Relationship between cyclooxygenase (COX)-2 and malignant tumors

Recently, epidemiologic studies and animal experiments have demonstrated that nonsteroidal anti-inflammatory drugs(NSAIDs) reduce the incidence of colorectal carcinoma. Cyclooxygenase(COX) is the principal target of NSAIDs. COX is the first oxidase in the process of prostaglandins(PGs) production from arachidonic acid(AA). PGs and COX enzyme may be involved in the initiation and/or the promotion of carcinogenesis because the major action of NSAIDs is the inhibition of COX. In this review, we demonstrated the expression of COX-2 in urological cancer(renal cell carcinoma, bladder tumor, prostate cancer, and testicular tumor) tissues as well as the effects of COX inhibitors.     

Origins of prostaglandin E2: involvements of cyclooxygenase (COX)-1 and COX-2 in human and rat systems

Prostaglandin (PG) E2 is a major cyclooxygenase (COX) product at inflammatory sites where it contributes to local increases in blood flow, edema formation, and pain sensitization. Using rats in vivo and rat and human blood in vitro, we have examined the roles of COX-1 and COX-2 in the production of PGE2. In anesthetized rats treated with bacterial lipopolysaccharide (LPS) to induce the expression of COX-2, the marked increase in PGE2 production that followed bolus intravenous injection of arachidonic acid (3 mg x kg(-1)) was strongly inhibited by diclofenac but largely unaffected by the COX-2-selective inhibitor DFP (5,5- dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone). In rat blood in vitro, aspirin strongly inhibited the production of PGE2 that followed either acute exposure to calcium ionophore, A23187 (calcimycin) (50 microM, 15 min), or incubation with LPS for 18 h. In contrast, human whole blood only produced significant levels of PGE2 when incubated with LPS. Rat leukocytes expressed COX-2 and produced PGE2 when exposed to LPS but not when acutely stimulated with A23187. Rat platelets, but not human platelets, also produced significant amounts of PGE2 when acutely stimulated with A23187. These data show that when exposed to an inflammatory stimulus, rat whole blood produces increased levels of PGE2 through induction of COX-2 in blood leukocytes. Rat blood, unlike human blood, may also produce copious amounts of PGE2 via the actions of COX-1 enzyme constitutively present in platelets. These data may well explain why in rats COX-2-selective inhibitors have been reported not to produce the full anti-inflammatory effects associated with standard nonsteroid anti-inflammatory drugs.     

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE2. PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.     

Role of cyclooxygenase (COX)-1 and COX-2 inhibition in nonsteroidal anti-inflammatory drug-induced intestinal damage in rats: relation to various pathogenic events

We recently reported that cyclooxygenase (COX)-2 expression was up-regulated in the rat small intestine after administration of indomethacin, and this may be a key to nonsteroidal anti-inflammatory drug (NSAID)-induced intestinal damage. In the present study, we investigated the effect of inhibiting COX-1 or COX-2 on various intestinal events occurring in association with NSAID-induced intestinal damage. Rats without fasting were treated with indomethacin, SC-560 (a selective COX-1 inhibitor), rofecoxib (a selective COX-2 inhibitor), or SC-560 plus rofecoxib, and the following parameters were examined in the small intestine: the lesion score, the enterobacterial number, myeloperoxidase (MPO) and inducible nitric-oxide synthase (iNOS) activity, and intestinal motility. Indomethacin decreased mucosal prostaglandin (PG)E2 content and caused damage in the intestine within 24 h, accompanied by an increase in intestinal contractility, bacterial numbers, and MPO as well as iNOS activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither SC-560 nor rofecoxib alone caused intestinal damage, but their combined administration produced lesions. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion, and COX-2 as well as iNOS mRNA expression, yet the iNOS and MPO activity was increased only when rofecoxib was also administered. Although SC-560 inhibited the PG production, the level of PGE2 was restored 6 h later, in a rofecoxib-dependent manner. We conclude that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion, and iNOS expression, up-regulates the expression of COX-2, and the PGE2 produced by COX-2 counteracts deleterious events, and maintains the mucosal integrity. This sequence of events explains why intestinal damage occurs only when both COX-1 and COX-2 are inhibited.     

Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: possible physiological and therapeutic implications

Summary— The discovery of an inducible isoform of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic and side effects of non-steroidal anti-inflammatory drugs (NSAIDs). Indeed, new pharmacological results suggest that COX-2 inhibition provides the therapeutic (ie, anti-inflammatory) activity of NSAIDs, whereas inhibition of constitutive COX-1 is responsible for their gastric and renal side effects as well as for their antithrombotic activity. However, a role of COX-1 in inflammation cannot be excluded. Furthermore, the functional relevance of COX-2 expression and induction in various tissues warrants further investigation. These studies should help in predicting potential adverse effects as well as new indications for selective COX-2 inhibitors.     

