Selective Cyclooxygenase-2 Inhibitor Celecoxib Research Articles

Celecoxib promotes survival and upregulates the expression of neuroprotective marker genes in two different in vitro models of Parkinson's disease

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease. Increasing evidence highlights the role of age-related chronic inflammation, oxidative stress and mitochondrial dysfunction in the pathogenesis of PD. A combination of these factors impairs the crosstalk between mitochondria and lysosomes, resulting in compromised cell homeostasis. Apolipoprotein D (APOD), an ancient and highly conserved anti-inflammatory and antioxidant lipocalin, and the transcription factor EB (TFEB), a master regulator of mitophagy, autophagy and lysosomal biogenesis, play key roles in these processes. Both APOD and TFEB have attracted attention as therapeutic targets for PD. The aim of this study was to investigate if the selective cyclooxygenase-2 inhibitor celecoxib (CXB) exerts a direct neuroprotective effect in 6-hydroxydopamine (6-OHDA) and paraquat (PQ) PD models. We found that CXB rescued SH-SY5Y cells challenged by 6-OHDA- and PQ-induced toxicity. Furthermore, treatment with CXB led to a marked and sustained upregulation of APOD and the two microphthalmia transcription factors TFEB and MITF. In sum, this study highlights the clinically approved drug CXB as a promising neuroprotective therapeutic tool in PD research that has the potential to increase the survival rate of dopaminergic neurons that are still alive at the time of diagnosis.

Silencing COX-2 blocks PDK1/TRAF4-induced AKT activation to inhibit fibrogenesis during skeletal muscle atrophy

Skeletal muscle atrophy with high prevalence can induce weakness and fatigability and place huge burden on both health and quality of life. During skeletal muscle degeneration, excessive fibroblasts and extracellular matrix (ECM) accumulated to replace and impair the resident muscle fiber and led to loss of muscle mass. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in synthesis of prostaglandin, has been identified as a positive regulator in pathophysiological process like inflammation and oxidative stress. In our study, we found injured muscles of human subjects and mouse model overexpressed COX-2 compared to the non-damaged region and COX-2 was also upregulated in fibroblasts following TGF-β stimulation. Then we detected the effect of selective COX-2 inhibitor celecoxib on fibrogenesis. Celecoxib mediated anti-fibrotic effect by inhibiting fibroblast differentiation, proliferation and migration as well as inactivating TGF-β-dependent signaling pathway, non-canonical TGF-β pathways and suppressing generation of reactive oxygen species (ROS) and oxidative stress. In vivo pharmacological inhibition of COX-2 by celecoxib decreased tissue fibrosis and increased skeletal muscle fiber preservation reflected by less ECM formation and myofibroblast accumulation with decreased p-ERK1/2, p-Smad2/3, TGF-βR1, VEGF, NOX2 and NOX4 expression. Expression profiling further found that celecoxib could suppress PDK1 expression. The interaction between COX-2 and PDK1/AKT signaling remained unclear, here we found that COX-2 could bind to PDK1/AKT to form compound. Knockdown of COX-2 in fibroblasts by pharmacological inactivation or by siRNA restrained PDK1 expression and AKT phosphorylation induced by TGF-β treatment. Besides, si-COX-2 prevented TGF-β-induced K63-ubiquitination of AKT by blocking the interaction between AKT and E3 ubiquitin ligase TRAF4. In summary, we found blocking COX-2 inhibited fibrogenesis after muscle atrophy induced by injury and suppressed AKT signaling pathway by inhibiting upstream PDK1 expression and preventing the recruitment of TRAF4 to AKT, indicating that COX-2/PDK1/AKT signaling pathway promised to be target for treating muscle atrophy in the future.

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

PurposeThe naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA.MethodsA panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models.ResultsGenetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours.ConclusionCyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies.

Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

BackgroundActivating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment...

