&dopt=Abstract celecoxib, Celebrex