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Objective: There is growing evidence that adding non-steroidal anti-inflammatory drugs to some psychopharmacological treatments may help to improve symptoms in patients suffering from major depressive disorder. The present study examined the therapeutic efficacy of adding celecoxib to escitalopram and the safety of doing so., Method: In this double-blind randomized controlled trial, 60 patients with major depressive disorder were randomly assigned to either treatment with escitalopram plus celecoxib (intervention group) or escitalopram and placebo. All patients were evaluated blind to treatment group with the Hamilton Depression Rating Scale (HDRS) before the intervention as well at 4 and 8 weeks after initiating treatment. Chi-square and paired t-test were used to examine between-group differences at those assessment times., Results: There was no significant difference in depressive symptoms between intervention and placebo groups at baseline. However, at 4 and 8 weeks after the beginning of treatment, there were significant between-group differences in HDRS scores, favoring the intervention group. No between-group differences were found in treatment-related side effects., Conclusions: Adding celecoxib to escitalopram may improve symptoms of depression in patients with major depressive disorder without increasing the risk of drug-related side effects., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In patients with a high recurrence risk after treatment for Dupuytren contracture (DC) by Collagenase Clostridium histolyticum (CCH), adjuvant medical therapy may improve the outcome. Non-steroidal anti-inflammatory drugs have been used in the treatment of similar fibroproliferative processes. The aim of this study was to investigate if adjuvant anti-inflammatory medication could improve the outcome of CCH treatment for DC. Methods: In a prospective double blinded randomised trial, the effect of adjuvant peroral celecoxib on the outcome of DC treated with CCH was investigated in 32 patients with a high fibrosis diathesis. Primary outcome was the increase in Total Passive Extension Deficit (TPED)/ray. Secondary outcomes were the TPED of the individual finger joints, Tubiana index, Disability of Arm, Shoulder and Hand score (DASH) and visual analogue scale (VAS) for pain and satisfaction. Results: A significantly greater improvement in the celecoxib group for TPED and metacarpophalangeal contracture was found. For the proximal interphalangeal joint, the effect was much less pronounced. The VAS for pain and satisfaction were better at 6 and 12 weeks in the celecoxib group. The other outcome parameters did not significantly differ between both groups. Conclusions: Adjuvant peroral administration of celecoxib might improve the gain in TPED after treatment with CCH in patients with DC and a high fibrosis diathesis, with a beneficial effect up to 24 months. Level of Evidence: Level II (Therapeutic).

The anti-inflammatory drug celecoxib, the only inhibitor of cyclooxygenase-2 (COX-2) with anticancer activity, is used to treat rheumatoid arthritis and can cause endoplasmic reticulum (ER) stress by inhibiting sarco/ER Ca 2 + -ATPase activity in cancer cells. This study aimed to investigate the correlation between celecoxib-induced ER stress and the effects of celecoxib against cell death signaling. Treatment of human colon cancer HCT116 cells with celecoxib reduced their viability and resulted in a loss of mitochondrial membrane potential ([Formula: see text]). Additionally, celecoxib treatment reduced the expression of genes involved in mitochondrial biogenesis and metabolism such as mitochondrial transcription factor A (TFAM) and uncoupling protein 2 (UCP2). Furthermore, celecoxib reduced transmembrane protein 117 (TMEM117), and RNAi-mediated knockdown of TMEM117 reduced TFAM and UCP2 expressions. These results suggest that celecoxib treatment results in the loss of [Formula: see text] by reducing TMEM117 expression and provide insights for the development of novel drugs through TMEM117 expression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Various side effects associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in analgesia have been reported. Among the NSAIDs, celecoxib has fewer side effects and is often used in therapeutic applications. However, the effect of celecoxib on aged skin is unknown. In this study, we investigated the effects of celecoxib administration on the skin of aged mice. We analyzed a 40-week-old mouse model and a 10-week-old mouse as the control group. The animals were orally administered celecoxib for four consecutive days and then killed and dissected the day after the last dose. In aged mice treated with celecoxib, the water content of the stratum corneum, which is one of the markers of dry skin, was lower than that in the control and young mice groups. In addition, serum hyaluronic acid, creatinine, and inflammatory cytokines in the collected blood samples of aged mice were elevated compared to those in other mice groups, suggesting the onset of acute renal injury. Therefore, it was considered that acute renal injury occurred from the administration of celecoxib to aged mice, whereas dry skin developed by the promotion of inflammatory cytokine secretion and release into the bloodstream in this group.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) designed to be a selective cyclooxygenase-2 (COX-2) inhibitor. It was approved by the U.S. Food and Drug Administration for the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. Additionally, celecoxib demonstrated potent antitumor and chemopreventive effects in vitro, in vivo, and in patients. The mechanism of celecoxib's chemopreventive effect is still not fully identified, but it is assumed to be multifactorial. Celecoxib's anticancer activity has been described both as independent of and dependent on its COX-2 inhibitory activity. The current review summarizes the recent advances published between 2000 and 2022 on the structure-based optimization of celecoxib to develop compounds with promising anticancer activity. The structure-activity relationships of celecoxib analogs are discussed, which may be beneficial in the design and development of novel analogs as potent antiproliferative agents in the future., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.

