arrest in oesophageal carcinoma cells. Concentrations between 0.1 to 1 μM of Celecoxib affect the suppression of PGE2 secretion. They have no effect on cell growth. The fact that Celecoxib, at a concentration higher than 100 μM, will stop cell growth shows that, except for COX-2, there might be other factors involved . Studies have shown that the cytochrome C pathway is the cause of Celecoxib apoptosis. In this way, cytochrome C is released from mitochondria and by activating caspase 3 and caspase 9 splits poly ADP-ribose polymerase (PARP). Moreover, the effect of NS398 was inhibited by caspase Z-DEVD-FMK inhibitor and prostaglandin E2.In contrast, BCL-2, bax, c-Myc, Fas and Fas-ligand showed minor changes. In total, the data suggest that induction of apoptosis by NS398 is associated with the expression of COX-2. This occurs through the cytochrome C-dependent pathway following by the activation of caspase 9, caspase 3 Clioz PARP (144). Factors such as asbcl-2, MAKs/ras, caspase-3, Par-4 are pro-and anti-apoptotic . Applying angiogenesis and blocking tumour growth cause high expression of COX-2, which in turn contributes to growth factors such as VDEG, PDGF, and bFGF and matrix metalloproteinases (MMPs) . Compared to the group receiving only carcinogens, prescribing topical 2500ppm Celecoxib can enhance total antioxidant levels. It seems that a reduction in the amount of antioxidants in this group reduces the formation of tumours and increases tumour cell mortality. Studies have also revealed that mice treated only with Celecoxib had higher antioxidant levels than the other groups under study, indicating a selective effect of the COX-2inhibitor in the antioxidant system. Topical administration of Celecoxib can be applied as an adjunctive treatment in patients with oral premalignant lesions with lower levels of antioxidants . Various studies show that selective COX-2 inhibitors play a critical role in improving the antioxidant system .Prescribing 2500ppm topical Celecoxib in the presence of carcinogens reduces tumour formation and increases bcl-2 expression as tumour suppressor genes. It also increases the level of tumour cell apoptosis . Celecoxib has antagonistic effects on anti- apoptotic proteins such as MCL-1 and Surviving . The maximum dose permissible and tolerable for Celecoxib along with Erlotinib in advanced lung cancer was 600mg to be taken twice daily . Cardiovascular complications are one of the common side effects of Celecoxib. Celecoxib has increasing does-related effects and is directly related to death by cardiovascular
compared to adherent GBM cells for phenotypic marker expression. For cytofluorimetric analysis, we used a FAC- SCalibur supplied with CellQuest software (Becton– Dickinson, San Jose, CA). The primary antibodies were used for immunophenotypic analysis: anti-β-tubulin III (Alexa Fluor 488, Catalog No. 560338), anti-SOX-2 (PE Mouse, Catalog No. 560291), anti-nestin (Alexa Fluor 647, Catalog No. 560393), all acquired from Becton– Dickinson (BD), anti-GFAP (Glial fibrillary acidic protein; Catalog No. G9269 Sigma–Aldrich). Secondary anti- body anti-rabbit FITC conjugated (Millipore) was used for detection of GFAP positive cells. Neurospheres were treated in the absence or presence of the selective COX-2inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4-nitrophenyl] methanesulfonamide) acquired from Sigma Aldrich (Sigma Aldrich, Saint Louis, MO, USA). Cells were firstly treated with different concentrations of NS398, as fol- lows: 10 µM, 100 µM, and 200 µM for 48 h. According to manufacturer instruction, the COX-2inhibitor was stored as stock solutions in DMSO at − 20 °C and diluted in cell culture medium just before use. The treatment with the vehicle alone was referred to as “control”, while the term “not-treated” was used for cells incubated with only culture medium. For all the parameters evaluated in this work, DMSO, used to dissolve NS398 at 0.6% (v/v) final concentration, did not have any effects on its own. Morphology and size of neurospheres were visualized by microscope Nikon Eclipse TS100 at the initial time (T0) and after 48 and 72 h from addition of COX-2inhibitor NS398 and at a longer incubation (range 96–144 h), after subculturing, with fresh medium and without inhibitor. To determine the area of the neurospheres, 10 bright field images (at 4× magnification) were randomly taken at each time points under the inverted microscope (Nikon Eclipse TS100). The size of the neurospheres was deter- mined using Image J software. The neurospheres’ average area (total area/number of neurospheres) was expressed in mm 2 , as previously reported . After NS398 expo-
