Effect Of Selective Cyclooxygenase-2 Inhibitor Research Articles

Морфобиохимический профиль крови при терапии ингибиторами ЦОГ-2 и циклофосфамидом

Abstract. In modern veterinary medicine, in the last decade, significant achievements have been noted in the treatment of malignant tumors in dogs, but nevertheless the number of oncologically ill animals is quite widespread, and tends to increase further. The use of only traditional methods for the treatment of oncological pathologies (radiation and chemotherapy, surgical) does not have a positive effect, and accordingly does not solve the problem as a whole. The scientific novelty lies in the study of the effect of selective COX-2 inhibitors in combination with cyclophosphamide on the morphobiochemical parameters of the blood of dogs with malignant neoplasms of the breast. The purpose of our work was to study the dynamics of morphobiochemical blood parameters during multimodal conservative therapy of breast cancer recurrence in dogs with selective COX-2 inhibitors (firocoxib, cimicoxib) and cyclophosphamide. Research methods. Clinical observations and studies were carried out in the veterinary clinic of the Center for Animal Beauty and Health “Zoostyle” in Volgograd. The object of the study was 6 female dogs of various breeds aged 10-14 years, with a morphologically confirmed diagnosis of recurrent breast adenocarcinoma. At the same time, an automatic hematological analyzer “Mindray BC-2800 Vet” and a semi-automatic biochemical analyzer “BioChem SA” were used. Stained blood smears were examined under a microscope “MIKMED-5”. Results. The results of the studies show that morphobiochemical blood parameters varied in both groups by the 90th day of therapy. The results obtained convincingly show that the use of a combination of selective COX-2 inhibitors and cyclophosphamide, in clinically significant doses, induced an increase in individual biochemical parameters of blood serum, without symptomatic manifestations. In the firocoxib group, creatinine and urea levels exceeded the reference values by 39.5 and 67.7 %, respectively. Thus, the combination of drugs in the first group demonstrates an increased risk of use in animals with renal insufficiency.

Celecoxib decreases mitochondrial complex IV activity and induces oxidative stress in isolated rat heart mitochondria: An analysis for its cardiotoxic adverse effect.

In spite of the cardiotoxic effect of selective cyclooxygenase-2 inhibitors, they are most widely used as anti-inflammatory and analgesic drugs. Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains. In this study, we focused on an analysis of celecoxib toxic effects on isolated mitochondria. Isolated rat heart mitochondria were obtained using differential centrifugation. Using flow cytometry and biochemical assays, we searched succinate dehydrogenases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, mitochondrial swelling, ATP/ADP ratio, lipid peroxidation, and mitochondrial complexes activity in rat heart isolated mitochondria. Herein, our results indicated a significant decrease in the activity of complex IV after exposure with celecoxib (16 µg/ml). This decrease in the activity of complex IV is paralleled by the MMP collapse, ROS formation, mitochondrial swelling, depletion of ATP, and lipid peroxidation. For the first time, this introductory study has shown a significant decrease in the activity of complexIV and mitochondrial dysfunction after exposure with celecoxib in rat heart isolated mitochondria.

Chondroprotective Actions of Selective COX-2 Inhibitors In Vivo: A Systematic Review.

Knee osteoarthritis (OA) is a condition mainly characterized by cartilage degradation. Currently, no effective treatment exists to slow down the progression of OA-related cartilage damage. Selective COX-2 inhibitors may, next to their pain killing properties, act chondroprotective in vivo. To determine whether the route of administration is important for the efficacy of the chondroprotective properties of selective COX-2 inhibitors, a systematic review was performed according to the PRISMA guidelines. Studies investigating OA-related cartilage damage of selective COX-2 inhibitors in vivo were included. Nine of the fourteen preclinical studies demonstrated chondroprotective effects of selective COX-2 inhibitors using systemic administration. Five clinical studies were included and, although in general non-randomized, failed to demonstrate chondroprotective actions of oral selective COX-2 inhibitors. All of the four preclinical studies using bolus intra-articular injections demonstrated chondroprotective actions, while one of the three preclinical studies using a slow release system demonstrated chondroprotective actions. Despite the limited evidence in clinical studies that have used the oral administration route, there seems to be a preclinical basis for considering selective COX-2 inhibitors as disease modifying osteoarthritis drugs when used intra-articularly. Intra-articularly injected selective COX-2 inhibitors may hold the potential to provide chondroprotective effects in vivo in clinical studies.