Background: Celecoxib, a selective cyclooxygenase-2 inhibitor, was recently associated with increased incidence of aortic stenosis and found to produce a valvular calcification risk in vitro. Several cyclooxygenase-2 independent celecoxib derivatives have been developed and identified as possible therapies for inflammatory diseases due to their cadherin-11 inhibitory functions. Potential cardiovascular toxicities associated with these cyclooxygenase-2 independent celecoxib derivatives have not yet been investigated. Furthermore, the mechanism by which celecoxib produces valvular toxicity is not known., Methods and Results: Celecoxib treatment produces a 2.8-fold increase in calcification in ex vivo porcine aortic valve leaflets and a more than 2-fold increase in calcification in porcine aortic valve interstitial cells cultured in osteogenic media. Its cyclooxygenase-2 independent derivative, 2,5-dimethylcelecoxib, produces a similar 2.5-fold increase in calcification in ex vivo leaflets and a 13-fold increase in porcine aortic valve interstitial cells cultured in osteogenic media. We elucidate that this offtarget effect depends on the presence of either of the two media components: dexamethasone, a synthetic glucocorticoid used for osteogenic induction, or cortisol, a natural glucocorticoid present at basal levels in the fetal bovine serum. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. By adding glucocorticoids or hydrocortisone to a serum substitute lacking endogenous glucocorticoids, we show that dimethylcelecoxib conditionally induces a 3.5-fold increase in aortic valve calcification and osteogenic expression. Treatment with the Mitogen-activated protein kinase kinase inhibitor, U0126, rescues the offtarget effect, suggesting that celecoxib and dimethylcelecoxib conditionally augment Mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase activity in the presence of glucocorticoids., Conclusion: Here we identify glucocorticoids as a possible source of the increased valvular calcification risk associated with celecoxib and its cyclooxygenase-2 independent derivatives. In the absence of glucocorticoids, these inhibitors effectively reduce calcification. Furthermore, the offtarget effects are not due to the drug's intrinsic properties as dual cyclooxygenase-2 and cadherin-11 inhibitors. These findings inform future design and development of celecoxib derivatives for potential clinical therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The present work describe the synthesis of a novel series of celecoxib derivatives (6a-m) and they were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, IV and IX which are involved in a variety of diseases such as glaucoma, retinitis pigmentosa, epilepsy and tumors etc. These compounds showed interesting inhibitory activity for these isoforms, with several low nanomolar derivatives identified against all these enzymes. The in-vivo anti-inflammatory activity of the synthesized compounds were evaluated using Celecoxib as reference standard by paw Oedema model on albino Wistar. Most of the compounds showed higher in-vivo anti-inflammatory activity compared to Celecoxib., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Two new series of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives containing either five membered heterocyclic rings or aryl hydrazones were synthesized and evaluated for their in vitro COX-1/COX-2 inhibitory activity. In vivo anti-inflammatory evaluation revealed that benzenesulfonamides bearing pyrazole moiety 19, 20 and its cyclized form 23 exhibited the highest anti-inflammatory activity with comparable potency to celecoxib. Furthermore, the ulcerogenic activity evaluation showed that compounds 19, 20 and 23 exerted the minimal ulcer index in comparison to indomethacin as a reference drug. Docking studies of the most selective COX-2 derivatives were also carried out against COX-2 active site. Benzenesulfonamide derivatives 19 and 20 displayed higher predicted binding affinities inside the COX-2 active site. Molecular modelling simulation and drug likeness studies showed good agreement with the obtained biological evaluation., (Crown Copyright © 2019. Published by Elsevier Masson SAS. All rights reserved.)

Dimethyl-celecoxib (DMC), a close derivative of celecoxib (CXB) with a low COX-2 inhibitory function, exhibits significant anti-neoplastic properties. In this study, we have investigated the effect of CXB and DMC on the human HT-29 cell line. The cellular viability, caspase-3 activity, and VEGF, NF-κB, and COX-2 genes expressions were assessed respectively with MTT, colorimetric, and real-time RT-PCR methods. DMC, a close analogue of CXB, was more potent in inhibiting the growth of cells (IC50: 23.45 µM at 24 hr) than CXB (IC50: 30.41 µM at 24 hr). Both CXB and DMC caused a significant difference in caspase-3 activity compared to the control group. DMC significantly decreased the NF-κB expression. Down-regulation of the COX-2 mRNA expression in the celecoxib-treated group was significant compared with that in the DMC-treated group. Alterations in the mRNA expression of VEGF were not significant between the groups. Owing to the more potent growth inhibitory effects of DMC compared to that of celecoxib, it may be important to conduct research on the anticancer application of this compound, which can reduce the side effects relating to COX2 inhibition.