To further determine whether the down-regulation of YAP and COX-2 were synergistic in apoptosis of these cells, we assessed the effects of shRNA targeting YAP and COX-2 on apoptosis sensitivity in HCT8 and 15/Tax cells. The shRNA targeting YAP or COX-2 effectively down- regulated expression of the target proteins, compared with the control shRNA (Fig. 11d). Then, the HCT8 cells were exposed to Taxol after shRNA treatment and were further analyzed by flow cytometry and MTT assays. Transfection with shRNA targeting YAP increased the apoptosis per- centage from 6% to 15% in HCT8/Tax cells and 9% to 18% in HCT15/Tax cell cultures (Fig. 11e, Additional file 4: Figure S4C). The shRNA targeting COX-2 had similar effects and increased apoptosis in HCT8 and 15/Tax cells too. The cotransfection of these two shRNAs synergistic- ally increased apoptosis in HCT8 and 15/Tax cells. We also found that both shRNAs had synergistic effects on decreasing cell viability in HCT8 and 15/Tax cells (Fig. 11e, Additional file 4: Figure S4C). Based on these results, YAP and COX-2 are important synergistic regulators of drug resistance in HCT8 and 15/Tax cells, which is consistent with G-4’s more potency on them than a YAP and COX-2inhibitor alone.
As a serious circumstance, prolonged labor contributes to increased perinatal loss and infant mortality and morbidity apart from causing psychological trauma to the mother. In recent decade, Spasmolytics and spasmo-analgesics combinations are frequently administered to facilitate dilatation of the cervix during delivery and to shorten first stage of labor as an attempt to speed up the process of labor. Among those, the anticholinergic spasmolytics have undesirable anticholinergic side-effects, which may leads to various pharmacological problems. Hence, Non-anticholinergic Spasmolytics are preferable choice during pregnancy now a day. The current review gives past development and the basis for selection of a significant combination of Aceclofenac, a COX-2inhibitor and Drotaverine HCl, an antispasmodic agent with non-anticholinergic action as a suitable choice to augment the labor over the other combinations.
Although basic NSAIDs such as glafenine and floctafenine are expected to be devoid of the primary insult effect, their damaging effect upon the stomach and kidney is still prominent as they inhibit prostaglandin biosynthesis as strongly as indomethacin 5-6 . The selective COX- 2inhibitor has high cardiovascular side effects, with low GI side effects, as compare to the conventional NSAID and it is proved that low dose of any drugs is always good for the health due to chances of less adverse effects. So the main objective of this
Case presentation: Herein, we report a 57-year-old woman who presented with recurrent epigastric pain and weight loss. An abdominal computed tomography scan showed an approximately 10-cm mass over the pancreatic head region and dilatation of the pancreatic duct. Tumor biopsy and bypass surgery were performed. A DT was confirmed on pathologic analysis. After resection, we prescribed treatment with the COX-2inhibitor celecoxib. The patient showed complete remission and there was no local recurrence or distant metastasis within the 24-month follow-up period.
Thus, for aliphatic amine we have used ethyl chloroacetate instead of chloroacetyl chloride as side product formed in this reaction is ethanol and not HCl , final product gets precipitated out in the reaction flask without adding it into ice cold water. The N-(Alkyl or Aryl)-2-(1H-benzotriazol-1-yl)- acetamide derivatives were synthesized by nucleophilic substitution reaction of Benzotriazole and 2-chloro-N- Alkyl/Aryl acetamides using potassium carbonate as a base in presence of DMF as a solvent. The structures of all the synthesized compounds were supported by chemical test for chloride and amide while conformation of structure was done by spectral data like FTIR, GC-MS. All N-(Alkyl or Aryl)-2-(1H-benzotriazol-1-yl)- acetamide derivatives were screened for peripheral analgesic activity by using acetic acid induced writhing test in mice. The results indicated that compound IIIb is having activity relatively similar to that of aspirin. This compound showed percent inhibition of 79.14%, which is almost similar to aspirin (79.18%), used as reference standard. Similarly, IIIg also showed interesting percent inhibition (76.78%).
