Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and hypoprothrombinemia.. J D Linder; K E Mönkemüller; J V Davis; C M Wilcox (2000) Southern medical journal display abstract
Gastrointestinal side effects from nonsteroidal anti-inflammatory drugs (NSAIDs) result mainly from inhibition of the enzyme cyclooxygenase (COX)-1; it is responsible for the synthesis of prostaglandin E2, which leads to increased mucosal blood flow, increased bicarbonate secretion, and mucus production, thus protecting the gastrointestinal mucosa. In inflammation, COX-2 is induced, causing synthesis of the prostaglandins in conditions such as osteoarthritis and rheumatoid arthritis. Two NSAIDs (celecoxib and rofecoxib) with very high specificity for COX-2 and virtually no activity against COX-1 at therapeutic doses have been approved for clinical use. In trials of celecoxib and rofecoxib, only 0.02% of patients had clinically significant gastrointestinal bleeding, compared to a 1% to 2% yearly incidence of severe gastrointestinal side effects with NSAIDs. Our patient had arthritis of the hips and chronic atrial fibrillation and was on warfarin therapy for stroke prevention; less than a week after starting celecoxib therapy, gastrointestinal bleeding and hypoprothrombinemia occurred.
Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not by other selective cyclooxygenase 2 inhibitors.. Natsuko Kusunoki; Ryuta Yamazaki; Shinichi Kawai (2002) Arthritis and rheumatism display abstract
OBJECTIVE: Selective cyclooxygenase 2 (COX-2) inhibitors are now being used as antiinflammatory agents that cause fewer gastrointestinal complications, compared with other antiinflammatory drugs, in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether selective COX-2 inhibitors could induce apoptosis of RA synovial fibroblasts (RASFs). METHODS: RASFs were exposed to selective COX-2 inhibitors, i.e., celecoxib, etodolac, meloxicam, nimesulide, N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide, and rofecoxib, under various conditions. Cell proliferation and cell viability were assessed by incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by identifying DNA fragmentation. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) was measured by the luciferase reporter gene assay with a PPAR response element-driven luciferase reporter plasmid and a PPARgamma expression plasmid. RESULTS: Celecoxib strongly inhibited the proliferation of RASFs, whereas other selective COX-2 inhibitors had little or no effect. In addition, celecoxib reduced the viability of RASFs by induction of apoptosis, in a concentration-dependent manner. This action was abolished by addition of caspase inhibitors. Interleukin-1beta had a weak enhancing effect on celecoxib-induced apoptosis in RASFs. In contrast, other selective COX-2 inhibitors at concentrations up to 100 microM did not induce apoptosis of RASFs. Indomethacin, a nonselective COX inhibitor, activated PPARgamma transcription, while celecoxib did not. CONCLUSION: Celecoxib suppressed the proliferation of RASFs by COX-2-independent and PPARgamma-independent induction of apoptosis. Although the mechanism involved remains unclear, celecoxib may have not only antiinflammatory activity, but also a disease-modifying effect on rheumatoid synovial proliferation.
A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy.. R S Pruthi; J E Derksen; D Moore (2004) BJU international display abstract
OBJECTIVES: To evaluate the efficacy of the cyclooxygenase (COX)-2 inhibitor celecoxib in prostate-specific antigen (PSA) recurrent prostate cancer after definitive radiation therapy (RT) or radical prostatectomy (RP), as recent evidence showed that COX-2 inhibitors have potent antitumour activity in prostate cancer both in vitro and in vivo but there are no human trials. PATIENTS AND METHODS: Twelve patients who had biochemical relapse after RT or RP were treated with celecoxib 200 mg twice daily. Follow-up PSA levels to assess efficacy were obtained at 3, 6 and 12 months after initiating treatment. Data were evaluated by calculating PSA doubling times and the slope of the curve of logPSA vs time, to assess rate of PSA rise before and after celecoxib treatment for each patient. Serum testosterone levels were also measured. RESULTS: Eight of the 12 patients had significant inhibition of their serum PSA levels after 3 months of treatment; five had a decline in their absolute PSA level and three a stabilization of the level. Of the remaining four patients, three had a marked decrease in their PSA doubling time, with a mean increase (i.e. slowing) of 3.1 times that before treatment. The short-term responses at 3 months also continued at 6 and 12 months. From the slope of log PSA vs time there was a significant flattening of the rate of PSA rise (P = 0.001). There was a significant change of patients with rapid doubling times towards slower doubling times or even stable/declining PSA values after treatment with celecoxib (P = 0.029). There was no significant change in testosterone levels, suggesting an androgen-independent mechanism. CONCLUSIONS: COX-2 inhibitors may have an effect on serum PSA levels in patients with biochemical progression after RT or RP. These results suggest that COX-2 inhibitors may help to delay or prevent disease progression in these patients, and thereby help extend the time until androgen deprivation therapy. Further study with more patients is currently underway to better evaluate the clinical potential of COX-2 inhibitors as an antitumour agents in prostate cancer.
From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors.. Jiuxiang Zhu; Jui-Wen Huang; Ping-Hui Tseng; Ya-Ting Yang; Joseph Fowble; Chung-Wai Shiau; Yeng-Jeng Shaw; Samuel K Kulp; Ching-Shih Chen (2004) Cancer research display abstract
The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC(50), 48 microM), requiring at least 30 microM to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC(50) values in PDK-1 inhibition and apoptosis induction in the low microM range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was approximately 3 microM for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.
Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9.. Shishir Shishodia; Bharat B Aggarwal (2004) Cancer research display abstract
Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-kappaB (NF-kappaB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-kappaB activation is not known, although the role of NF-kappaB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-kappaB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-kappaB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-kappaB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of inhibitory subunit of NF-kappaB kinase (IkappaB), as examined by immunocomplex kinase assay, IkappaB phosphorylation, and IkappaB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-kappaB-dependent reporter gene expression. CSC-induced NF-kappaB reporter activity induced by NF-kappaB inducing kinase and IkappaB alpha kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-kappaB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-kappaB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-kappaB and NF-kappaB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.
Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor celecoxib.. Anna Di Fiore; Carlo Pedone; Katia D'Ambrosio; Andrea Scozzafava; Giuseppina De Simone; Claudiu T Supuran (2006) Bioorganic & medicinal chemistry letters display abstract
The high resolution X-ray crystal structure of the adduct of human carbonic anhydrase (CA, EC 18.104.22.168) isoform II (hCA II) with the clinically used painkiller valdecoxib, acting as a potent CA II and cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a hydrophobic pocket, simultaneously establishing van der Waals interactions with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face stacking interaction with the aromatic ring of Phe131 (the chi1 angle of which is rotated about 90 degrees with respect to what was observed in the structure of the native enzyme and those of other sulfonamide complexes). Celecoxib, a structurally related COX-2 inhibitor for which the X-ray crystal structure was reported earlier, binds in a completely different manner to hCA II as compared to valdecoxib. Celecoxib completely fills the entire CA II active site, with its trifluoromethyl group in the hydrophobic part of the active site and the p-tolyl moiety in the hydrophilic one, not establishing any interaction with Phe131. In contrast to celecoxib, valdecoxib was rotated about 90 degrees around the chemical bond connecting the benzensulfonamide and the substituted isoxazole ring allowing for these multiple favorable interactions. These different binding modes allow for the further drug design of various CA inhibitors belonging to the benzenesulfonamide class.
Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells.. Fabio Cianchi; Camillo Cortesini; Lucia Magnelli; Elena Fanti; Laura Papucci; Nicola Schiavone; Luca Messerini; Alfredo Vannacci; Sergio Capaccioli; Federico Perna; Matteo Lulli; Valentina Fabbroni; Giuliano Perigli; Paolo Bechi; Emanuela Masini (2006) Molecular cancer therapeutics display abstract
Cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) are key enzymes involved in arachidonic acid metabolism. Their products, prostaglandins and leukotrienes, are involved in colorectal tumor development. We aimed at evaluating whether combined blocking of the COX-2 and 5-LOX pathways might have additive antitumor effects in colorectal cancer. The expression/activity of COX-2 and 5-LOX were assessed in 24 human colorectal cancer specimens. The effects of the COX-2 inhibitor celecoxib and the 5-LOX inhibitor MK886 on prostaglandin E(2) and cysteinyl leukotriene production, tumor cell proliferation, cell apoptosis, and Bcl-2/Bax expression were evaluated in the Caco-2 and HT29 colon cancer cells. We also investigated the effect of the enzymatic inhibition on mitochondrial membrane depolarization, one of the most important mechanisms involved in ceramide-induced apoptosis. Up-regulation of the COX-2 and 5-LOX pathways was found in the tumor tissue in comparison with normal colon mucosa. Inhibition of either COX-2 or 5-LOX alone resulted in activation of the other pathway in colon cancer cells. Combined treatment with 10 micromol/L celecoxib and MK886 could prevent this activation and had additive effects on inhibiting tumor cell proliferation, inducing cell apoptosis, decreasing Bcl-2 expression, increasing Bax expression, and determining mitochondrial depolarization in comparison with treatment with either inhibitor alone. The administration of the ceramide synthase inhibitor fumonisin B1 could prevent some of these antineoplastic effects. In conclusion, our study showed that inhibition of 5-LOX by MK886 could augment the antitumor activity of celecoxib in human colorectal cancer.
Celecoxib inhibits serum amyloid a-induced matrix metalloproteinase-10 expression in human endothelial cells.. Yulan Zhao; Shuli Zhou; Chew-Kiat Heng (2009) Journal of vascular research display abstract
BACKGROUND: Although serum amyloid A (SAA) is an established biomarker of coronary artery disease (CAD), its direct role in matrix degradation is obscure. This study investigated the effect of SAA on the expression of matrix metalloproteinase-10 (MMP-10) in endothelial cells. The effect of celecoxib on SAA-dependent MMP-10 expression and its possible mediator were also investigated. METHODS AND RESULTS: From our time course microarray screening, SAA (20 microg/ml) was found to increase MMP-10 mRNA expression over time (4-48 h) in human endothelial cells. Quantitative real-time PCR confirmed this transcriptional induction. Correspondingly, secreted MMP-10 protein was also markedly induced by SAA treatment for 24 h in a dose-dependent manner. We further examined cyclooxygenase-2 (COX-2) and its major product, prostaglandin E(2) (PGE(2)), as possible mediators of MMP-10 induction. Direct PGE(2) treatment could result in MMP-10 induction. Celecoxib, a selective COX-2 inhibitor, suppressed MMP-10 secretion induced by SAA. CONCLUSIONS: SAA induced MMP-10 expression and celecoxib prevented its induction. MMP-10 induction was at least partly mediated by PGE(2).