Celecoxib substituted biotinylated poly(amidoamine) G3 dendrimer as potential treatment for temozolomide resistant glioma therapy and anti-nematode agent

Glioblastoma multiforme (GBM) is a one of the most widely diagnosed and difficult to treat type of central nervous system tumors. Resection combined with radiotherapy and temozolomide (TMZ) chemotherapy prolongs patients' survival only for 12 - 15 months after diagnosis. Moreover, many patients develop TMZ resistance, thus important is search for a new therapy regimes including targeted drug delivery. Most types of GBM reveal increased expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2), that are considered as valuable therapeutic target. In these studies, the anti-tumor properties of the selective COX-2 inhibitor celecoxib (CXB) and biotinylated third generation of the poly(amidoamine) dendrimer substituted with 31 CXB residues (G3BC31) on TMZ –resistantU-118 MG glioma cell line were examined and compared with the effect of TMZ alone including viability, proliferation, migration and apoptosis, as well as the cellular expression of COX-2, ATP level, and PGE2 production. Confocal microscopy analysis with the fluorescently labeled G3BC31 analogue has shown that the compound was effectively accumulated in U-118 MG cells in time–dependent manner and its localization was confirmed in lysosomes but not nuclei. G3BC31 reveal much higher cytotoxicity for U-118 MG cells at relatively low concentrations in the range of 2–4 µM with compared to CBX alone, active at 50–100 µM. This was due to induction of apoptosis and inhibition of proliferation and migration. Observed effects were concomitant with reduction of PGE2 production but independent of COX-2 expression. We suggest that investigated conjugate may be a promising candidate for therapy of TMZ-resistant glioblastoma multiforme, although applicable in local treatment, since our previous study of G3BC31 did not demonstrate selectivity against glioma cells compared to normal human fibroblasts.However, it has to be pointed that in our in vivo studies conducted with model organism, Caenorhabditis elegans indicated high anti-nematode activity of G3BC31 in comparison with CXB alone that confirms of usefulness of that organism for estimation of anti-cancer drug toxicity.

Effects of Celecoxib on Electroconvulsive Therapy-Induced Cognitive Impairment in Patients With Major Depressive Disorder: A Pilot, Double-Blind, Placebo-Controlled Trial

Cognitive impairment, an important side effect of electroconvulsive therapy (ECT), may be related to the release of prostaglandins in the brain. Cyclooxygenase-2 (COX-2), constitutively expressed in the CNS, has a functional role in glutamate-mediated learning and memory. The goal of this pilot, double-blind, placebocontrolled trial was to evaluate the effects of the selective COX-2 inhibitor celecoxib on the adverse cognitive effects of ECT. Twenty patients diagnosed with the major depressive disorder for which ECT was indicated as a treatment for their current episode randomly received either celecoxib (200 mg orally twice a day, a total dose of 400 mg/day) or placebo. All patients underwent the same protocol for anesthesia and ECT procedures. The patients received celecoxib or the placebo for the whole period of ECT treatment, starting the day before ECT and continuing until the sixth (last) session of ECT. The Wechsler Mental Scale-III (WMS-III), the Mini-Mental Scale Examination (MMSE), and Stroop Color test were used to assess cognition before the first session and after the first, third and sixth sessions of ECT. Hamilton rating scale for depression was also used for the assessment of depression before and after the trial. Our data showed that celecoxib group did not have significant improvement in cognition based on WMS-III or MMSE scores. There was an improvement in the Stroop Color test but not statistically significant. Our results demonstrated that although celecoxib was well tolerated in patients undergoing ECT, it did not improve related cognitive impairment. Clinical trial registration number: IRCT201201247202N2. CNS, central nervous system; COX-2, Cyclooxygenase-2; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision; ECT, electroconvulsive therapy; ECS, electroconvulsive shocks; HAM-D, Hamilton rating scale for depression; LTP, long term potentiation; MDD, major depressive disorder; MMSE, Mini-Mental State Examination; NSAIDs, nonsteroidal anti-inflammatory drugs; WMS-III, Wechsler Memory Scale-III.