We previously reported that celecoxib, a selective COX-2 NSAID, interrupted excitation contraction coupling in cardiomyocytes (Baek et al., 2010). Another recent study shows that high doses of NSAIDs alters expression of genes regulating the cell cycle, proliferation, signal transduction, DNA damage and repair, apoptosis, autophagy and the inflammatory response (Palayoor et al., 2012). Recently, a study investigated the cardiovascular side effects of celecoxib and diclofenac and their effects on vascular smooth muscle through ion channels (Brueggemann et al., 2009). Several mechanisms are involved in cardiotoxicity including stress-response proteins (heat shock cognate 71 kDa protein, mitochondrial stress 70 protein and mitochondrial heat shock protein 60), cytoskeletal proteins (myosin regulatory light chain 2 cardiac muscle isoform, tropomyosin α-1 chain, myosin light chain 3, cardiac actin isoforms, prolyl 4-hyroxylase) and proteins involved in membrane assembly (Golgi reassembly-stacking protein 2 and septin-8) (Baek et al., 2010; Bläser et al., 2002; Takahashi et al., 2002). We found similar alterations in off-target gene expression, which may contribute to previously reported cardiotoxicity. These results are consistent with a previous study based on proteomic analysis of NSAIDs-treated primary cardiomyocytes (Baek et al., 2010).
Cyclooxygenases (COX), the key enzymes involved in the metabolic conversion of arachidonic acid to pros- taglandins, consist of at least two isoforms, constitutive form of COX-1 and inducible form of COX-2. Since the overexpression of COX-2 was known to be associated with neoangiogenic, antiapoptotic, and invasive or me- tastatic property in certain cell types [7-11], COX-2 has come to the surface as a therapeutic target of several ma- lignant tumors including HCC. Several growing evi- dences of preclinical studies have indicated that COX-2 inhibitors exert antineoplastic effects on hepatoma cells both in vitro and in vivo [12-18]. However, the degree of impact of COX-2inhibitor on growth control of heap- toma cells are controversial and its growth inhibitory mechanisms remain unclear thus far.
indices were not improved after 2−week administra− tion of 25 mg, b.i.d. rofecoxib, a COX−2inhibitor . From another observation of rofecoxib admin− istration for 2 years, there was no difference in regression of intestinal metaplasia considered to be a precancerous lesion of gastric cancer, and COX−2inhibitor could not return intestinal metaplasia of gastric mucosa to normal . From these results, gastric cancer prevention should now be focused on H. pylori eradication. However, serum interleukin−8 (IL−8), tumor necrosis factor− α (TNF− α ), progastrin and gastrin level were decreased in observation before and after administration of 25 mg, b.i.d. rofe− coxib for 2 weeks in gastric cancer patients. In addi− tion, the expression level of BAX and caspase−3 increased, and the expression level of Bcl−2 and sur− vivin decreased . From these data, the above animal experiments and in vitro results, it is expect− ed that a COX−2inhibitor could be useful for gas− tric cancer treatment, and a large clinical trial must be needed.
of disturbance in the balance of thromboxanes and prostaglan- dins on platelet aggregability alone are insufficient to explain the heightened cardiovascular risk. Furthermore, the expres- sion of COX-2 on platelets and the effect on overall platelet function are still matters of controversy . In contrast, whereas healthy endothelial cells in culture express only COX- 1, COX-2 can be readily induced under conditions of vascular injury [25-27]. In this respect, the microenvironment imposed on the vessel wall may be a more important determinant of car- diovascular risk than the influences of platelet function. Fur- thermore, almost complete thromboxane inhibition must be attained before in vivo effects on platelet activation are observed and this is unlikely to be achieved with serum levels attainable with standard doses of NSAIDs [28,29]. Disruption of the integrity of atheromatous plaque architecture adds to the vulnerability for in situ thrombus formation, and it has been suggested that combined inhibition of COX-2 and TXA 2 could be detrimental to plaque stability [23,30]. Our results suggest that defective reverse cholesterol transport may be another important contributor to atheromatous plaque progression under conditions of COX-2 inhibition (Figure 9). Although the selective COX-2inhibitor NS398 is not used in humans, the concentration achieved in pigs upon intravenous administration is 30 to 50 μM, comparable to the levels used in our studies .