Effect of Selective COX-2 Inhibitor on IL-1β and Glasgow Coma Scale (GCS) Score in Moderate Traumatic Brain Injury Patients

Effect of Selective COX-2 Inhibitor on IL-1β and Glasgow Coma Scale (GCS) Score in Moderate Traumatic Brain Injury Patients

Evaluation of Cytotoxicity Effects of Chalcone Epoxide Analogues as a Selective COX-II Inhibitor in the Human Liver Carcinoma Cell Line.

ObjectivesStudy of the mechanisms involved in cancer progression suggests that cyclooxygenase enzymes play an important role in the induction of inflammation, tumor formation, and metastasis of cancer cells. Thus, cyclooxygenase enzymes could be considered for cancer chemotherapy. Among these enzymes, cyclooxygenase 2 (COX-2) is associated with liver carcinogenesis. Various COX-2 inhibitors cause growth inhibition of human hepatocellular carcinoma cells, but many of them act in the COX-2 independent mechanism. Thus, the introduction of selective COX-2 inhibitors is necessary to achieve a clear result. The present study was aimed to determine the growth-inhibitory effects of new analogues of chalcone epoxide as selective COX-2 inhibitors on the human hepatocellular carcinoma (HepG2) cell line.MethodsEstimation of both cell growth and the amount of prostaglandin E2 (PGE2) production were used to study the effect of selective COX-2 inhibitors on the hepatocellular carcinoma cell. Cell growth determination has done by MTT assay in 24 h, 48 h and 72 h, and PGE2 production has estimated by using ELYSA kit in 48 h and 72 h.ResultsThe results showed growth inhibition of the HepG2 cell line in a concentration and time-dependent manner, as well as a reduction in the formation of PGE2 as a product of COX-2 activity. Among the compounds those analogues with methoxy and hydrogen group showed more inhibitory effect than others.ConclusionThe current in-vitro study indicates that the observed significant growth-inhibitory effect of chalcone-epoxide analogues on the HepG2 cell line may involve COX-dependent mechanisms and the PGE2 pathway parallel to the effect of celecoxib. It can be said that these analogues might be efficient compounds in chemotherapy of COX-2 dependent carcinoma specially preventing and treatment of hepatocellular carcinomas.

Abstract 847: Anti-cancer effects of selective Cox-2 and EP2 inhibition through suppression of EMT and the clinical implications of overexpression of Cox-2 and downregulation of E-cadherin in pharyngeal squamous cell carcinoma

Abstract Background: Overexpression of cyclooxygenase 2 (Cox-2), an inducible prostaglandin (PG) synthetase, is assumed to promote cancer progression through its multifaceted function, including induction of angiogenesis, stimulation of cell proliferation, restraint on apoptosis, and immunosuppression. Furthermore, recently its inverse relationship with E-cadherin expression was reported. The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin is supposed to promote metastasis. However, neither the anti-cancer effect of selective Cox-2 inhibitors on the regulation of E-cadherin nor its specific mechanism has been examined in pharyngeal squamous cell carcinoma (PhSCC). In addition, the anti-tumor effect of EP2 antagonist, a possibly more selective inhibitor of PGE2, remains to be elucidated. Methods: We used quantitative real-time PCR to examine the effects of a selective Cox-2 inhibitors, Celecoxib, and a selective EP2 antagonist, PF-04418948, on the gene expressions of CDH-1, its transcriptional repressors (snail, ZEB1, twist), and vimentin in the human PhSCC cell lines BICR6 and FaDu. Alteration in E-cadherin expression on the cell surface was evaluated by immunofluorescent staining. In vitro proliferation and migration assays were performed to assess cellular behaviors. Clinicopathological factors and immunohistochemical expressions of Cox-2 and E-cadherin were evaluated using surgical specimens from 54 patients with PhSCC who underwent transoral resection. Results: Both Celecoxib and PF-04418948 upregulated the CDH-1 expression and the membranous E-cadherin expression and downregulate the vimentin expression in the PhSCC cells through the suppression of snail, ZEB1, and twist expression. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. Additionally, the cell migration was attenuated by both Celecoxib and PF-04418948, whereas the cell proliferation was not affected. Univariate analysis showed that differentiation, overexpression of Cox-2, and decreased expression of E-cadherin were significantly correlated with lymph node metastasis. Multivariate logistic regression revealed that overexpression of Cox-2 (odds ratio [OR]=53.49, P<0.001) and decreased expression of E-cadherin (OR=0.06, P=0.016) were the independent risk factors affecting lymph node metastasis. Conclusions: These findings suggest that the appropriately selective administration of the Cox-2 inhibitor and EP2 antagonist may have an anti-metastatic effect through suppression of EMT by restoring E-cadherin expression. In addition, overexpression of Cox-2 and downregulation of E-cadherin may be closely implicated in lymph node metastasis in PhSCC. Citation Format: Yoshihiro Watanabe, Yorihisa Imanishi, Hiroyuki Ozawa, Kaori Kameyama, Koji Sakamoto, Ryoichi Fujii, Seiji Shigetomi, Noboru Habu, Kuninori Otsuka, Yoichiro Sato, Mariko Sekimizu, Fumihiro Ito, Yuichi Ikari, Shin Saito, Kaoru Ogawa. Anti-cancer effects of selective Cox-2 and EP2 inhibition through suppression of EMT and the clinical implications of overexpression of Cox-2 and downregulation of E-cadherin in pharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 847. doi:10.1158/1538-7445.AM2017-847