3,3\u2032-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most aggressive tumors in the world. Aryl hydrocarbon receptor (AHR) has been reported to promote tumor metastasis and epithelial-mesenchymal transition (EMT) is a vital process of conferring cancer cells capabilities of migration and invasion. However, the mechanism by which modulation of AHR can inhibit tumor metastasis remains unknown. Thus, we aim to investigate the underlying mechanism regarding reversing EMT process of ESCC through modulation of AHR.MethodsWe used AHR selective modulator 3,3′-diindolylmethane (DIM) to treat ESCC cell lines TE1 and KYSE150 so as to examine alterations of migration and invasion by wound healing and Transwell assay. Western blotting (WB) and qPCR were performed to detect relative genes and proteins changes regarding EMT process. Cell transfection was utilized for confirming pathways involved in DIM-induced reversal of EMT and in vivo assay was conducted for verification of the underlying mechanism. Co-IP assay was conducted for detecting protein-protein interactions.ResultsAHR was overexpressed in ESCC and modulation of AHR by DIM could inhibit migration and invasion as well as downregulate mesenchymal cell markers β-Catenin, Vimentin and Slug and upregulate epithelial cell marker Claudin-1. Meanwhile, synergically overexpression of AHR, RhoA and ROCK1 correlated with poor clinical outcomes. DIM could inhibit COX2/PGE2 pathway by targeting AHR, and COX2 selective inhibitor Celecoxib could suppress EMT and metastasis. Results of PGE2 treatment were opposite to that of Celecoxib. Meanwhile, blockade of RhoA/ROCK1 pathway also exerted prohibitive effects on EMT and metastasis. WB results showed COX2/PGE2 pathway could be regulated by RhoA/ROCK1 pathway and DIM could inhibit RhoA/ROCK1 pathway through modulation of AHR. In vivo assay verified the results in vitro. Co-IP results showed DIM could modulate AHR to reverse EMT directly through inhibition of interaction between AHR and EGFR (epidermal growth factor receptor) so as to block RhoA/ROCK1-mediated COX2/PGE2 pathway which was connected by NF-κB.ConclusionsIn brief, modulation of AHR by DIM can reverse EMT process and inhibit metastasis of ESCC through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway.

Celecoxib induces apoptosis through Akt inhibition in 5-fluorouracil-resistant gastric cancer cells.

Gastric cancer is the fifth leading cause of cancer and a global public health problem. 5-Fluorouracil (5-FU) is the primary drug chosen for the treatment of advanced gastric cancer, but acquired cancer drug resistance limits its effectiveness and clinical use. Proliferation assays showed that a gastric carcinoma cell line, AGS and 5-FU-resistant AGS cells (AGS FR) treated with 3-100μM 5-FU for 48h or 72h showed different sensitivities to 5-FU. Immunoblot assay demonstrated that AGS FR cells expressed more COX-2 and PGE2-cognated receptor EP2 than AGS cells. AGS FR cells considerably produced PGE2 than AGS upon stimulation with 5-FU. These results suggest that COX-2 expression is associated with 5-FU resistance. Unlike AGS FR cells, AGS cells showed increased levels of both cleaved caspase-3 and Bax following 5-FU treatment. Treatment of cells with the COX-2 selective inhibitor celecoxib induced cell death of AGS FR cells in a time- and concentration-dependent manner. FACS analysis showed that celecoxib at high doses caused apoptotic cell death, demonstrating a concentration-dependent increase in the cell populations undergoing early apoptosis and late apoptosis. This apoptotic induction was strongly supported by the expression profiles of apoptosis- and survival-associated proteins in response to celecoxib; pro-apoptotic cellular proteins increased while expressions of COX-2 and p-Akt were downregulated in a concentration-dependent manner. An increase in PTEN expression was accompanied with downregulation of p-Akt. Based on the data that downregulation of COX-2 was correlated with the concentrations of celecoxib, COX-2 may play a key role in celecoxib-induced cell death of AGS FR cells. Butaprost, the EP2 agonist, promoted proliferative activity of AGS FR cells in a concentration-dependent manner compared with AGS cells. In cells exposed to butaprost, expressions of COX-2 and p-Akt were increased in a concentration-dependent manner with concomitantly reduced PTEN levels. Taken together, 5-FU-resistance in gastric cancer is correlated with COX-2 expression, and therefore the selective inhibition of COX-2 leads to suppression of cell proliferation of AGS FR cells. Modulation of COX-2 expression and its catalytic activity may be a potential therapeutic strategy to overcome 5-FU-resistant gastric cancer.

Effects of Genetic and Pharmacologic Inhibition of COX-2 on Colitis-associated Carcinogenesis in Mice.