Background: The aim of this study was to evaluate the safety and analgesic efficacy of polmacoxib 2 mg versus placebo in a superiority comparison or versus celecoxib 200 mg in a noninferiority comparison in patients with osteoarthritis (OA)., Methods: This study was a 6-week, phase III, randomized, double-blind, and parallel-group trial followed by an 18-week, single arm, open-label extension. Of the 441 patients with knee or hip OA screened, 362 were randomized; 324 completed 6 weeks of treatment and 220 completed the extension. Patients were randomized to receive oral polmacoxib 2 mg (n = 146), celecoxib 200 mg (n = 145), or placebo (n = 71) once daily for 6 weeks. During the extension, all participants received open-label polmacoxib 2 mg. The primary endpoint was the change in Western Ontario and McMaster Universities (WOMAC)-pain subscale score from baseline to week 6. Secondary endpoints included WOMAC-OA Index, OA subscales (pain, stiffness, and physical function) and Physician's and Subject's Global Assessments at weeks 3 and 6. Other outcome measures included adverse events (AEs), laboratory tests, vital signs, electrocardiograms, and physical examinations., Results: After 6 weeks, the polmacoxib-placebo treatment difference was -2.5 (95% confidence interval [CI], -4.4 to -0.6; p = 0.011) and the polmacoxib-celecoxib treatment difference was 0.6 (CI, -0.9 to 2.2; p = 0.425). According to Physician's Global Assessments, more subjects were "much improved" at week 3 with polmacoxib than with celecoxib or placebo. Gastrointestinal and general disorder AEs occurred with a greater frequency with polmacoxib or celecoxib than with placebo., Conclusions: Polmacoxib 2 mg was relatively well tolerated and demonstrated efficacy superior to placebo and noninferior to celecoxib after 6 weeks of treatment in patients with OA. The results obtained during the 18-week trial extension with polmacoxib 2 mg were consistent with those observed during the 6-week treatment period, indicating that polmacoxib can be considered safe for long-term use based on this relatively small scale of study in a Korean population. More importantly, the results of this study showed that polmacoxib has the potential to be used as a pain relief drug with reduced gastrointestinal side effects compared to traditional nonsteroidal anti-inflammatory drugs for OA., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Using celecoxib as lead, two novel series of sulfonamides incorporating the pyridotriazolopyrimidine scaffold have been synthesized and evaluated in vitro as inhibitors against four relevant human (h) carbonic anhydrases (CAs, EC 4.2.1.1), the cytosolic and ubiquitous hCA I and II as well as the transmembrane hCA IV and hCA IX. Most of the reported sulfonamides acted as efficient, low micromolar inhibitors of hCAI, II and IV, whereas they displayed higher efficacy in inhibiting the tumor-associated isoform hCA IX. Many derivates herein reported showed better hCA IX versus hCA II selectivity ratios compared to celecoxib or acetazolamide. Considering isoform IX is a validated target for the diagnosis and treatment of hypoxic tumors, discovery of selective CA IX inhibitors represents a promising step to unveil more effective anticancer therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We previously reported that celecoxib, a selective COX-2 inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/β-catenin signaling pathway. 2,5-Dimethylcelecoxib (DM-celecoxib), a celecoxib analog that does not inhibit COX-2, has also been reported to have an antitumor effect. In the present study, we elucidated whether DM-celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM-celecoxib with that of celecoxib on the human colon cancer cell lines HCT-116 and DLD-1. 2,5-Dimethylcelecoxib suppressed cell proliferation and inhibited T-cell factor 7-like 2 expression with almost the same strength as celecoxib. 2,5-Dimethylcelecoxib also inhibited the T-cell factor-dependent transcription activity and suppressed the expression of Wnt/β-catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM-celecoxib using the Mutyh -/- mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM-celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated treatment with celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer effect of celecoxib derivatives is the suppression of the Wnt/β-catenin signaling pathway but not the inhibition of COX-2, and that DM-celecoxib might be a better lead compound candidate than celecoxib for the development of novel anticancer drugs., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Inhibition of cyclooxygenase-2 (COX-2) has been investigated in clinical trials. Currently, NS398 and celecoxib are the most commonly used COX-2 inhibitors. The purpose of this study was to identify conditions that would increase the sensitivity of resistant cancer cells to antimitotic drugs., Materials and Methods: We tested whether COX-2 inhibitors can sensitize drug-resistant KBV20C cancer cells. We also compared the efficacy of NS398 with that of celecoxib., Results: Both NS398 and celecoxib could sensitize KB and KBV20C cells to a similar extent, suggesting that COX-2 inhibitors could be used for sensitive, as well as resistant, cancer cells. We demonstrated that the NS398 and celecoxib sensitization mechanism is independent of the inhibition of p-glycoprotein (P-gp), suggesting that resistant KBV20C cells are sensitized through targeting of signaling pathways by both drugs. Furthermore, through using microscopic observation, assessment of cleaved poly ADP ribose polymerase (C-PARP) and annexin V staining we determined that both COX-2 inhibitors strongly sensitized resistant KBV20C cells to vinblastine (VIB) or paclitaxel (PAC) treatment. These results suggest that antimitotic drug-resistant cancer cells can be strongly sensitized by co-treatment with COX-2 inhibitors, without P-gp inhibitory activity., Conclusion: These findings provide important information regarding the sensitization of drug-resistant cells and indicate that COX-2 inhibitors may be used for potentially resistant cancer patients, without the toxic effects of P-gp inhibition., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Gliomas are among the most commonly diagnosed central nervous system tumors. Celecoxib has been utilized with success in the treatment of several types of cancer, including gliomas. The present study examined the antiproliferative effects of celecoxib and its benzimidazole-based analog, LLW-3-6, when used as co-treatment with sulfasalazine against human glioma LN18 cells. At 48-h treatment, the glioma cells maintained 60% viability in the presence of celecoxib or LLW-3-6 at the maximum concentration tested (40 μM). Co-treatment of glioma cells under a non-lethal dose (50 μM) of sulfasalazine and either celecoxib or LLW-3-6 (administered at different concentrations) resulted in improved inhibition of cell viability. The concentration of the molecules required to reduce cell growth in the combined treatment was significantly less than that needed when either molecule was administered independently. Based on computational values, LLW-3-6 has physiochemical characteristics that should allow for improved bioavailability in comparison to that of celecoxib., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Celecoxib is a selective cyclooxygenase-2 inhibitor applied to the treatment of arthritis. Repositioning the anti-inflammatory drug as an anti-inflammatory bowel disease drug has obstacles such as controversial anti-colitic efficacy and potential side effects. We examined whether colonic delivery of celecoxib could circumvent the therapeutic limitations. N-succinylglutam-1-yl celecoxib (SG1C), a colon-specific prodrug of celecoxib), was administered orally to rats with colitis and the anti-inflammatory activity and pharmacologic mechanisms were investigated. SG1C alleviated the colonic injury and lowered myeloperoxidase activity in the inflamed colonic tissues much more effectively than conventional celecoxib. While suppressing expression of pro-inflammatory nuclear factor kappaB gene products including cyclooxygenase-2, SG1C elevated an anti-inflammatory nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2) and its target gene product heme oxygenase (HO)-1 in the inflamed colon. In contrast, no significant molecular effects were observed with conventional celecoxib. Unlike conventional celecoxib, SG1C did not lower the serum level of 6-keto-PGF1α, an inverse indicator of cardiovascular adverse effects. Collectively, colonic delivery of celecoxib, likely improving therapeutic and toxicological properties of celecoxib, may be a feasible pharmaceutical strategy to therapeutically switch celecoxib to an anti-colitic drug.

It has been reported previously that celecoxib shows antitumor effects in many types of cancers. Here, we detected its effects on DLD-1 and SW480 (two human colon cancer cell lines) and investigated the dynamic relationship between the 78-kDa glucose-regulatory protein (GRP78) and the phosphoinositide 3-kinase (PI3K)/Akt pathway. Gene expression was detected by real-time PCR and western blot analysis; the cytotoxicity was determined by the MTT assay and flow cytometry. First, the results showed that celecoxib induced cytotoxicity in a dose-dependent and time-dependent manner. Furthermore, we found the celecoxib-triggered unfolded protein response and the bidirectional regulation of Akt activation in both cell lines. Inhibiting the Akt activation by the PI3K inhibitor LY294002 markedly enhanced GRP78 expression. Besides, silencing the GRP78 expression regulated Akt activation in a time-dependent manner and increased the induction of the C/EBP homologous protein (CHOP) as well as considerably promoted celecoxib-induced apoptosis. In conclusion, these findings provide evidence that under the celecoxib treatment, GRP78 plays a protective role by modulating Akt activation and abrogating CHOP expression. However, Akt activation can provide a feedback loop to inhibit GRP78 expression. These studies can lead to novel therapeutic strategies for human colon cancer.