Opioid-sparing effect of selective cyclooxygenase-2 inhibitors on surgical outcomes after open colorectal surgery within an enhanced recovery after surgery protocol

Opioid-sparing effect of selective cyclooxygenase-2 inhibitors on surgical outcomes after open colorectal surgery within an enhanced recovery after surgery protocol

Madecassoside suppresses proliferation and invasiveness of HGF-induced human hepatocellular carcinoma cells via PKC-cMET-ERK1/2-COX-2-PGE2 pathway

Recent studies showed that Madecassoside (MAD), a pentacyclic triterpene isolated from Centella asitica (L.), was used as a therapeutic agent in wound healing and also as an anti-inflammatory, anti-oxidative activities and anti-aging agent. However, its role in cancer has not been elucidated. In our present study, hepatocyte growth factor (HGF) induced the phosphorylation of its corresponding receptor cMET, increased expression of cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in human hepatocellular carcinoma (HCC) cells lines (HepG2 and SMMC-77), and this effect was inhibited by MAD in a dose-dependent manner. In addition, MAD exhibited significant anti-proliferative and anti-invasive effect in HGF-induced HepG2 and SMMC-77 cells. Moreover, MAD inhibited the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the protein kinase C (PKC) activity in HGF-induced HepG2 and SMMC-77 cells. This conclusion was consistent with the effect of selective COX-2 inhibitor (NS-398) and knockdown of COX-2 by siRNA on attenuating the proliferation and invasiveness potential, and over-expression of COX-2 on abolishing the effects of MAD on proliferation and invasiveness potential, and was also in parallel with the effect of PKC inhibitor (Bisindolylmaleimide) on inhibiting PKC activity, MEK/ERK1/2 inhibitor (PD98059) inhibited MEK/ERK1/2 pathways in HGF-induced HepG2 and SMMC-77 cells. Collectively, MAD could inhibit the HGF-activated proliferation and invasiveness of HCC cells via regulating the activation of cMET-PKC-ERK1/2-COX-2-PGE2 cascade, which indicated that MAD might help control HGF-linked HCC.

Opioid-sparing effect of selective cyclooxygenase-2 inhibitors on surgical outcomes after open colorectal surgery within an enhanced recovery after surgery protocol.