COX-2 has been inappropriately overexpressed in various human malignancies, and is considered as one of the representative targets for the chemoprevention of inflammation-associated cancer. In order to assess the role of COX-2 in colitis-induced carcinogenesis, the selective COX-2 inhibitor celecoxib and COX-2 null mice were exploited in an azoxymethane (AOM)-initiated and dextran sulfate sodium (DSS)-promoted murine colon carcinogenesis model. The administration of 2% DSS in drinking water for 1 week after a single intraperitoneal injection of AOM produced colorectal adenomas in 83% of mice, whereas only 27% of mice given AOM alone developed tumors. Oral administration of celecoxib significantly lowered the incidence as well as the multiplicity of colon tumors. The expression of COX-2 and inducible nitric oxide synthase (iNOS) was upregulated in the colon tissues of mice treated with AOM and DSS, and this was inhibited by celecoxib administration. Likewise, celecoxib treatment abrogated the DNA binding of NF-κB, a key transcription factor responsible for regulating expression of aforementioned pro-inflammatory enzymes, which was associated with suppression of IκBα degradation. In the COX-2 null (COX-2–/–) mice, there was about 30% reduction in the incidence of colon tumors, and the tumor multiplicity was also markedly reduced (7.7 ± 2.5 vs. 2.43 ± 1.4, P < 0.01). As both pharmacologic inhibition and genetic ablation of COX-2 gene could not completely suppress colon tumor formation following treatment with AOM and DSS, it is speculated that other pro-inflammatory mediators, including COX-1 and iNOS, should be additionally targeted to prevent inflammation-associated colon carcinogenesis.

Development of celecoxib-derived antifungals for crop protection.

Selective COX-2 inhibitor celecoxib was found directly inhibiting the growth of tested phytopathogenic fungi with the inhibitory rate ranging from 30 to 40% at 100µg/ml. Lead optimization of celecoxib led to the identification of compound 12 among its derivatives as the most active antifungal candidate. The antifungal effect of compound 12 was supposed to be independent of COX-2 inhibition. Transcriptome profiling analysis of Fusarium graminearium (PH-1) treated with compound 12 brought about 406 up-regulated and 572 down-regulated differentially express genes (DEGs) respectively.

Interaction of epidermal growth factor with COX-2 products and peroxisome proliferator-activated receptor-γ system in experimental rat Barrett's esophagus.

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1) vehicle, 2) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3) ranitidine or pantoprazole, and 4) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1β, TNFα, and mucosal PGE2 content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE.NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.

Effect of tumor cell-derived debris and IgG on metastasis of pancreatic cancer and inflammation through tumor-associated macrophages.

e15764 Background: The progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumor microenvironment. Most tumor-associated macrophages (TAMs) are M2 phenotypic macrophages, which normally show anti-inflammatory functions in numerous disorders. We previously found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation of hepatoma cell-derived debris, but the molecular mechanism was unclear. Methods: Macrophages were induced using tumor cell debris. Xenograft mouse model was established. Immunoblotting and immunochemistry were used to test protein expression. Results: The M2 macrophages-derived inflammation also existed in PDAC. We proved that the necrotic debris of PDAC cells induced potent IL-1β release by M2 macrophages via TLR4/TRIF/NF-κB signaling, and this effect was further boosted by IgG that also derived from PDAC cells. We further revealed that increased IL-1β promoted epithelial-mesenchymal transition (EMT) and consequent metastasis of PDAC cells. Using a selective COX-2 inhibitor celecoxib, we enhanced the anti-tumoral efficacy of gemcitabine. Conclusions: These data revealed a special pro-inflammatory phenomenon and mechanism in PDAC, and indicated that IL-1β and COX-2 can be therapeutic targets of anti-inflammatory strategy in PDAC treatment.

The protective effects of ursodeoxycholic acid and the selective cyclooxygenase-2 inhibitor celecoxib on liver damage in an experimental cholestasis model

Aim: Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Hepatic cyclooxygenase-2 (COX-2) expression increases in various chronic liver diseases caused either by viruses or toxins. The present study was conducted to investigate the effects of UDCA and the selective COX-2 inhibitor celecoxib on inflammation and fibrogenesis in a rat model of cholestasis induced by bile duct ligation (BDL). Methods: Fifty Sprague–Dawley rats that underwent common BDL for 21 days were assigned to one of five treatment groups (sham-operation, BDL, daily UDCA treatment following BDL, daily celecoxib treatment following BDL, and daily celecoxib and UDCA combination treatment following BDL). Serum and liver samples were collected after 21 days. Fibrosis, ductular proliferation, and portal inflammation were scored in liver samples. Liver function tests were evaluated. Results: In comparison with the control group, the BDL group showed hepatic damage as evidenced by elevation in serum biochemical and histological changes such as ductular reaction, fibrosis, and inflammation. These pathophysiological changes were attenuated by chronic UDCA and selective COX-2 inhibitor celecoxib supplementation. Conlusion: Our findings indicate that the addition of Celecoxib to UDCA reduces liver inflammation and fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases. The beneficial effects of chronic UDCA and Celecoxib supplementation may be associated with their potential cytoprotective, anti-oxidative and anti-inflammatory effects.

