Is COX-2 a ‘collateral’ target in cancer prevention?

2005 ◽  
Vol 33 (4) ◽  
pp. 724-727 ◽  
Author(s):  
K. Kashfi ◽  
B. Rigas
Keyword(s):  
Cancer Prevention ◽  
Malignant Lesion ◽  
Aberrant Crypt Foci ◽  
Cardiovascular Side Effects ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
In Vitro Data ◽  
Modest Effect

NSAIDs (non-steroidal anti-inflammatory drugs) prevent colon and other cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug-developmental work focusing on COX (cyclo-oxygenase) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, one COX-2 inhibitor has been withdrawn from the market because of cardiovascular side effects, and there are concerns about a class effect. Evidence suggests that COX-2 may not be the only, or the ideal, target for cancer prevention; for example, COX-2 is not expressed in human aberrant crypt foci, the earliest recognizable pre-malignant lesion in the colon; COX-2 is expressed in less than half of the adenomas; in vitro data show that NSAIDs do not require the presence of COX-2 to prevent cancer; in familial adenomatous polyposis, the COX-2 inhibitor, celecoxib, had a modest effect, which was weaker than that of a traditional NSAID; and COX-2-specific inhibitors have several COX-2-independent activities, which may account for part of their cancer-preventive properties. The multiple COX-2-indpendent targets, and the limitations of COX-2 inhibitors, suggest the need to explore targets other than COX-2.

Cyclooxygenase inhibitors

2013 ◽  
pp. 588-599
Author(s):  
Burkhard Hinz ◽  
Kay Brune
Keyword(s):  
Pain Treatment ◽  
Cyclooxygenase Inhibitors ◽  
Current Debate ◽  
Cox Inhibitors ◽  
Cardiovascular Side Effects ◽  
Gastrointestinal Tolerability ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Cyclooxygenase (COX) inhibitors are widely used to relieve musculoskeletal pain. COX inhibitors are a group of heterogenous substances including non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen). Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with improved gastrointestinal tolerability as compared with conventional NSAIDs have been established for symptomatic pain treatment in recent years. This chapter addresses the pharmacology of all of these drugs with particular emphasis on their rational use based on their diverse pharmacokinetic characteristics and adverse drug reaction profiles. Referring to the current debate, cardiovascular side effects associated with the long-term use of COX-2 inhibitors and NSAIDs as well as novel insights into the safety profile of paracetamol are discussed.

New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity

2018 ◽  
Vol 18 (2) ◽  
pp. 295-301 ◽  
Author(s):  
Shabnam Farzaneh ◽  
Elnaz Zeinalzadeh ◽  
Bahram Daraei ◽  
Soraya Shahhosseini ◽  
Afshin Zarghi
Keyword(s):  
Cell Lines ◽  
Inhibitory Activity ◽  
Fibroblast Cell ◽  
Breast Cancer Cell Lines ◽  
Ferrocene Derivatives ◽  
Cox 2 ◽  
Cytotoxicity Effects ◽  
Cox 2 Inhibitors ◽  
Mcf 7