This study reports a facile and controllable synthetic method for the preparation of both 1,3- and 1,5-isomers of 4-(3(5)-aryl-3(5)-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamides, as well as a new series of 4-(3-aryl-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides, from the cyclocondensation reaction of 4-aryl-1,1,1-trifluoro-4-methoxybut-3-en-2-ones or 1-aryl-4,4,4-trifluoro-butane-1,3-diones or their enolic forms with 4-hydrazinylbenzenesulfonamide. All compounds of the new series of 3-substituted 1-(4-benzenesulfonamide)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazoles were tested for their effect on a pathological pain model in mice. The compounds 3a, 3b, 3c, 3e, and 3f presented anti-hyperalgesic action, while the compounds 3a, 3c, 3d, 3f, and 3g exhibited anti-edematogenic effects, without causing locomotive disorders in animals, thus making them comparable to Celecoxib in an arthritic pain model., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Inhibition of cyclooxygenase-2 (COX-2) is a promising anti-inflammatory therapeutic strategy, but long-term medication with COX-2-inhibitors (coxibs) may be associated with adverse cardiovascular effects. Functionalization of existing lead structures with nitric oxide (NO)-releasing moieties is an auspicious approach to minimize these effects. In this regard, an organic nitrate (-O-NO2) substituent was introduced at a (pyrazolyl)benzenesulfonamide lead structure. The novel NO-coxibs selectively inhibited COX-2 in a low micromolar range (IC50(COX-2): 0.22-1.27 μM) and are supposed to be promising anti-inflammatory compounds with, in parallel, positive effects on vascular homeostasis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats., Materials and Methods: Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed., Key Findings: Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue., Significance: The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, or nonselective NSAIDs or totally unexposed to NSAIDs., Methods: We performed a national register-based cohort study on patients with AS or SpA (n = 21,872) identified in the Swedish national patient register from 1987-2009. Treatment exposure was assessed time dependently based on the prescription drug register from 2006-2009, adjusting for sociodemographics and comorbidities derived from national population-based registers., Results: Exposure to etoricoxib, celecoxib, and nonselective NSAIDs was 7.6%, 3.9%, and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal, or renal adverse events were seen among the 3 exposure groups. Patients unexposed to NSAIDs had more baseline comorbidities and an increased relative risk for congestive heart failure events during the study period (2.0, 95% confidence interval [95% CI] 1.3-3.2). The relative risk for atherosclerotic events was nonsignificant when compared to the nonselective NSAID group (1.0, 95% CI 0.7-1.5), while the relative risk for gastrointestinal events was lower for unexposed patients (0.5, 95% CI 0.4-0.7)., Conclusion: Overall, serious adverse events related to nonselective NSAIDs, etoricoxib, and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerably more baseline comorbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAIDs in clinical practice., (© 2015, American College of Rheumatology.)

Celecoxib has been reported to switch the human SULT2A1-catalyzed sulfonation of 17β-estradiol (17β-E2) from the 3- to the 17-position. The effects of celecoxib on the sulfonation of selected steroids catalyzed by human SULT2A1 were assessed through in vitro and in silico studies. Celecoxib inhibited SULT2A1-catalyzed sulfonation of dehydroepiandrosterone (DHEA), androst-5-ene-3β, 17β-diol (AD), testosterone (T) and epitestosterone (Epi-T) in a concentration-dependent manner. Low μM concentrations of celecoxib strikingly enhanced the formation of the 17-sulfates of 6-dehydroestradiol (6D-E2), 17β-dihydroequilenin (17β-Eqn), 17β-dihydroequilin (17β-Eq), and 9-dehydroestradiol (9D-E2) as well as the overall rate of sulfonation. For 6D-E2, 9D-E2 and 17β-Eqn, celecoxib inhibited 3-sulfonation, however 3-sulfonation of 17β-Eq was stimulated at celecoxib concentrations below 40 μM. Ligand docking studies in silico suggest that celecoxib binds in the substrate-binding site of SULT2A1 in a manner that prohibits the usual binding of substrates but facilitates, for appropriately shaped substrates, a binding mode that favors 17-sulfonation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. However, a phase III clinical trial found that monotherapy with the mTOR inhibitor everolimus did not significantly improve the overall survival of patients with advanced gastric cancer. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of mTOR inhibitors. Here, we demonstrate that Akt phosphorylation is increased in the rapamycin-resistant gastric cancer cell lines MGC803 and SGC7901. We further show that combined treatment with celecoxib and rapamycin results in an additive inhibitory effect on the growth of gastric cancer cells through suppression of rapamycin-induced Akt activation. Moreover, celecoxib upregulated the expression of the ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b). Knockdown of Cbl-b significantly attenuated celecoxib-mediated inhibition of Akt phosphorylation and impaired the additive anticancer effect of celecoxib and rapamycin. Our results suggest that celecoxib-mediated upregulation of Cbl-b is responsible, at least in part, for the additive antitumor effect of celecoxib and rapamycin via inhibition of rapamycin-induced Akt activation.

Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant K562 cells (IR-K562) via PGE2-cAMP-PKC-NF-κB pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: The goal of the present study was to evaluate the effects of celecoxib on treatment outcomes of squamous cell carcinoma of the mobile tongue., Patients and Methods: Among 158 patients who were diagnosed with mobile tongue cancer, 19 received celecoxib during the preoperative, postoperative, or post-recurrence phase. Differences in disease-specific survival (DSS) and recurrence-free survival (RFS) between patients who received celecoxib (study group) and those who did not (control group) were analyzed., Results: For the entire cohort, DSS and RFS were not significantly different according to duration of celecoxib treatment (p=0.293 and 0.703, respectively). Among patients who received chemotherapy, DSS was significantly higher in the study group than in the control group (p=0.048), but RFS was not different between the two groups (p=0.117)., Conclusion: When combined with chemotherapy, celecoxib may have a beneficial effect on the survival of patients with mobile tongue cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Helicobacter pylori (H. pylori) is a major causative agent for the induction of chronic gastritis, gastric ulcer and gastric cancer. Celecoxib (COX-2 inhibitor) inhibits gastric cancer cell proliferation, but with low treatment efficacy, limiting its applications. It is important to develop a better strategy to improve the efficacy of celecoxib. Lewis Y (LeY) is a difucosylated oligosaccharide, highly expressed in 60-90% of human epithelial cancers, including gastric cancer. We previously found that H. pylori infection was associated with high level of LeY in gastric cancer., Material and Methods: Herein, we analyzed the correlation between H. pylori and cyclo-oxygenase-2 (COX-2), LeY, gastric markers (CA724 and GRN) in gastric patient's tissue and serum samples by IHC and ELISA. Furthermore, we treated the primary gastric cancer cells with celecoxib, anti-LeY antibody or the combination, and analyzed their therapeutic efficacy on CA724, GRN and COX-2 expression by Western blot, flow cytometry and ELISA., Results: We found that gastric cancer had significantly high expression of H. pylori, COX-2, CA724, and GRN compared to gastric ulcers and chronic gastritis (P < 0.0001). H. pylori level showed significant correlation with COX-2 (R--0.552), LeY (R--0.861), CA724 (R--0.714) and GRN (R--0.664) (P < 0.0001). Additionally, the combination therapy led to impressive inhibition of gastric cancer cell proliferation, with decreased expression of COX-2, CA724 and GRN through downregulation of MAPKs/COX-2 pathway (P < 0.01)., Conclusions: Our findings suggest that anti-LeY antibody enhances the cancer cell proliferation inhibitory effects of celecoxib, which might be a new feasible way for gastric cancer therapy.

Objective: To evaluate the potential ototoxicity of high-dose celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor., Study Design: Prospective animal study., Setting: Laboratory., Methods: Twenty adult male Sprague Dawley rats were divided into 2 groups for hearing and tinnitus tests, respectively. The auditory brain-stem response (ABR) and the gap prepulse inhibition of acoustic startle (GPIAS) were used as indicators of hearing loss and tinnitus, respectively, and were measured before and at 2, 4, 6, 8, 12, 24, and 48 hours after administration of celecoxib (2 g/kg) via gavage., Results: ABR threshold and wave III latencies did not increase significantly at any frequency following celecoxib administration, at any time point (P > .05). GPIAS remained below 30% after celecoxib, from a baseline of 20.03% ± 3.62%; no change was significant., Conclusion: High-dose celecoxib (2 g/kg), a selective COX-2 inhibitor, did not cause hearing loss or tinnitus in Sprague Dawley rats within 48 hours of administration. Further studies are needed to explore the roles played by COX-related mechanisms when nonselective COX inhibitors induce ototoxicity., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Objective: To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was coadministered with NSAIDs., Methods: Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co-primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patient's Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs., Results: Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy., Conclusions: Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes., Trial Registration Number: NCT00809354., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: The purpose of our study was to investigate the therapeutic potential of Celecoxib for epithelial ovarian cancer, especially on cellular morphological changes, proliferation invasion and epithelial-mesenchymal transition (EMT)., Method: The MTT and transwell assays were performed to evaluate the effect of Celecoxib on proliferation and invasion ability of ovarian cancer cell lines, respectively. Western blot was carried out to detect the expression of epithelial phenotypes, E-cadherin and Keratin, and mesenchymal phenotypes, N-cadherin and Vimentin, as well as p-AKT, p-ERK and ZEB1. ZEB1 small-interfering RNA (siRNA) was used to downregulate the expression of ZEB1 to further inquiring into the downstream of Celecoxib-induced EMT., Results: Cellular morphological assessment revealed that both A2780 and SKOV3 cells gradually appeared in the morphology of mesenchymal cells after Celecoxib treatment. The MTT assay demonstrated that celecoxib had no effect on cell proliferation. Transwell assay showed that Celecoxib significantly increased the cell invasion ability. Western blot data proved that the expression of E-cadherin and keratin was elevated, whereas the expression of N-cadherin and Vimentin was decreased in a dose-dependent manner compared with the untreated cells, the expression of p-AKT, p-ERK and ZEB1 was also obviously elevated. However, ZEB1 siRNA reversed Celecoxib-induced E-cadherin expression and N-cadherin expression, as well as cellular invasiveness., Conclusion: Our results indicated that Celecoxib might induce EMT and increase cellular invasiveness in ovarian cancer cells in vitro, which also implied that it needed a comprehensive evaluation in preclinical researches before introducing Celecoxib into the clinical regimen.

Objective: To compare clinical effects of spinal leveraging manipulation and medicine for the treatment of degenerative scoliosis in pain and function., Methods: From July 2010 to June 2013, 38 patients with degenerative scoliosis were randomly divided into spinal leveraging manipulation group and medicine group by coin tossing. In manipulation group, there were 9 males and 11 females aged from 58 to 74 years old with an average of (66.63±7.73), the courses of diseases ranged from 3 to 8 months with an average of (5.65±2.58), spinal leveraging manipulation(following meridian to straighten tendon,relieving spasm, osteopathy and massage, clearing and activating the channels and collaterals) were performed for 30 min, once a day, 4 days for a period treatment, totally 9 courses. In medicine group, there were 8 males and 10 females aged from 57 to 70 years old with an average of (63.51±6.61) the courses of diseases ranged from 3 to 5 months with an average of (4.82±1.43), celecoxib with eperisone hydrochloride were orally taken, 4 days for a period treatment, totally 9 courses. VAS score, Cobb angle and ODI score were measured., Results: After treatment, VAS score in manipulation group was (5.38±0.99), (6.36±1.31) in medicine group,and had significant meaning (t=2.618, P<0.05); there was significant differences in Cobb angle between manipulation group (16.51±4.89)° and medicine group (19.85±5.03) °(t=2.074,P<0.05); and had obviously meaning in ODI score between manipulation group (20.20±2.93) and medicine group (26.01±3.11) (t=5.592, P<0.05)., Conclusion: Spinal leveraging manipulation for degenerative scoliosis could regulate muscle balance on both side of spine, correct coronal imbalances in spine, recover normal sequence of spine, reduce and remove opperssion and stimulation of nerve root, relieve pain in leg and waist and further improve quality of life.