Effect of Caffeic Acid on Ischemia-Reperfusion-Induced Acute Renal Failure in Rats

Background: Cyclooxygenase (COX)-lipooxygenase (LOX) pathway plays a key role in the pathogenesis of renal ischemia/reperfusion (IR). Objective: This study was aimed to evaluate the role of dietary phenol caffeic acid (CA), alone and in combination with selective COX-2 inhibitor celecoxib (CEL) in IR-induced acute renal failure (ARF) in rats. Materials and Methods: Renal IR was induced by bilateral occlusion of renal pedicels for 90 min followed by reperfusion for 24 h. Rats were randomized into 4 groups: Sham, IR, CA + IR, and CA + CEL + IR, with 7 day treatment before IR. Serum creatinine (SCr), blood urea nitrogen (BUN), antioxidant enzymes, tumor necrosis factor alpha (TNF-α), and histopathological changes were evaluated in the kidney after IR. Results: Renal IR caused significant derangement in renal function and histology. In the IR group, an increase in lipid peroxidation and decreased antioxidant defense enzyme activity were observed. Pretreatment with CA and CA + CEL showed a significant decrease in the BUN, SCr, TNF-α, oxidative stress markers and corrected the histological changes in the kidney. Conclusion: This study demonstrated the renoprotective potential of CA and combination of CA + CEL in IR-induced ARF in rats. The plausible mechanisms for the efficacy of CA could be attributed to its ability to modulate the ­COX-LOX system in renal IR.

Potentially inappropriate concomitant medicine use with the selective COX-2 inhibitor celecoxib: Analysis and comparison of spontaneous adverse event reports from Australia, Canada and the USA.

ABSTRACTBackground: To perform an international comparison and analysis of celecoxib spontaneous adverse event reports (AERs) from Canada, Australia and the United States, focusing on gastrointestinal, renal and cardiovascular events. This study also examined concomitant medicines use which may have potentiated the risk of the reported adverse events.Research, design and methods: Three databases were searched for spontaneous AERs associated with celecoxib, submitted within the past 10 years: Australian Therapeutic Goods Administration Database of Adverse Event Notifications; Canada Vigilance Adverse Reaction Online Database; and the United States Food and Drug Administration Adverse Event Reporting System Database. Analysis of the AERs focussed on the identification of gastrointestinal, cardiovascular and renal adverse events and concomitant medications suspected of potentiating adverse event risks.Results: A total of 24,232 celecoxib AERs were identified. Gastrointestinal disorders were the most frequently reported adverse events at the system organ class (SOC) level in the AERs. A large number of AERs documented the use of potentially inappropriate concomitant medicines which may have increased the risk of the reported adverse events.Conclusions: The large number of reports that involved a concomitant medicine that was in contravention with prescribing guidelines indicates an increased need for efforts to support the safe prescribing of celecoxib.

Celecoxib alleviates AKT/c-Met-triggered rapid hepatocarcinogenesis by suppressing a novel COX-2/AKT/FASN cascade.

Previous studies have demonstrated that the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib shows efficacy against multiple cancers, including hepatocellular carcinoma. However, whether celecoxib is effective in alleviating steatosis during hepatocarcinogenesis is unknown. In a rapid hepatocellular carcinoma (HCC) mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes, we investigated the antisteatotic and anticarcinogenic efficacy of celecoxib in vivo. Multiple HCC cell lines were employed for in vitro evaluation. Additionally, immunoblotting, immunohistochemistry, hematoxylin and eosin staining and Oil Red O staining were applied for mechanistic investigation. The results revealed that if celecoxib was administered in the early stage of AKT/c-Met-induced HCC, it resulted in disease stabilization. Moreover, celecoxib could alleviate lipid accumulation in the HCC mice and in an oleic acid-induced in vitro hepatic steatosis model. Further evidence at the molecular level indicated that celecoxib down-regulated the expression of phospho-ERK (Thr202/Tyr204) and proliferating cell nuclear antigen (PCNA) in the HCC mice. In addition, celecoxib efficiently repressed the phosphor-Akt (Thr308)/fatty acid synthase (FASN) axis both in vivo and in vitro. Altogether, this study suggests that celecoxib exerts its antilipogenic efficacy by targeting a COX-2/AKT/FASN cascade, which contributes to its ability to delay hepatocarcinogenesis.