Background: Due to the astonishing properties of ferrocene and its derivatives, it has a broad application in diverse areas. Numerous ferrocene derivatives demonstrated anti-proliferative activity. Also COX-2, as a key isoenzyme for production of prostaglandins, is frequently overexpressed in various cancers. It is now recognized that COX-2 over expression promotes tumorigenic functions which can be suppressed by COX-2 inhibitors, a phenomenon useful for the preventing of tumor progression. The combination of COX-2 inhibitors with other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Objective: Owing to high anticancer potential of ferrocene derivatives and considerable COX-2 inhibitory and cytotoxicity effects of our previously synthesized chalcones, we decided to incorporate the ferrocenyl moiety into appropriate COX-2 inhibitor chalcone based scaffold, to evaluate COX-2 inhibitory activity as well as anticancer activities. Methods: Chalcones were synthesized via clasien-schmidt condensation of methylsulfonyl aldehyde and acetyl ferrocene. Further different amines with solvent free and ultra sound condition were reacted with chalcones to have different 1-ferrocenyl-3-amino carbonyl compounds. Docking study was carried out with Auto Dock vina software. All the newly-synthesized compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity using chemiluminescent enzyme assays as well as cytotoxicity activity against MCF-7 and T47D and fibroblast cell lines by MTT assay. Results: In vitro COX-1/COX-2 inhibition studies demonstrated that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.05-0.12 µM range, and COX-2 selectivity indexes (SI) in the 148.3-313.7 range. These results indicated that either potency or selectivity of COX-2 inhibitory activity was affected by the nature and size of the substituents on C-3 of propane-1-one. Also anti-proliferative and toxicity activities of synthesized compounds against breast cancer cell lines MCF-7 and T47D and fibroblast cell lines showed that the synthesized compounds had mild to moderate cytotoxicity against MCT7 and T47D breast cancer cell lines at 10 µM concentration. In vitro COX-1/COX-2 inhibition studies and anticancer activity against MCF-7, identified 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one as a potent compound (IC50 COX-2 = 0.05 µM, MCF-7: % inhibition (at concentration of 10 µM) = 32.7%), and also 1-ferrocenyl-3- (propan-1-amine)-3-(4-methylsulfonylphenyl) propan-1-one showed the most selectivity on COX-2 inhibition (selectivity index= 313.7). Conclusion: A novel group of ferrocene compounds, possessing a methyl sulfonyl COX-2 pharmacophore were synthesized to investigate the effect of different substituents on selectivity and potency of COX-2 inhibitory activity and their cytotoxicity effects. This study indicates that 1-ferrocenyl-3-amino carbonyl compounds having ferrocene motif and methyl sulfonyl COX-2 pharmacophore is a suitable scaffold to design COX-2 inhibitors and anti-cancer agents.

The role of celecoxib as a potential inhibitor in the treatment of inflammatory diseases - a review

2021 ◽  
Vol 28 ◽  
Author(s):  
Josiane Viana Cruz ◽  
Joaquín María Campos Rosa ◽  
Njogu Mark Kimani ◽  
Silvana Giuliatti ◽  
Cleydson Breno Rodrigues dos Santos
Keyword(s):  
Side Effects ◽  
Inflammatory Diseases ◽  
Structural Basis ◽  
Potential Inhibitor ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

: This article presents a simplified view of celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) has, predominantly, two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role that is related to homeostatic effects in renal and platelets, while the latter is mainly responsible for induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and without side effects. To this end, of the generation of non-steroidal anti-inflammatory drugs from “coxibs”, celecoxib is the only potent selective COX-2 inhibitor that is still commercially available. Thus, the compound celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for COX-2 enzyme. In this review, we provide highlights where such inhibition should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs) which act as COX-2 inhibitors with lesser side effects on the human body.

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

1999 ◽  
Vol 276 (3) ◽  
pp. R913-R921 ◽  
Author(s):  
Ronald I. Clyman ◽  
Pierre Hardy ◽  
Nahid Waleh ◽  
Yao Qi Chen ◽  
Françoise Mauray ◽  
...  
Keyword(s):  
Significant Role ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Fetal Lamb ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

scholarly journals COX-2: A Pivotal Enzyme in Mucosal Protection and Resolution of Inflammation

2006 ◽  
Vol 6 ◽  
pp. 577-588 ◽  
Author(s):  
John L. Wallace
Keyword(s):  
Digestive System ◽  
Intestinal Inflammation ◽  
Mucosal Protection ◽  
Cox Inhibitors ◽  
Gastrointestinal Injury ◽  
Inflammatory Drugs ◽  
Long Term Consequences ◽  
Cox 2 ◽  
Cox 2 Inhibitors