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer., (© 2014 Wiley Periodicals, Inc.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4׳,6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Phosphoinositide-3 kinase (PI3K) inhibition attenuates proliferation and survival in B-cell malignancies. Celecoxib induces endoplasmic reticulum (ER) stress-induced apoptosis via a cyclo-oxgenase-2 (COX2)-independent manner in certain types of cancer cells. In the present study, we assessed the effects of combinations of drugs with a p110δ-specific inhibitor, CAL-101, and celecoxib to induce apoptosis in Epstein-Barr virus (EBV)-transformed B-cells and non-Hodgkin's lymphoma (NHL) cells., Materials and Methods: The apoptotic effect of combination treatment with CAL-101 and celecoxib on B-cell malignancies was determined by flow cytometry and immunoblotting., Results: Exposure to CAL-101 and celecoxib significantly increased apoptosis, which was accompanied by the inactivation of AKT, Ras homolog gene family, member A (RHOA), Rho-associated coiled-coil containing protein kinase 1 (ROCK1), and ROCK2 as well as up-regulation of Phosphatase and tensin homolog (PTEN). Co-treatment with CAL-101 and celecoxib triggered the ER stress response and the down-regulation of BCL2 and BCL-XL. SB203580, SP600125, and salubrinal effectively inhibited apoptosis and attenuated expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP). Levels of apoptosis signal-regulating kinase 1 (ASK1) were also increased after treatment with CAL-101 and celecoxib., Conclusion: The apoptosis of EBV-transformed B-cells and NHL cells caused by CAL-101 and celecoxib might be related to inhibiting the RHOA/ROCK pathway and might also be associated with mitogen-activated protein kinase (MAPK)-mediated ER stress., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Liver fibrosis may lead to portal hypertension, liver failure or hepatocellular carcinoma, and predominantly results from the proliferation and activation of hepatic stellate cells. OSU‑03012, a non‑cyclooxygenase‑inhibiting celecoxib derivative, has been previously demonstrated to promote apoptosis in certain cell types, however, its function in hepatic fibrosis remains unclear. In the current study, the inhibitory effect of OSU‑03012 on the proliferation of the LX2 human hepatic stellate cell line was evaluated by cell counting kit‑8 assay. Reverse transcription‑quantitative polymerase chain reaction was performed in order to examine the expression of α‑smooth muscle actin and type I collagen, which are representative of LX2 cell activation. The senescence of LX2 cells was measured by senescence‑associated β‑galactosidase staining, and the cell cycle and apoptosis levels were assessed by flow cytometry. The impact of senescence‑associated signaling on protein expression was assessed by western blot analysis. OSU‑03012 was observed to inhibit cell proliferation and prevent the secretion of profibrotic factors in LX2 cells in a dose‑dependent manner. Furthermore, the results demonstrated that OSU‑03012 inhibited the proliferation and activation of LX2 via the induction of cell senescence at the G1 phase, rather than via cell apoptosis. The induction of senescence may be via the upregulation of p16, p21 and p27. In conclusion, the current study provided insight into the pharmacological mechanisms of OSU‑03012 in preventing the proliferation and activation of hepatic stellate cells through cell senescence. The current study supports the theory that OSU‑03012 is a novel agent for potential use against liver fibrosis.