Our objective was to evaluate the effect of the COX-2inhibitor, celecoxib, on (1) proliferation and apoptosis in human ovarian cancer cell lines and primary cultures of ovarian cancer cells, and (2) inhibition of tumor growth in a genetically engineered mouse model of serous ovarian cancer under obese and non-obese conditions. Celecoxib inhibited cell proliferation in three ovarian cancer cell lines and five primary cultures of human ovarian cancer after 72 hours of exposure. Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis, inhibition of cellular adhesion and invasion and reduction of expression of hTERT mRNA and COX- 2 protein in all of the ovarian cancer cell lines. In the KpB mice fed a high fat diet (obese) and treated with celecoxib, tumor weight decreased by 66% when compared with control animals. Among KpB mice fed a low fat diet (non-obese), tumor weight decreased by 46% after treatment with celecoxib. In the ovarian tumors from obese and non-obese KpB mice, treatment with celecoxib as compared to control resulted in decreased proliferation, increased apoptosis and reduced COX-2 and MMP9 protein expression, as assessed by immunohistochemistry. Celecoxib strongly decreased the serum level of VEGF and blood vessel density in the tumors from the KpB ovarian cancer mouse model under obese and non-obese conditions. This work suggests that celecoxib may be a novel chemotherapeutic agent for ovarian cancer prevention and treatment and be potentially beneficial in both obese and non-obese women.
Postmortem analysis was performed to identify pathologies responsible for the observed mortality in neonates born to dams chronically treated with a COX-2inhibitor (on gestation days 15–18). Lungs, heart, kidney, liver, pancreas, spleen, thymus, intestine, and stomach of neonates from dams treated with SC-236 were indistinguishable in histological analyses from vehicle-treated controls. The only pathology observed in neonates following chronic COX-2inhibitor treatment during gestation was patent DA. Considerable variability in the duration of neonatal survival was observed following chronic treatment with SC-236 during gestation. To determine whether vari- ability in DA closure could explain the differences in survival duration, the extent of DA closure was com- pared with survival duration for neonates that died at different times during the first 48 hours after birth. Histological analysis of the DA from neonates that died during the first 24 hours after birth shows no evidence of closure (Figure 3d). Partial closure of the DA with narrowing of the DA lumen was evident in neonates that died from 24 to 48 hours after birth (Figure 3e), as compared with the completely occluded DA of neonates that survived longer than 48 hours and were sacrificed (Figure 3f). Therefore, partial closure of the DA correlated with prolonged survival up to 48 hours, whereas the complete failure of DA closure correlated with mortality during the first 24 hours after birth.
COX-2 inhibition has been shown to sensitize tumor cells to chemotherapy or radiotherapy, and appears to induce apoptosis as well, potentially by inhibiting AKT, Survivin, and other molecules responsible for cell division and survival (Jendrossek, 2013). The exact mechanisms underlying the rationale for COX-2 inhibition in cancer treatment remain unclear, as COX-independent anti-neoplastic and pro-apoptotic effects following NSAID administration have been observed (Sade, Tuncay, Cimen, Severcan, & Banerjee, 2012). This suggests that there may be promiscuous activities from either the drugs themselves or their metabolites that are partially responsible for their effects. Nevertheless, strong data from in vitro, in vivo, and clinical studies support the potential for NSAIDs, particularly the COX-2inhibitor celecoxib (Celebrex), in preventing and treating CRC (Lee et al., 2012; Pyrko et al., 2006; Nan et al., 2015; Jendrossek, 2013; Andersen & Vogel, 2014).
Tendon healing in in vitro as well as in vivo studies shows inconsistent responses to NSAIDs [23–25, 28]. For selective COX-2 inhibitors, some authors describe no effect on tendon healing . Others report the time of application as decisive factor. While early usage seems to inhibit tendon repair, selective COX-2 inhibi- tor treatment at later time points does not negatively affect tendon stability [44–46]. For example, Virchenko et al. report a damaging effect of injective Parecoxib application directly after Achilles tendon dissection. At later time points, an improvement of the mechanical properties was observed . Using our data, we can- not show evidence for the effect of late COX-2inhibitor application. However, in contrast to the current opinion, there was the tendency of increased mechanical load capacity after 3 weeks of COX-2inhibitor treatment, although this was not statistical significant (p = 0.171). Furthermore, macroscopic tendon examination and failure mode indicate a favorable effect of early COX-2inhibitor use (Table 2).