The discovery of a second form of cyclooxygenase, COX-2, led to a burst of research aimed at the development of nonsteroidal anti-inflammatory drugs that would not damage the gastrointestinal tract. In the years since, this promise has only been partially fulfilled. Selective COX-2 inhibitors cause less gastric damage than conventional, nonselective COX inhibitors, but their use is still associated with significant gastrointestinal injury, and with toxicity in the renal and cardiovascular systems. COX-2 is now recognized as a source of mediators that produce many beneficial and detrimental effects in the digestive system. In this review, the roles of COX-2 in mucosal defense and injury are discussed. Furthermore, contributions of COX-2–derived products to the long-term consequences of intestinal inflammation, including cancer, are reviewed.

Involvement of cyclooxygenase 2 (COX-2) in intrinsic tone of isolated guinea pig

1995 ◽  
Vol 73 (11) ◽  
pp. 1561-1567 ◽  
Author(s):  
L. Charette ◽  
C. Misquitta ◽  
J. Guay ◽  
D. Riendeau ◽  
T. R. Jones
Keyword(s):  
Guinea Pig ◽  
Time Course ◽  
Cyclooxygenase 2 ◽  
Maximal Response ◽  
Pharmacological Agents ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Indomethacin and related nonsteroidal anti-inflammatory drugs relax prostanoid-dependent intrinsic tone of isolated guinea pig trachea by inhibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX-2) was discovered, which differed from COX-1 with respect to protein structure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselectively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibitor of COX-2. In the present study we compared the activity of a selective (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrinsic tone of isolated guinea pig trachea. NS-398 ≥ indomethacin produced a reversal of intrinsic tone with a similar concentration-dependent (10 nM to 1 μM) time course (Tmax approximately 20–45 min), potency (EC50 1.7 and 5.6 nM, respectively), and maximal response. Contractions to cholinergic nerve stimulation (45 V, 0.5 ms, 0.1–32 Hz) and histamine were similarly modulated in tissues relaxed with the selective or nonselective COX-2 inhibitors. Immunoblot analyses showed that COX-2 protein synthesis was induced in both the cartilage and smooth muscle portions of the trachea during changes in intrinsic tone. These findings are consistent with pharmacological results and provide the first demonstration that prostanoid tone in isolated guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likely related to COX-2 inhibition.Key words: cyclooxygenase 2, relaxation, guinea pig trachea, cyclooxygenase 1.

scholarly journals Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors

2020 ◽  
Vol 21 (24) ◽  
pp. 9623
Author(s):  
Łukasz Szczukowski ◽  
Edward Krzyżak ◽  
Adrianna Zborowska ◽  
Patrycja Zając ◽  
Katarzyna Potyrak ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Studies ◽  
One Pot ◽  
Design Synthesis ◽  
Biological Studies ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Dna Strand ◽  
Cox 2 Inhibitors

The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b–6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.

Does a coxib-associated thrombotic risk limit the clinical use of the compounds as analgesic, antiinflammatory drugs?

2006 ◽  
Vol 96 (10) ◽  
pp. 413-416 ◽  
Author(s):  
Thomas Hohlfeld ◽  
Sebastian Harder ◽  
Artur-Aron Weber
Keyword(s):  
Clinical Practice ◽  
Therapeutic Option ◽  
Benefit Assessment ◽  
Clinical Use ◽  
Antiinflammatory Drugs ◽  
Thrombotic Risk ◽  
Risk Benefit Assessment ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors

SummaryThe issue of the risk-benefit assessment of cyclooxygenase-2 (COX-2) inhibitors, as compared to traditional non-steroidal anti-inflammatory drugs (tNSAIDs), is far from being resolved. These compounds need to be carefully re-evaluated in order to avoid hasty conclusions, as it happened when COX-2 inhibitors were introduced into clinical practice. Several arguments support the concept, that COX-2 inhibitors remain a valuable therapeutic option at least for selected patients.

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