celecoxib, Celebrex
Effect of cyclooxygenase-2 inhibitor (celecoxib) on the infarcted heart in situ.

Yamamoto T, Kakar NR, Vina ER, Johnson PE, Bing RJ.

Huntington Medical Research Institutes, Department of Experimental Cardiology, Pasadena, Calif 91101, USA.

Several attempts have been made to replace aspirin with compounds without gastric toxicity; a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and a nitric oxide-aspirin, NCX-4016, have been developed for this purpose. This paper compares effects of celecoxib, NCX-4016 and aspirin on production of prostacyclin (PGI2) and thromboxane A2 (TXA2) and activation of the inducible form of nitric oxide synthase (iNOS) in infarcted heart in situ. Aspirin was most effective in reducing myocardial PGI2 synthesis and formation of TXA2. Myocardial effects of celecoxib resemble those of NCX-4016, although the two compounds have different modes of action. Copyright 2001 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11408829&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells.

Kulp SK, Yang YT, Hung CC, Chen KF, Lai JP, Tseng PH, Fowble JW, Ward PJ, Chen CS.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Regarding the involvement of cyclooxygenase-2 (COX-2)-independent pathways in celecoxib-mediated antineoplastic effects, the following two issues remain outstanding: identity of the non-COX-2 targets and relative contributions of COX-2-dependent versus -independent mechanisms. We use a close celecoxib analog deficient in COX-2-inhibitory activity, DMC (4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide), to examine the premise that Akt signaling represents a major non-COX-2 target. Celecoxib and DMC block Akt activation in PC-3 cells through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1) with IC(50) of 48 and 38 micro M, respectively. The consequent effect on Akt activation is more pronounced (IC(50) values of 28 and 20 micro M, respectively), which might be attributed to the concomitant dephosphorylation by protein phosphatase 2A. In serum-supplemented medium, celecoxib and DMC cause G(1) arrest, and at higher concentrations, they induce apoptosis with relative potency comparable with that in blocking Akt activation. Moreover, the effect of daily oral celecoxib and DMC at 100 and 200 mg/kg on established PC-3 xenograft tumors is assessed. Celecoxib at both doses and DMC at 100 mg/kg had marginal impacts. However, a correlation exists between the in vitro potency of DMC and its ability at 200 mg/kg to inhibit xenograft tumor growth through the inhibition of Akt activation. Analysis of the tumor samples indicates that a differential reduction in the phospho-Akt/Akt ratio was noted in celecoxib- and DMC-treated groups vis-a-vis the control group. Together, these data underscore the role of 3-phosphoinositide-dependent protein kinase-1/Akt signaling in celecoxib-mediated in vitro antiproliferative effects in prostate cancer cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14973075&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib.

Yamada Y, Yoshimi N, Hirose Y, Hara A, Shimizu M, Kuno T, Katayama M, Qiao Z, Mori H.

Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. y-yamada cc.gifu-u.ac.jp

Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that beta-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of beta-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts / lesion) of beta-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs) / nucleus in beta-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of beta-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that beta-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that beta-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11429049&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Stimulated release of arachidonic acid from rat liver cells by celecoxib and indomethacin.

Levine L.

Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA. llevine brandeis.edu

The selective cyclooxygenase-2 (COX) inhibitor, celecoxib, and the non-selective COX-1 and COX-2 inhibitor, indomethacin, at microM concentrations, stimulate the release of arachidonic acid from rat liver cells (the C-9 cell line). Other non-steroidal anti-inflammatory drugs were tested, including salicylic acid, acetylsalicylic acid, sulindac sulfone, sulindac sulfide, ibuprofen, piroxicam and the selective COX-2 inhibitor, rofecoxib, and the analgesic, acetaminophen. These compounds do not stimulate the release of arachidonic acid. The stimulated release by celecoxib is not affected by dexamethasone or the translation and transcription inhibitors, actinomycin and cycloheximide. The increased arachidonic acid release may be associated with induction of apoptosis. Copyright 2001 Harcourt Publishers Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11487305&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries.

Hennan JK, Huang J, Barrett TD, Driscoll EM, Willens DE, Park AM, Crofford LJ, Lucchesi BR.

University of Michigan Medical School, Department of Pharmacology, Ann Arbor 48109-0632, USA.

BACKGROUND: Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a component of the inflammatory response. Prostacyclin, a product of COX-2 in vascular endothelium, has important physiological roles, such as increasing blood flow to injured tissues, reducing leukocyte adherence, and inhibiting platelet aggregation. We examined the possibility that selective COX-2 inhibition could suppress the protective effects of prostacyclin, resulting in an alteration of the hemostatic balance and vascular tone. METHODS AND RESULTS: Circumflex coronary artery thrombosis was induced in dogs by vascular electrolytic injury. Orally administered celecoxib (COX-2 inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not alter time to occlusive thrombus formation compared with controls (celecoxib 77.7+/-7.2 minutes, HDA 72.0+/-18.5 minutes, control 93.0+/-21.8 minutes). Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibition) produced a significant increase in time to vessel occlusion (257.0+/-41.6 minutes). The observed increase in time to occlusion was abolished when celecoxib was administered to animals dosed with HDA-ER (80.7+/-20.6 minutes). The vasomotor effect of endothelium-derived prostacyclin was examined by monitoring coronary flow during intracoronary administration of arachidonic acid or acetylcholine. In celecoxib-treated animals, vasodilation in response to arachidonic acid was reduced significantly compared with controls. CONCLUSIONS: The results indicate important physiological roles for COX-2-derived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased in individuals with underlying inflammatory disorders, including coronary artery disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11502709&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
A stable prostacyclin analog enhances ectopic activity in rat sensory neurons following neuropathic injury.