To evaluate the opioid-sparing effect of selective cyclooxygenase-2 (COX-2) inhibitors on short-term surgical outcomes after open colorectal surgery. Patients undergoing open colorectal resection within an enhanced recovery after surgery protocol from 2011 to 2015 were reviewed. Patients with combined general anesthesia and epidural anesthesia, and those with acute colonic obstruction or perforation were excluded. Patients receiving selective COX-2 inhibitor were compared with well-matched individuals without such a drug. Outcome measures included numeric pain score and morphine milligram equivalent (MME) consumption on postoperative day (POD) 1-3, gastrointestinal recovery (time to tolerate solid diet and time to defecate), complications and length of postoperative stay. There were 75 patients in each group. Pain score on POD 1-3 was not significantly different between two groups. However, MME consumption and MME consumption per kilogram body weight on POD 1-3 was significantly less in patients receiving a selective COX-2 inhibitor (P < 0.001). Median MME consumption per kilogram body weight on POD 1-3 was 0.09, 0.06 and nil, respectively in patients receiving a selective COX-2 inhibitor and 0.22, 0.25 and 0.07, respectively in the comparative group (P < 0.001), representing at least 59% opioid reduction. Patients prescribing a selective COX-2 inhibitor had a shorter median time to resumption of solid diet [1 (IQR 1-2) d vs 2 (IQR 2-3) d; P < 0.001] and time to first defecation [2 (IQR 2-3) d vs 3 (IQR 3-4) d; P < 0.001]. There was no significant difference in overall postoperative complications between two groups. However, median postoperative stay was significantly 1-d shorter in patients prescribing a selective COX-2 inhibitor [4 (IQR 3-5) d vs 5 (IQR 4-6) d; P < 0.001]. Perioperative administration of oral selective COX-2 inhibitors significantly decreased intravenous opioid consumption, shortened time to gastrointestinal recovery and reduced hospital stay after open colorectal surgery.

Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria

Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48±2.74μM)>celecoxib (IC50: 14.92±6.40μM)>valdecoxib (IC50: 161.4±28.6μM)>rofecoxib (IC50: 238.4±79.2μM)>etoricoxib (IC50: 405.1±116.3μM). Mechanism based inhibition of ATP synthesis (Kinact 0.078min−1 and KI 21.46μM and Kinact/KI ratio 0.0036min−1μM−1) was shown by lumiracoxib and data suggest that the opening of the MPT pore may not be the mechanism of toxicity. A positive correlation (with r2=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs and these metabolites did not alter the inhibition profile of ATP synthesis of the parent compound. The results suggest that coxibs themselves could be involved in the hepatotoxic action through inhibition of ATP synthesis.

The Effect of Selective COX-2 Inhibitor on Pain Control and Rotator Cuff Healing Following Arthroscopic Repair: Prospective Randomized Comparative Study

The Effect of Selective COX-2 Inhibitor on Pain Control and Rotator Cuff Healing Following Arthroscopic Repair: Prospective Randomized Comparative Study

Effects of parecoxib on analgesia benefit and blood loss following open prostatectomy: a multicentre randomized trial.

BackgroundThis multi-centre, prospective, randomized, double-blind, placebo-controlled study was designed to test the hypotheses that parecoxib improves patients’ postoperative analgesia without increasing surgical blood loss following radical open prostatectomy.Methods105 patients (64 ± 7 years old) were randomized to receive either parecoxib or placebo with concurrent morphine patient controlled analgesia. Cumulative opioid consumption (primary objective) and the overall benefit of analgesia score (OBAS), the modified brief pain inventory short form (m-BPI-sf), the opioid-related symptom distress scale (OR-SDS), and perioperative blood loss (secondary objectives) were assessed.ResultsIn each group 48 patients received the study medication for 48 hours postoperatively. Parecoxib significantly reduced cumulative opioid consumption by 24% (43 ± 24.1 mg versus 57 ± 28 mg, mean ± SD, p=0.02), translating into improved benefit of analgesia (OBAS: 2(0/4) versus 3(1/5.25), p=0.01), pain severity (m-BPI-sf: 1(1/2) versus 2(2/3), p < 0.01) and pain interference (m-BPI-sf: 1(0/1) versus 1(1/3), p=0.001), as well as reduced opioid-related side effects (OR-SDS score: 0.3(0.075/0.51) versus 0.4(0.2/0.83), p=0.03). Blood loss was significantly higher at 24 hours following surgery in the parecoxib group (4.3 g⋅dL−1 (3.6/4.9) versus (3.2 g⋅dL−1 (2.4/4.95), p=0.02).ConclusionsFollowing major abdominal surgery, parecoxib significantly improves patients’ perceived analgesia. Parecoxib may however increase perioperative blood loss. Further trials are needed to evaluate the effects of selective cyclooxygenase-2 inhibitors on blood loss.Trial registrationClinicalTrials.gov Identifier: NCT00346268

The effects of cyclooxygenase inhibitors on the gastric emptying and small intestine transit in the male rats following traumatic brain injury.