Cyclooxygenase-1 and -2 Play Contrasting Roles in Listeria-Stimulated Immunity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are commonly used for pain relief and fever reduction. NSAIDs are used following childhood vaccinations and cancer immunotherapies; however, how NSAIDs influence the development of immunity following these therapies is unknown. We hypothesized that NSAIDs would modulate the development of an immune response to Listeria monocytogenes-based immunotherapy. Treatment of mice with the nonspecific COX inhibitor indomethacin impaired the generation of cell-mediated immunity. This phenotype was due to inhibition of the inducible COX-2 enzyme, as treatment with the COX-2-selective inhibitor celecoxib similarly inhibited the development of immunity. In contrast, loss of COX-1 activity improved immunity to L. monocytogenes Impairments in immunity were independent of bacterial burden, dendritic cell costimulation, or innate immune cell infiltrate. Instead, we observed that PGE2 production following L. monocytogenes is critical for the formation of an Ag-specific CD8+ T cell response. Use of the alternative analgesic acetaminophen did not impair immunity. Taken together, our results suggest that COX-2 is necessary for optimal CD8+ T cell responses to L. monocytogenes, whereas COX-1 is detrimental. Use of pharmacotherapies that spare COX-2 activity and the production of PGE2 like acetaminophen will be critical for the generation of optimal antitumor responses using L. monocytogenes.

MP54-08 PROSTAGLANDIN RECEPTORS INDUCE UROTHELIAL TUMOURIGENESIS AS WELL AS BLADDER CANCER PROGRESSION AND CISPLATIN RESISTANCE PRESUMABLY VIA MODULATING PTEN EXPRESSION

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2018MP54-08 PROSTAGLANDIN RECEPTORS INDUCE UROTHELIAL TUMOURIGENESIS AS WELL AS BLADDER CANCER PROGRESSION AND CISPLATIN RESISTANCE PRESUMABLY VIA MODULATING PTEN EXPRESSION Eiji Kashiwagi, Satoshi Inoue, Taichi Mizushima, Jinbo Chen, Hiroki Ide, Takashi Kawahara, Leonardo Reis, Alexander Baras, George Netto, and Hiroshi Miyamoto Eiji KashiwagiEiji Kashiwagi More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Taichi MizushimaTaichi Mizushima More articles by this author , Jinbo ChenJinbo Chen More articles by this author , Hiroki IdeHiroki Ide More articles by this author , Takashi KawaharaTakashi Kawahara More articles by this author , Leonardo ReisLeonardo Reis More articles by this author , Alexander BarasAlexander Baras More articles by this author , George NettoGeorge Netto More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1699AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostaglandin E2 (PGE2) has been shown to play a central role in not only inflammation but also cell proliferation as an antiapoptotic molecule. Accordingly, inhibition of PGE2 is considered a possible anticancer strategy. Meanwhile, PGE2 exerts its effects via G-protein-coupled receptors (GPCRs), including PGE2 receptor 2 (EP2) and EP4. Nonetheless, it remains to be resolved whether and how GPCR signaling is involved in bladder cancer (BC) initiation and outgrowth. The present study aimed to investigate the functional role of prostaglandin receptors, as well as the efficacy of a selective cyclooxygenase-2 inhibitor celecoxib, in urothelial tumorigenesis and cancer progression. METHODS We performed immunohistochemistry in bladder cancer tissue microarrays consisting of 129 urothelial neoplasms and separate 37 muscle-invasive BCs from patients who subsequently received cisplatin-based neoadjuvant chemotherapy, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/RTPCR/cell growth assays in BC lines. RESULTS EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumors or positivity of EP2/EP4 in muscle-invasive tumors strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene (MCA) considerably increased and decreased the expression of EP2/EP4 and PTEN, respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in MCA-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines. CONCLUSIONS EP2 and EP4 play an important role in inducing urothelial tumorigenesis, bladder tumor progression, and chemoresisance in BC cells, via downregulating PTEN expression. Thus, EP2/EP4 inactivation, using available inhibitors, has the potential of being not only a chemopreventive and therapeutic option for urothelial cancer but also a means of chemosensitization particularly in patients with EP2/EP4-positive tumors. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e714-e715 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Eiji Kashiwagi More articles by this author Satoshi Inoue More articles by this author Taichi Mizushima More articles by this author Jinbo Chen More articles by this author Hiroki Ide More articles by this author Takashi Kawahara More articles by this author Leonardo Reis More articles by this author Alexander Baras More articles by this author George Netto More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Influence of the selective COX-2 inhibitor celecoxib on sex differences in blood pressure and albuminuria in spontaneously hypertensive rats