Omana-Zapata I, Bley KR.

CNS Therapy Area, Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304, USA. imelda.omana-zapata roche.com

Prostanoids sensitize sensory afferents during inflammation. However, their role in neuropathic pain is still unclear. We analyzed the actions of prostanoids, non-selective (indomethacin) or selective (celecoxib and NS-398) cyclooxygenase-2 (COX or COX-2) inhibitors, on the ectopic activity of dorsal root ganglia (DRG) and dorsal horn (DH) neurons in a model of neuropathic injury. Extracellular recordings of DRG and DH neurons and cardiovascular measurements were performed on anesthetized, paralyzed and artificially ventilated adult male Sprague-Dawley rats whose sciatic nerve had been transected. PGD(2), PGE(2), PGF(2alpha), carbaprostacyclin (cPGI(2); a stable prostacyclin analog), and carbocyclic thromboxane (cTXA(2)) were administered at cumulative doses (0.0001-5 mg/kg, i.p.) at 5 or 10 min intervals. Only cPGI(2) significantly increased the DRG and DH activity in a dose-dependent manner, with ED(50) values of 0.05 (0.01-0.96) and 0.69 (0.11-1.04) mg/kg, respectively. The other prostanoids did not significantly increase activity, although they reduced heart rate for up to 5 min following administration. Time course experiments with single doses of cPGI(2) (1 mg/kg, i.v.) increased DH discharge rate 3-17 min after injection. Indomethacin (3 mg/kg, s.c.), but not celecoxib or NS-398 (both at 6 mg/kg, s.c.), reduced both DRG and DH activity. Our results indicate that cPGI(2) excites DRG and DH neurons of neuropathic rats, and may suggest a role for IP prostanoid receptors in pain episodes associated with nerve injury. The inhibitory effect of indomethacin, but not celecoxib or NS-398, on ectopic activity may suggest that a tonic generation of PGI(2) by COX-1 could contribute to neuropathic pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11516414&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Modulation of cyclooxygenase-2 activities by the combined action of celecoxib and decosahexaenoic acid: novel strategies for colon cancer prevention and treatment.

Swamy MV, Cooma I, Patlolla JM, Simi B, Reddy BS, Rao CV.

Chemoprevention and Nutritional Carcinogenesis Program, Institute for Cancer Prevention, American Health Foundation-Cancer Center, Valhalla, NY, USA.

To develop efficient synergistic or additive combinations of chemopreventive and nutritional agents to reduce the risk of colon cancer, experiments were designed to test the application of a selective cyclooxygenase-2 (COX-2) inhibitor together with dietary omega-3 polyunsaturated fatty acids (PUFAs), such as decosahexaenoic acid (DHA). Thus, individual application of celecoxib, a COX-2 inhibitor, DHA, a omega-3 PUFA, and combinations of both were tested for their effectiveness using cell proliferation, apoptosis, and COX-2 expression as markers in the human colon cancer HCA-7 cell line. HCA-7 cells exposed to various subtoxic doses of celecoxib, DHA, or combinations of both were analyzed for inhibition of cell proliferation by trypan blue exclusion and proliferating cell nuclear antigen methods, induction of apoptosis by 4',6-diamidino-2-phenylindole method, and COX-2 by reverse transcription-PCR and Western blot analysis. In addition, we examined the inhibitory potential of celecoxib and DHA on (14)C-arachidonic acid metabolism mediated by COX-2 in the HCA-7 cell line. We found that treatment with celecoxib (50-150 micro M) or DHA (150-225 micro M) individually induces apoptosis and inhibits cell proliferation only at high concentrations in HCA-7 cell lines. A synergistic effect was observed on induction of apoptosis and inhibition of proliferation when cells were exposed to low doses of celecoxib (50-100 micro M) together with DHA (75 micro M). At high concentrations, celecoxib and DHA blocked the increase in COX-2 protein and mRNA expression in HCA-7 cells. Importantly, the inhibition of COX-2 expression was more pronounced in cells treated with low-dose combinations than with individual agents at high concentrations. In addition, celecoxib and DHA at low-dose levels inhibited (14)C-arachidonic acid metabolism (50-85%, P < 0.0001) leading to very low levels of type 2 series prostaglandin formation. These findings provide the basis for the development of combinations of low-dose regimens of a COX-2 inhibitor and omega-3 PUFAs such as DHA for the prevention and treatment of colon cancer. We are currently testing this concept in preclinical models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14985462&dopt=Abstract celecoxib, Celebrex