This study was carried out to investigate the effects of COX-2 selective inhibitor (Celecoxib) or non-selective COX inhibitor (Ibuprofen) on gastrointestinal motility. THE RATS WERE RANDOMLY DIVIDED INTO FIVE GROUPS INCLUDING: intact, sham, traumatic brain injury (TBI) group (intact rats under TBI), Celecoxib group (10 mg/kg), Ibuprofen group (10 mg/kg). Rats of the treatment groups received gavages at 1 hr before the TBI induction. The TBI was moderate and diffused using the Marmarou method. The gastric emptying and small intestine transit were measured by phenol red method. The gastric emptying didn't change following TBI induction compared to intact group. The consumption of ibuprofen or celecoxib didn't have any effect on gastric emptying compared to sham group. TBI induction didn't have any effect on the intestinal transit. Also, there was no significant difference between ibuprofen or celecoxib consumption vs. sham group (P>0.05). The COX-2 selective inhibitor (celecoxib) or non-selective COX inhibitor (ibuprofen) have no effects on gastric or small bowel transit. Further work is necessary to investigate the effects of non-selective COX inhibitors and their impact on gastrointestinal motility disorders.

Pharmacological characterization of carrageenan induced heat muscle hyperalgesia in rats using non-selective, preferential and selective COX-2 inhibitors

BackgroundPrevious studies have shown that unilateral injection of carrageenan into the gastrocnemius muscle produces chronic thermal and mechanical hyperalgesia. AimIn the present study, we have characterized this model of muscoskeletal inflammatory pain, by evaluating the antihyperalgesic effects of selective and non-selective COX-2 inhibitors after systemic administration. Materials and methodsRats were injected with 3% carrageenan in the left gastrocnemius muscle and hyperalgesia to heat stimuli (measured as decreased withdrawal latency) to paws was assessed before and at varying times after injection, till end of 2nd week. Histological changes and the determination of prostaglandin E2 (PGE2) concentration were performed after the completion of drug treatment protocol. ResultsIntraperitoneal administrations of the selective COX-2 inhibitor celecoxib (7mg/kg) as well as preferential COX-2 inhibitors like nimisulide (5mg/kg) and aceclofenac (5mg/kg) attenuated hyperalgesia whereas non-COX-2 selective inhibitors like ibuprofen (40mg/kg) and indomethacin (10mg/kg) did not. Also the histopathological evidence suggests the beneficial effects of COX-2 selective inhibitors. The data suggest that selective inhibition of COX-2 produce good anti-inflammatory, analgesic and antihyperalgesic effects on Carrageenan-induced thermal inflammatory hyperalgesia. ConclusionIn the present carrageenan induced chronic pain model we have determined the role of analgesics in the reversal and inhibition of the state of chronic hyperalgesia. While considering the characterization of the present model our observations suggest the importance of a spinal COX-2 mechanism, a spinal action of systemically delivered drugs in the face of peripheral inflammation.

Celecoxib exerts protective effects on extracellular matrix metabolism of mandibular condylar chondrocytes under excessive mechanical stress

ObjectiveExcessive mechanical stress is considered a major cause of temporomandibular joint osteoarthritis (TMJ-OA). High magnitude cyclic tensile strain (CTS) up-regulates pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in chondrocytes, while selective cyclooxygenase (COX)-2 inhibition has been shown to be beneficial to cytokine-induced cartilage damage. However, the effect of selective COX-2 inhibitors on mechanically stimulated chondrocytes remains unclear. This study evaluated the effect of celecoxib, a selective COX-2 inhibitor, on extracellular matrix (ECM) metabolism of mandibular condylar chondrocytes under CTS. MethodsPorcine mandibular chondrocytes were subjected to CTS of 0.5 Hz, 10% elongation with celecoxib for 24 h. The gene expressions of COX-2, MMPs, aggrecanase (ADAMTS), type II collagen and aggrecan were examined by real-time PCR. Also, prostaglandin E2 (PGE2) concentrations were determined using enzyme immunoassay kit. The levels of MMP and transcription factor NF-κB were measured by western blot while MMP activity was determined by casein zymography. ResultsThe presence of celecoxib normalized the release of PGE2 and diminished the CTS-induced COX-2, MMP-1, MMP-3, MMP-9 and ADAMTS-5 gene expressions while recovered the downregulated type II collagen and aggrecan gene expressions. Concurrently, celecoxib showed inhibition of NF-κB and suppression of MMP production and activity. ConclusionsCelecoxib exerts protective effects on mandibular condylar chondrocytes under CTS stimulation by diminishing degradation and restoring synthesis of ECM.