Background: Cyclooxygenase-2 (COX-2) is an inducible enzyme that is rapidly upregulated in response to injury, resulting in the production of prostaglandin E2 (PGE2), a primary mediator of inflammation and wound healing. The selective COX-2 inhibitor, celecoxib, is was used to treat pain and inflammation. When used to treat injuries, we postulated that loss of PGE2 activity by COX-2 inhibition would have detrimental effects on wound healing. Our objective was to study the effect of selective COX-2 inhibition with celecoxib on cutaneous wound healing., Materials and Methods: C57BL/6J mice with uniform full-thickness wounds (1 cm(2)) to their dorsum were fed diet with or without celecoxib (1500 ppm). Wound closure analysis measured wound contraction, reepithelialization, and open wound as a percentage of the initial wound area, and was quantified by planimetry. Wounds were excised en bloc at day 7 to examine cellular proliferation, angiogenesis, cytokine production, and extracellular matrix (ECM) formation., Results: Celecoxib-induced reduction in wound PGE2 levels was documented by enzyme-linked immunosorbent assay on day 7 after wounding. Wound contraction and reepithelialization were significantly reduced by celecoxib treatment, resulting in a 20% greater open wound area at day 7 (P < 0.05). In response to celecoxib treatment, immunohistochemistry analysis showed epithelial cell proliferation, angiogenesis, and ECM components including collagen and myofibroblasts were significantly decreased., Conclusions: Wound healing is significantly delayed by celecoxib treatment. These data indicate that COX-2 and its downstream product PGE2 modulate the activity of multiple essential functions of the inflammatory stroma, including epithelial proliferation, angiogenesis, and ECM production. As a result, reepithelialization and wound closure are delayed by celecoxib treatment. These findings have potential clinical implications in postoperative wound management., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The immunosuppressant drug cyclosporine (CSA) is used with nonsteroidal antiinflammatory drugs (NSAIDs) in arthritic conditions. In this study, we investigated whether NSAIDs modify the deleterious hypertensive action of CSA and the role of endothelin (ET) receptors in this interaction. Pharmacologic, protein expression, and histopathologic studies were performed in rats to investigate the roles of endothelin receptors (ETA/ETB) in the hemodynamic interaction between CSA and two NSAIDs, indomethacin and celecoxib. Tail-cuff plethysmography measurements showed that CSA (20 mg kg(-1) day(-1), 10 days) increased systolic blood pressure (SBP) and heart rate (HR). CSA hypertension was associated with renal perivascular fibrosis and divergent changes in immunohistochemical signals of renal arteriolar ETA (increases) and ETB (decreases) receptors. While these effects of CSA were preserved in rats treated concomitantly with indomethacin (5 mg kg(-1) day(-1)), celecoxib (10 mg kg(-1) day(-1)) abolished the pressor, tachycardic, and fibrotic effects of CSA and normalized the altered renal ETA/ETB receptor expressions. Selective blockade of ETA receptors by atrasentan (5 mg kg(-1) day(-1)) abolished the pressor response elicited by CSA or CSA plus indomethacin. Alternatively, BQ788 (ETB receptor blocker, 0.1 mg kg(-1) day(-1)) caused celecoxib-sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Together, the improved renovascular fibrotic and endothelin receptor profile (ETA downregulation and ETB upregulation) mediate, at least partly, the protective effect of celecoxib against the hypertensive effect of CSA. Clinically, the use of celecoxib along with CSA in the management of arthritic conditions might provide hypertension-free regimen., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To study the effect of perioperative immunomodulatory therapy on postoperative recurrence of rectal cancer., Methods: This prospective study was conducted among 238 rectal/anal cancer patients undergoing intersphincteric resection at our center between January, 2010 and January, 2011, among whom 150 were eligible to be included and completed the study. The 150 patients were randomized in a double-blinded fashion into 3 equal groups to receive immunomodulatory therapy with 8 mg/kg celecoxib (group A), 0.4 mg/kg Sou-Medrol (group B), or placebo (group C), given daily from 5 days before surgery to 5 days after surgery, and the postoperative cancer recurrence were compared., Results: At 3 days after the operation, the 3 groups showed significantly different C-reactive protein (CRP) levels, which decreased obviously in all the 3 groups compared with those at 1 day following the operation (P=0.022), especially in group B. The levels of interleukin-6 (IL-6) at 3 days after the operation also differed significantly between the 3 groups but were lower in all the 3 groups than those at 1 day after the operation (P=0.046), and this reduction was the most obvious in group A. COX-2 expression differed significantly between the 3 groups (P=0.017), among which group A showed the most obvious suppression of COX-2 expression. During the follow-up for a mean of 45 months, no significant difference in the recurrence rate was found between the 3 groups (P=0.549)., Conclusion: With a lower efficacy than Sou-Medrol in decreasing postoperative inflammation, celecoxib produces a better effect in inhibiting COX-2 expression, but it does not lower postoperative recurrence rate of rectal cancer.

Objective: Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects ≈1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild-type mice, increased expression of the gene encoding cyclooxygenase 2 (COX2; Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed., Approach and Results: In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells before calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic valvular interstitial cells with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacological inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression., Conclusions: COX2 expression is upregulated in CAVD, and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo., (© 2015 American Heart Association, Inc.)

A simple and rapid quantitative analytical method for the simultaneous detection of celecoxib and its two main metabolites, hydroxycelecoxib (celecoxib-OH) and celecoxib carboxylic acid (celecoxib-COOH), in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. The plasma sample was prepared through simple protein precipitation, and the reconstitution solution (0.1% formic acid in 50% methanol) was optimized to achieve the best peak shape and recovery. The analytes were separated using an Atlantis T3 column (2.1 mm × 100 mm, 3 μm), and the mobile phase was composed of 10 mM ammonium formate in either 5% acetonitrile or 95% acetonitrile. The detection of the analytes was performed in alternating polarity switching mode using electrospray ionization. As celecoxib-OH and celecoxib-COOH were slightly unstable following freeze-thaw cycles and long-term storage at -80°C in stability tests, every analysis was carefully conducted with one-freeze thaw cycle and a short storage duration (<1 week). Acceptable accuracy (<15%) and precision (<15%) were obtained in intra- and inter-day validations. The method was successfully applied to the pharmacokinetic study of celecoxib, celecoxib-OH and celecoxib-COOH following the oral administration of celecoxib in rats at a dose of 10mg/kg. Comparing the related pharmacokinetic parameters of celecoxib and its metabolites, celecoxib was quickly metabolized into celecoxib-OH and subsequently converted to celecoxib-COOH in short intervals. The AUCs for the two metabolites were less than 10% of that for celecoxib, indicating that the rate of celecoxib metabolism was low., (Copyright © 2014 Elsevier B.V. All rights reserved.)

X-linked inhibitor of apoptosis protein (XIAP) has been shown to be highly expressed in lung cancer, but not in normal lung tissue, which makes it an attractive target for lung cancer treatment. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, is in wide clinical use for the treatment and prevention of non-small cell lung cancer (NSCLC). Therefore, in our study, we combined short hairpin RNA (shRNA) targeted to XIAP (XIAP-shRNA) with CXB and tested the effects of this combination on lung cancer cells to identify more effective therapeutics against lung cancer. An XIAP-shRNA plasmid was constructed and transfected into the A549 NSCLC cell line. The cells were then treated with CXB and XIAP-shRNA alone or in combination for indicated time periods, and the treatments were assessed for their effects on cell proliferation, apoptosis, migration, invasion and receptor signaling using the MTT, TUNEL, wound healing and Matrigel invasion assays and western blotting, respectively. In addition, an NSCLC xenograft model was prepared to observe tumor growth. It was found that both CXB and XIAP‑shRNA significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in vitro, as well as suppressed tumor growth in vivo. Moreover, the combination of the agents significantly enhanced these effects compared to the single agent treatments. We also found that the combination treatment significantly suppressed constitutive phosphorylation of PI3K and AKT, which may contribute to the inhibition of tumor growth. These findings suggest that the combination of XIAP‑shRNA and CXB is a promising drug candidate for the treatment of NSCLC.