We previously reported that female spontaneously hypertensive rats (SHR) have greater cyclooxygenase-2 (COX-2) expression in the renal medulla and enhanced urinary excretion of prostaglandin (PG) E2 (PGE2) metabolites compared to male SHR. Based on the role of COX-2-derived prostanoids in the regulation of cardiovascular health, the aim of the current study was to test the hypothesis that blood pressure (BP) in female SHR is more sensitive to COX-2 inhibition than in males. Seven week old male and female SHR were implanted with telemetry transmitters for continuous BP recording. After one week of baseline BP recording, male and female SHR were randomized to receive the selective COX-2 inhibitor celecoxib (10 mg/kg/day) or vehicle for six weeks (from 9 to 14 weeks of age). Female SHR had lower BP and albuminuria compared to male SHR as well as enhanced urinary excretion of PGE metabolite (PGEM), 6-keto PGF1α and thromboxane B2, indicators of PGE2, PGI2 and TXA2, respectively. Treatment with celecoxib did not significantly alter BP or albuminuria in either female or male SHR. Celecoxib did not change PGs metabolites excretion in male SHR; however, excretion levels of PGEM and 6-keto PGF1α were reduced in female SHR. COX-2 derived PG can also induce oxidative stress. Markers of oxidative stress (thiobarbituric acid reactive substances (TBARs) and H2O2 excretion) were lesser in female SHR versus male SHR. Celecoxib treatment did not significantly change markers of oxidative stress in female SHR, however, urinary TBARs excretion was significantly reduced in male SHR after 6 weeks of treatment with celecoxib. Therefore, although celecoxib treatment appears to have distinct effects on prostanoids levels in female SHR vs. males, it is unlikely that COX-2 contributes to established sex differences in BP in SHR.

Effect of COX-2 inhibition on tendon-to-bone healing and PGE2 concentration after anterior cruciate ligament reconstruction

BackgroundNon-steroidal anti-inflammatory drugs are commonly used to reduce pain and inflammation in orthopaedic patients. Selective cyclooxygenase-2 (COX-2) inhibitors have been developed to minimize drug-specific side effects. However, they are suspected to impair both bone and tendon healing. The objective of this study is to evaluate the effect of COX-2 inhibitor administration on tendon-to-bone healing and prostaglandin E (PGE2) concentration.MethodsThirty-two New Zealand white rabbits underwent reconstructions of the anterior cruciate ligaments and were randomized into four groups: Two groups postoperatively received a selective COX-2 inhibitor (Celecoxib) on a daily basis for 3 weeks, the two other groups received no postoperative COX-2 inhibitors at all and were examined after three or 6 weeks. The PGE2 concentration of the synovial fluid, the osseous integration of the tendon graft at tunnel aperture and midtunnel section, as well as the stability of the tendon graft were examined via biomechanic testing.ResultsAfter 3 weeks, the PGE2 content of the synovial fluid in the COX-2 inhibitor recipients was significantly lower than that of the control group (p = 0.018). At the same time, the COX-2 inhibitor recipients had a significantly lower bone density and lower amount of new bone formation than the control group (p = 0.020; p = 0.028) in the tunnel aperture. At the 6-week examination, there was a significant increase in the PGE2 content within synovial fluid of the COX-2 inhibitor recipients (p = 0.022), whose treatment with COX-2 inhibitors had ended 3 weeks earlier; in contrast, the transplant stability decreased and was reduced by 37% compared to the controls.ConclusionsSelective COX-2 inhibitors cause impaired tendon-to-bone healing, weaken mechanical stability and decrease PGE2 content of the synovial fluid. The present study suggests a reluctant use of COX-2 inhibitors when tendon-to-bone healing is intended.