Overexpression of Cyclooxygenase-2 in Malignant Peripheral Nerve Sheath Tumor and Selective Cyclooxygenase-2 Inhibitor-Induced Apoptosis by Activating Caspases in Human Malignant Peripheral Nerve Sheath Tumor Cells

BackgroundCyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST.MethodsWe evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1.ResultsOverexpression of COX-2 (≥50% positive cells) was observed in 29 cases (65.9%), was significantly associated with a poor overall survival (P = 0.0495), and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis.ConclusionsSelective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses.

Usefulness of selective COX-2 inhibitors as therapeutic agents against canine mammary tumors

Cyclooxygenase-2 (COX-2) is a key enzyme for converting arachidonic acids to prostanoids, which are known to be induced during inflammation and cancer initiation. Previously, it has been reported that COX inhibitors, such as aspirin, reduce the incidence of human colorectal cancer; therefore, it is widely believed that COX-2 is a potential therapeutic and chemoprevention target for several types of human cancer. However, whether selective COX-2 inhibitors have antitumor effects against canine mammary tumor cells remains unclear. In the present study, to elucidate the antitumor effect of selective COX-2 inhibitors against canine mammary tumors, we investigated the antitumor effects of meloxicam, etodolac and celecoxib using COX-2-expressing canine mammary tumor (CF33) cells. We analyzed the effects of selective COX-2 inhibitors on COX-2 protein expression levels in CF33 cells. Celecoxib (100 µM) was found to induce downregulation of COX-2 protein expression. We examined the effect of selective COX-2 inhibitors on CF33 cell proliferation. All the selective COX-2 inhibitors suppressed CF33 cell growth. Specifically, etodolac and celecoxib inhibited cell proliferation via a decrease in S-phase cells and an increase in G0/G1 arrest. We examined the apoptotic effect of selective COX-2 inhibitors on CF33 cells. Our data suggested that etodolac and celecoxib induced apoptosis in CF33 cells. In particular, celecoxib led to apoptosis mediated by the activation of the mitochondrial apoptosis pathway, including the upregulation of BAX expression, downregulation of Bcl-2 expression and activation of caspase-3/7. Furthermore, celecoxib increased the percentages of cells in both early apoptosis and late apoptosis. Our results revealed that celecoxib induced apoptosis and cell cycle arrest in CF33 cells. The data suggested that celecoxib is the most viable candidate as a therapeutic agent for the treatment of canine mammary tumors. Furthermore, our findings provide the first indication that COX-2 inhibition can provide a new therapeutic strategy for treating canine mammary tumors.

The Adverse Effect of Selective Cyclooxygenase-2 Inhibitor on Random Skin Flap Survival in Rats

BackgroundCyclooxygenase-2(COX-2) inhibitors provide desired analgesic effects after injury or surgery, but evidences suggested they also attenuate wound healing. The study is to investigate the effect of COX-2 inhibitor on random skin flap survival.MethodsThe McFarlane flap model was established in 40 rats and evaluated within two groups, each group gave the same volume of Parecoxib and saline injection for 7 days. The necrotic area of the flap was measured, the specimens of the flap were stained with haematoxylin-eosin(HE) for histologic analysis. Immunohistochemical staining was performed to analyse the level of VEGF and COX-2 .Results7 days after operation, the flap necrotic area ratio in study group (66.65±2.81)% was significantly enlarged than that of the control group(48.81±2.33)%(P <0.01). Histological analysis demonstrated angiogenesis with mean vessel density per mm2 being lower in study group (15.4±4.4) than in control group (27.2±4.1) (P <0.05). To evaluate the expression of COX-2 and VEGF protein in the intermediate area II in the two groups by immunohistochemistry test .The expression of COX-2 in study group was (1022.45±153.1), and in control group was (2638.05±132.2) (P <0.01). The expression of VEGF in the study and control groups were (2779.45±472.0) vs (4938.05±123.6)(P <0.01).In the COX-2 inhibitor group, the expressions of COX-2 and VEGF protein were remarkably down-regulated as compared with the control group.ConclusionSelective COX-2 inhibitor had adverse effect on random skin flap survival. Suppression of neovascularization induced by low level of VEGF was supposed to be the biological mechanism.