selective NSAID hypersensitivity, especially since some studies included patients with a long time interval, up to 72 hours, between intake of the culprit non selective NSAID and onset of symptoms [26,29,33]. Incorrect diagnosis of non selective NSAID hypersensitivity may consequently lead to a lower estimate of the percentage of COX-2inhibitor hypersensitivity. The majority of pa- tients in our study were also included based on a sug- gestive history. However, we used strict criteria: only patients with objective symptoms and within 5 hours after intake were included. Furthermore, 53 (58%) pa- tients had re-intake of the same culprit drug followed by a similar hypersensitivity reaction, which strongly sup- ports the diagnosis. 44 patients with a repeated reaction did not underwent a challenge with the culprit drug. In addition, the percentages of COX-2 hypersensitivity did not differ between the patients diagnosed by careful his- tory only versus those in which the diagnosis was con- firmed by challenge.
HIF-1α expression in HCC is considered to be a negative prognostic factor for clinical outcome after surgery and is associated with metastatic potential 18 . A plethora of pathways that regulate cell metabolism, proliferation, angiogenesis and metastasis are found to be regulated by HIF-1α. HIF-1α is also reported to directly induce up- regulation of vascular endothelial growth factor (VEGF) which has a major part in the process of angiogenesis 19 . Vascular endothelial growth factor (VEGF) is widely reported to be an inducer of angiogenesis. It acts as a highly specific mitogen for endothelial cells. VEGF induced signal transduction proceeds by the binding of these factors to tyrosine kinase receptors resulting in endothelial cell proliferation, migration, and angiogenesis 20 . The immunoblotting result confirms the up-regulation of HIF-1α and VEGF in the BPA treated cells whereas expressions of HIF- 1α and VEGF were found to be significantly inhibited in the BPA + Meloxicam treated cells. In the present study we found that BPA increases cell viability of cancer cells at lower concentrations and induces the overexpression of Akt, COX-2, HIF-1α and VEGF, which are generally found to aid cancer progression. The treatment with Meloxicam, a COX-2inhibitor, reduced the cell viability in HepG2 cells and treatment with Meloxicam was found to down regulate the expression of Akt, COX-2, HIF-1α and VEGF, thus, corroborating our hypothesis that BPA helps in cancer progression by up regulating the factors that link inflammation and cancer progression.
Abstract: Objective: To investigate whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can attenu- ate proliferation, migration, invasion and MMP-14 expression in pancreatic cancer cells PANC-1 and the possible anti-tumor mechanism of celecoxib. Methods: Human pancreatic cancer cell line PANC-1 cells were treated with diverse concentrations of celecoxib (20, 60, 100 μmol/L). Cell proliferation, invasion and migration capabilities were measured by MTT colorimetry, transwell invasion assay, and scratch assay separately. At the same time, the protein expression of COX-2 and MMP-14 was assessed by ELISA. Results: The capabilities of proliferation, invasion and migration in PANC-1 cells were attenuated in a concentration-dependent manner after treated with celecoxib, followed by the down-regulation of the protein expression of COX-2 and MMP-14. In addition, MMP-14 expression was significantly positively correlated with COX-2 expression. Conclusions: COX-2inhibitor celecoxib can inhibit the proliferation, invasion and migration of PANC-1 cells via down-regulating the expression of MMP-14 in a concentra- tion-dependent manner, thus contributing to its anti-tumor effect in pancreatic cancer.
Celecoxib is a selective cyclooxygenase (COX)-2inhibitor and an effective analgesic for acute postoperative pain . Although pre-operative non-selective NSAID use increases the risks of bleeding [10,17], celecoxib (1200 mg daily) has no effects on serum thromboxane or plate- let functions . Celecoxib (400 mg) also has similar analgesic effects in comparison with conventional non- selective NSAID . To achieve less postoperative pain and better rehabilitation after TKA surgery, especially in the first week, prescription of oral celecoxib preemptively for pain management of TKA patients is reasonable. Although previous studies have evaluated the analgesic efficacy of rofecoxib, few studies to date have evaluated the efficacy of celecoxib for TKA. In this study, we hypoth- esized that celecoxib provides better efficacy than the use of patient-controlled analgesic (PCA) morphine, which is currently the standard therapy in our institute. We aimed to compare the difference in the pain scores at rest and ambulation, along with range of motion (ROM), mor- phine-sparing effects, PONV, and perioperative blood loss between patients receiving celecoxib treatment and patients receiving PCA morphine treatment after TKA sur- geries.