Celecoxib plays antitumor roles via multiple mechanisms in a variety of human cancers. The aim of this study was to clarify the mechanism of action of celecoxib in canine mammary tumors. We examined the antitumor effects of celecoxib in AZACB canine mammary tumor cells expressing low levels of cyclooxygenase‑2 (COX‑2) to minimize the effect of COX‑2 on its activity. Our data revealed that celecoxib inhibited cell proliferation mainly via COX‑2‑independent mechanisms. Specifically, celecoxib decreased the proportion of cells in S phase and increased G2/M arrest, which was associated with increased expression of the cyclin‑dependent kinase inhibitors (CDKIs) p21 and p27. In addition, treatment with celecoxib downregulated COX‑2 expression, and induced apoptosis via both the intrinsic and extrinsic pathways. These findings suggest that celecoxib might be a useful agent for the treatment of canine mammary tumors, regardless of COX‑2 expression. In the future, it might be possible to use a combination of celecoxib and other antitumor agents to treat canine mammary tumors.

The purpose of this study was to develop a novel multipaticulate drug delivery technology suitable for the delivery of pre-solubilized celecoxib to the gastrointestinal tract and more specifically to the colon. The solubility of celecoxib in a range of oils, surfactants and co-solvents was evaluated. Celecoxib was solubilized in mixtures of these vehicles to produce liquid formulations. The in vitro dissolution of these liquid formulations was assessed and the data obtained was used to design microbead formulations containing celecoxib dissolved within an emulsion/micellar solution core. Microbead formulations were optimized to increase drug loading, avoid precipitation and to achieve good in vitro dissolution performance. An optimized formulation with a celecoxib loading of 6% w/w was produced and yielded an in vitro dissolution result of 80% over 6 h. The structure of these microbead formulations was characterized using light microscopy to reveal a correlation between droplet size and dissolution performance.

Background: Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy., Methods: The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide., Results: The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia., Conclusions: The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma., Clinicaltrialsgov Identifier: NCT00112502., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate the synergistic cytotoxicity of cis-dichlorodiamine platinum (DDP) and celecoxib on nasopharyngeal carcinoma TW03 cell which is resistant to DDP (TW03/DDP)., Methods: The mRNA and protein levels of lung resistance-related protein (LRP) were detected by reverse transcription PCR and Western blotting in TW03/DDP cells after (0.05-1.00) μg/mL DDP treatment. TW03/DDP clone which highly expressed LRP was transfected with siRNA targeting LRP mRNA. Nasopharyngeal carcinoma TW03 cells, TW03/DDP cells and TW03/DDP-siRNA cells were treated respectively with DDP or celecoxib or combination of the two. CCK-8 assay was performed for detecting proliferation. Annexin V-FITC/PI staining combined with flow cytometry were used for detecting apoptosis rate., Results: Both DDP and celecoxib treatment inhibited the proliferation and induced the apoptosis of TW03 cells and TW03/DDP cells, but only celecoxib showed a significant effect on TW03/DDP cells, but not DDP. Combination of DDP and celecoxib showed a synergistic role in inducing the apoptosis of both TW03 cells and TW03/DDP cells. Meanwhile, LRP mRNA and protein levels were down-regulated in celecoxib-treated TW03/DDP cells., Conclusion: DDP and celecoxib showed a synergistic effect on proliferation inhibition and apoptosis induction of TW03/DDP cells by down-regulating LRP mRNA and protein levels.

5‑fluorouracil (5‑FU) is commonly used in the treatment of gastric cancer; however, resistance to this drug occurs under hypoxic conditions. Celecoxib may be used to reverse this resistance. The aim of the present study was to elucidate the inhibitory effects and mechanisms of 5‑FU and celecoxib on the gastric cancer cell line SGC7901 under hypoxic conditions. SGC7901 cells were divided into four groups: Hypoxic control group, 5‑FU group, celecoxib group and 5‑FU/celecoxib combination group. Following treatment, the inhibition rates of cells were determined using an MTT assay. Protein and messenger RNA (mRNA) expression of hypoxia‑inducible factor 2α (HIF‑2α), adenosine triphosphate‑binding cassette sub‑family G member 2 (ABCG2) and octamer binding protein 4 (Oct‑4) were determined using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. The results demonstrated that the 5‑FU/celecoxib combination group had a significantly higher inhibition rate than the individually treated 5‑FU and celecoxib groups (P<0.05); inhibition rates were 66.09, 52.61 and 46.1%, respectively. mRNA and protein expression levels of HIF‑2α, ABCG2 and Oct‑4 were significantly lower in the celecoxib and 5‑FU/celecoxib combination groups (P<0.01) compared with those of the hypoxia control and 5‑FU groups. The 5‑FU group demonstrated the highest levels of the respective mRNA and proteins. In conclusion, the results of the present study indicated that celecoxib had anti‑tumor effects, as it was shown to inhibit tumor cell growth via the inhibition of HIF‑2α, ABCG2 and Oct‑4. The 5‑FU/celecoxib combination had a synergic effect on tumor growth inhibition. This therefore suggested that inhibition of HIF‑2α, ABCG2 and Oct‑4 may be a potential method of reducing chemotherapy resistance and enhancing the effectiveness of chemotherapy treatment.

Background: Vitamin D exhibits multiple anti-proliferative and pro-differentiating actions. Prostaglandin-(PG)E2 is a tumor-promoting tissue hormone anabolized by cyclooxygenase-2 (COX-2). Recently, a link between the PG and vitamin D metabolism was reported., Materials and Methods: The influence of calcitriol and celecoxib on the proliferation of ovarian cancer cell lines was measured and the impact of calcitriol on the protein and mRNA expression of COX-2 was quantified by western blot and qRT-PCR, respectively., Results: After COX-2 induction with interleukin (IL)-1β, 10 μM celecoxib did not significantly inhibit the proliferation of OVCAR-3 cells, whereas calcitriol showed such an effect; however, the combination of the two substances had an additive influence. After induction by IL-1β, calcitriol inhibited the COX-2 protein, as well as its mRNA expression significantly in OVCAR-3 and SKOV-3 cells., Conclusion: These data suggest a correlation between PG and vitamin D metabolism in their anti-tumorigenic activity in ovarian carcinomas., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)