Celecoxib, a selective cyclooxygenase-2 inhibitor, reduces level of a bone resorption marker in postmenopausal women with rheumatoid arthritis

Celecoxib (CEL), a selective cyclooxygenase-2 (COX-2) inhibitor, has been reported to suppress osteoclastogenesis in vitro, reduce levels of bone resorption markers in ovariectomized (OVX) mice, and prevent bone destruction in rheumatoid arthritis (RA) model mice; however, no clinical data has been reported. Here, we prospectively evaluated the changes in bone turnover markers in RA patients who switched from nonsteroidal anti-inflammatory drugs (NSAIDs) to CEL, to examine the effects of selective COX-2 inhibitor on bone metabolism. RA patients who had been treated with NSAIDs for more than 12weeks were switched to CEL (400mg/day) without any other changes in previously prescribed medications. Urinary type I collagen cross-linked N-telopeptide (uNTX), serum bone alkaline phosphatase (BAP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and matrix metalloproteinase-3 (MMP-3) were evaluated before switching to CEL and 16weeks later. Significant reductions in uNTX, a bone resorption marker, were observed in 60 female patients (P=0.042), especially in 52 postmenopausal women (P=0.033). However, uNTX level did not significantly change in premenopausal women or in men. There were no significant changes in BAP, a bone formation marker. CRP significantly decreased (P=0.007), while ESR and MMP-3 were unchanged. CEL reduced the levels of a bone resorption marker in postmenopausal RA patients, suggesting that this drug may attenuate the accelerated osteoclastic bone resorption associated with menopause.

COX-2 Selective Nonsteroidal Anti-inflammatory Drugs and Risk of Gastrointestinal Tract Complications and Myocardial Infarction

Instrumental variable analysis can estimate treatment effects in the presence of residual or unmeasured confounding. We compared ordinary least squares regression versus instrumental variable estimates of the effects of selective cyclooxygenase-2 inhibitors (COX-2s) relative to nonselective nonsteroidal anti-inflammatory drug (NSAID) prescriptions on incidence of upper gastrointestinal complications and myocardial infarction (MI). We sampled a cohort of 62,933 first-time users of COX-2s or nonselective NSAIDs older than 60 years in the Clinical Practice Research Datalink. The instruments were physicians' previous prescriptions of COX-2s or nonselective NSAIDs, which are surrogates for physician preferences. We estimated risk differences of incident upper gastrointestinal complications and MI within 180 days of first COX-2 versus nonselective NSAID prescription. Using ordinary least squares regression, adjusted for baseline confounders, we observed little association of COX-2 prescriptions with incident upper gastrointestinal complications (risk difference = -0.08 [95% confidence interval = -0.20 to 0.04]) or MI (0.06 [-0.06 to 0.17]) per 100 patients treated. Our adjusted instrumental variable results suggested 0.46 per 100 (-0.15 to 1.07) fewer upper gastrointestinal complications and little difference in acute MIs (0.08 per 100 [-0.61 to 0.76]), within 180 days of being prescribed COX-2s. Estimates were more precise when we used 20 previous prescriptions; the instrumental variable analysis implied 0.74 (0.28 to 1.19) fewer MIs per 100 patients prescribed COX-2s. Using instrumental variable analysis, we found some evidence that COX-2 prescriptions reduced the risk of upper gastrointestinal complications, consistent with randomized controlled trials. Our results using multiple instruments suggest that COX-2s may have heterogeneous within-class effects on MI.