celecoxib, Celebrex
[First spontaneous reports of adverse reactions to the new selective COX-2 non-steroidal anti-inflammatory drugs]

[Article in Spanish]

Pedros C, Cereza G, Laporte JR.

Fundacio Institut Catala de Farmacologia. Barcelona. Spain.

BAKCGROUND: The new selective cyclooxygenase 2 non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with a lower incidence of adverse gastrointestinal effects. MATERIAL AND METHOD: The first Yellow Cards received at the Catalan Centre of Pharmacovigilance reporting adverse effects of rofecoxib and celecoxib were reviewed and compared to those attributed to non-selective NSAIDs. RESULTS: Most frequent adverse effects of rofecoxib were gastrointestinal and cardiovascular; those of celecoxib were mostly cutaneous and gastrointestinal; and those of non-selective NSAIDs were gastrointestinal and neuropsychiatric. CONCLUSIONS: Rofecoxib and celecoxib are not devoid of gastrointestinal toxicity; they may also induce cardiovascular adverse effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11943104&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells.

Song X, Lin HP, Johnson AJ, Tseng PH, Yang YT, Kulp SK, Chen CS.

Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, USA.

BACKGROUND: The antitumor activity of cyclooxygenase-2 (COX-2) inhibitors is thought to involve COX-2 enzyme inhibition and apoptosis induction, but it is unclear whether COX-2 inhibition is required for apoptosis. Different COX-2 inhibitors have similar IC(50) values (concentration for 50% inhibition) for COX-2 inhibition but differ considerably in their abilities to induce apoptosis, suggesting the involvement of a COX-2-independent pathway in apoptosis. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis and performed a structure-activity analysis of the COX-2 inhibitor celecoxib in the androgen-independent prostate cancer cell line PC-3. METHODS: Tetracycline-inducible (Tet-On) COX-2 antisense clones were isolated to assess the effect of COX-2 expression on cell viability and sensitivity to apoptosis induced by COX-2 inhibitors. Untreated Tet-On clones differentially expressed COX-2, and doxycycline-treated clones were depleted of COX-2. We synthesized and characterized various celecoxib derivatives with various COX-2 inhibitory activities and determined their apoptotic activity in PC-3 cells. Apoptosis was assessed with four tests. RESULTS: In contrast to the effect of COX-2 inhibitors, which induced apoptosis, COX-2 depletion did not induce cell death. Susceptibility to COX-2 inhibitor-induced apoptosis was independent of the level of COX-2 expression. Structure-activity analysis found no correlation between apoptosis induction and COX-2 inhibition. Some celecoxib derivatives that lacked COX-2 inhibitory activity facilitated apoptosis and vice versa. Moreover, celecoxib and apoptosis-active celecoxib derivatives mediated cell death by inhibiting the same pathway. CONCLUSION: We have dissociated the apoptosis-inducing activity from the COX-2 inhibitory activity by structural modifications of the COX-2 inhibitor celecoxib. This separation of activities may provide a molecular basis for the development of new classes of apoptosis-inducing agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11959891&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib modulates the capacity for prostaglandin E2 and interleukin-10 production in alveolar macrophages from active smokers.

Mao JT, Roth MD, Serio KJ, Baratelli F, Zhu L, Holmes EC, Strieter RM, Dubinett SM.

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: Preclinical data suggest that the cyclooxygenase (COX)-2/prostaglandin (PG) E2 signaling pathway plays an essential role in conferring the malignant phenotype in non-small cell lung cancer. We hypothesized that treatment with oral celecoxib, a selective COX-2 inhibitor, would favorably alter biomarkers of lung cancer risk. This study evaluated the feasibility of COX-2 inhibition as a form of chemoprevention for lung cancer. EXPERIMENTAL DESIGN: Heavy active smokers were enrolled into a pilot study and treated with celecoxib. Bronchoscopy with bronchoalveolar lavage was performed both before 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 nonsmoking control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation. RESULTS: Treatment with celecoxib significantly reduced calcium ionophore-stimulated PGE2 production from AMs recovered from smokers. AMs recovered from smokers, but not nonsmokers, were primed to produce high levels of PGE2 and interleukin (IL-10) when stimulated with lipopolysaccharide, and SC58236 significantly abrogated the production of these factors. Moreover, both plasma and bronchoalveolar lavage fluid obtained from treated subjects significantly reduced the production of PGE2 that resulted when a lung cancer cell line, A549, was stimulated with IL-1beta or A23187. CONCLUSIONS: Our findings suggest that oral celecoxib is capable of inhibiting the overproduction of PGE2, as well as modulating the production of IL-10 in the lung microenvironment in individuals at risk for lung cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14676104&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test.

Torres-Lopez JE, Ortiz MI, Castaneda-Hernandez G, Alonso-Lopez R, Asomoza-Espinosa R, Granados-Soto V.

Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Granjas Coapa, Mexico, DF, Mexico.

The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11991254&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Protective effects of Celecoxib on lung injury and red blood cells modification induced by carrageenan in the rat.

Cuzzocrea S, Mazzon E, Sautebin L, Dugo L, Serraino I, De Sarro A, Caputi AP.

Institute of Pharmacology, University of Messina, Messina, Italy. salvator www.unime.it

In the present study, we evaluated the effect of Celecoxib, a selective COX-2 inhibitor, in an acute model of lung injury induced by carrageenan administration in the rats. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear neutrophils (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of prostaglandin E(2) (PGE(2)), tumor necrosis factor alpha (TNFalpha), and interleukin-1beta. All parameters of inflammation were attenuated by Celecoxib. Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly(ADP-ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PARS was reduced by Celecoxib. These results clearly confirmed that COX-2 plays a critical role in the development of the inflammatory response by altering key components of the inflammatory cascade. Therefore, selective inhibitor of COX-2 such as Celecoxib, offers a therapeutic approach for the management of various inflammatory diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11992649&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib has a positive effect on the overall metabolism of hyaluronan and proteoglycans in human osteoarthritic cartilage.

El Hajjaji H, Marcelis A, Devogelaer JP, Manicourt DH.

ICP Christian de Duve Institute of Cellular Pathology and the Department of Rheumatology, Saint-Luc University Hospital, Catholic University of Louvain, Avenue Mounier, 1200 Brussels, Belgium.

OBJECTIVE: To assess the effects of celecoxib, a cyclooxygenase (COX-2) selective inhibitor, on the metabolism of hyaluronan (HA) and proteoglycans (PG) in human cartilage explants with midrange severity of osteoarthritis (OA). Results were compared with those of diclofenac, a non-selective COX inhibitor. METHODS: Cartilage specimens (OA grade 4-8 on Mankin's scale) were pulsed with 3H -glucosamine and chased in the absence or presence of 1-10 micro g/ml of celecoxib or diclofenac. After papain digestion, the labeled chondroitin sulfate and HA molecules were purified by anion-exchange chromatography. RESULTS: Diclofenac did not affect the metabolic balance of PG and HA whereas, in a relatively dose-dependent manner, celecoxib increased the synthesis of HA and PG; celecoxib also reduced the net loss of labeled HA and PG molecules from cartilage explants. CONCLUSION: In short term in vitro cultures, celecoxib has a favorable effect on the overall metabolism of PG and HA. It is therefore unlikely that this drug would have a detrimental effect on articular cartilage during longterm administration. Further, celecoxib might help counteract the depletion of HA seen in OA cartilage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14677191&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line.

Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, Ogier-Denis E.

INSERM U504 Glycobiologie et Signalisation Cellulaire 16 avenue Paul-Vaillant-Couturier, Villejuif Cedex 94807, France.

Nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase (COX) activity, are powerful antineoplastic agents that exert their antiproliferative and proapoptotic effects on cancer cells by COX-dependent and/or COX-independent pathways. Celecoxib, a COX-2-specific inhibitor, has been shown to reduce the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis. Here, we show that celecoxib induces apoptosis in the colon cancer cell line HT-29 by inhibiting the 3-phosphoinositide-dependent kinase 1 (PDK1) activity. This effect was correlated with inhibition of the phosphorylation of the PDK1 downstream substrate Akt/protein kinase B (PKB) on two regulatory sites, Thr(308) and Ser(473). However, expression of a constitutive active form of Akt/PKB (myristoylated PKB) has a low protective effect toward celecoxib-induced cell death. In contrast, overexpression of constitutive active mutant of PDK1 (PDK1(A280V)) was as potent as the pancaspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, to impair celecoxib-induced apoptosis. By contrast, cells expressing a kinase-defective mutant of PDK1 (PDK1(K114G)) remained sensitive to celecoxib. Furthermore, in vitro measurement reveals that celecoxib was a potential inhibitor of PDK1 activity with an IC(50) = 3.5 microm. These data indicate that inhibition of PDK1 signaling is involved in the proapoptotic effect of celecoxib in HT-29 cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12000750&dopt=Abstract celecoxib, Celebrex