Cyclooxygenase (COX)-1 and COX-2 participate in 5,6-epoxyeicosatrienoic acid-induced contraction of rabbit intralobar pulmonary arteries

Epoxyeicosatrienoic acids (EETs) have been reported to contract intralobar pulmonary arteries (PA) of the rabbit in a cyclooxygenase (COX)-dependent manner. In the present study, we observed that COX-1 and COX-2 isoforms were expressed in freshly isolated PA of healthy rabbits. We examined the hypothesis that both COX isoforms participate in 5,6-EET-induced contraction of rabbit intralobar PA. Selective inhibition of COX-1 with 300 nM 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) prevented 5,6-EET (1x10(-8)-1x10(-5) M)-induced contractions of isolated intralobar rabbit PA rings in a manner similar to that observed with the nonselective cyclooxygenase inhibitor indomethacin at 10 microM. Selective inhibition of COX-2 with either 100 nM 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl) thiophene (DUP-697) or 3 microM N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) shifted the EC50 value of 5,6-EET-induced PA contraction to the right but with considerably lower efficacy than SC-560. In rabbit PA, 5,6-EET-induced contraction was primarily dependent on COX-1 activity. Differential metabolism of 5,6-EET by COX-1 and COX-2 does not explain the primary dependence of PA contraction on COX-1 activity because 5,6-EET was metabolized similarly by both COX isoforms. COX-1 and -2 were expressed primarily in PA endothelium where COX-1 expression was dense and uniform, whereas COX-2 expression was sparse and nonuniform. 5,6-EET-induced PA contraction was endothelium-dependent. These results suggest that 5,6-EET-induced contraction is primarily dependent on COX-1 activity.     

4,5-Diaryloxazole inhibitors of cyclooxygenase-2 (COX-2)

A series of methysulfonyl or sulfonamido substituted 4,5-diaryloxazole were prepared and evaluated for their ability to inhibit the inducible form of cyclooxygenase (COX-2) in vitro and in vivo. Several unique substitution patterns were identified that led to potent and selective inhibitors of COX-2. In general, 2-trifluoromethly-4,5-diaryloxazoles substituted with a methylsulfonyl or sulfonamido group were particularly potent inhibitors. One of the more potent compounds with a selectivity for COX-2 of about 800 fold was 4b (SC-299). SC-299, a highly fluorescent molecule, may be useful for spectroscopic studies on preferential inhibitor binding to COX-2.     

Selective cyclooxygenase-2 (COX-2) inhibitors: importance and limitations

The discovery of an inducible form of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic effects and side-effects of non-steroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have demonstrated in clinical trials a significantly better gastrointestinal tolerability than classical NSAIDs, for the same anti-inflammatory activity. Their tolerability in patients with active ulcer or with a recent history of ulcer as well as in patients suffering from cardiovascular or renal diseases has still to be investigated in detail. Their therapeutic potential in several new indications, including pre-term labour, colorectal cancer and Alzheimer's disease, is currently being investigated.     

COX-2、VEGF在腹腔粘连组织中的表达及其意义

目的 检测环氧化酶2(cyclooxygenase 2,COX-2)和血管内皮生长因子(vascular endothelial growth factor,VEGF)在腹腔粘连组织中的表达,探讨其与腹腔粘连的关系.方法 采用免疫组化SP法检测40例腹腔粘连患者粘连组织中COX-2和VEGF的表达水平.结果 粘连组织中COX-2和VEGF高表达的阳性率分别为72.5%、65%.COX-2和VEGF的表达均与患者的性别、年龄、防粘连剂的使用无显著相关性,而随粘连程度的增加而增加,且差异有统计学意义(P<0.05);COX-2的高表达与手术时间间隔无显著相关性,而VEGF的高表达与粘连程度及手术时间间隔显著相关(P<0.05);COX-2和VEGF表达之间具有相关性(r=0.605,P<0.01).结论 COX-2和VEGF在粘连组织存在高表达,为粘连组织的形成提供有利条件,可作为腹腔粘连中重要生物学指标和治疗靶点.     

Isolation,identification and molecular docking as cyclooxygenase (COX) inhibitors of the main constituents of Matricaria chamomilla L. extract and its synergistic interaction with diclofenac on nociception and gastric damage in rats

Chamomile (Matricaria chamomilla L., Asteraceae) is a medicinal plant widely used as remedy for pain and gastric disorders. The association of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase its antinociceptive activity, permit the use of lower doses and limit side effects. The aim was to isolate and identify the main chemical constituents of Matricaria chamomilla ethanolic extract (MCE) as well as to explore their activity as cyclooxygenase (COX) inhibitors in silico; besides, to examine the interaction between MCE and diclofenac on nociception in the formalin test by isobolographic analysis, and to determine the level of gastric injury in rats. Three terpenoids, α-bisabolol, bisabolol oxide A, and guaiazulene, were isolated and identified by ¹H NMR. Docking simulation predicted COX inhibitory activity for those terpenoids. Diclofenac, MCE, or their combinations produced an antinociceptive effect. The sole administration of diclofenac and the highest combined dose diclofenac-MCE produced significant a gastric damage, but that effect was not seen with MCE alone. An isobologram was constructed and the derived theoretical ED₃₅ for the antinociceptive effect was significantly different from the experimental ED₃₅; hence, the interaction between diclofenac and MCE that mediates the antinociceptive effect is synergist. The MCE contains three major terpenoids with plausible COX inhibitory activity in silico, but α-bisabolol showed the highest affinity. Data suggest that the diclofenac-MCE combination can interact at the systemic level in a synergic manner and may have therapeutic advantages for the clinical treatment of inflammatory pain.     

The pharmacology and therapeutic relevance of endocannabinoid derived cyclo-oxygenase (COX)-2 products

The discovery of anandamide and 2-arachidonyl glycerol (2-AG) as naturally occurring mammalian endocannabinoids has had important and wide-reaching therapeutic implications. This, to a large extent, ensues from the complexity of endocannabinoid biology. One facet of endocannabinoid biology now receiving increased attention is the cyclo-oxygenase-2 (COX-2) derived oxidation products. Anandamide and 2-AG are oxidized to a range of PG-ethanolamides and PG-glyceryl esters that closely approaches that of the prostaglandins (PGs) formed from arachidonic acid. The pharmacology of these electrochemically neutral PG-ethanolamides (prostamides) and PG-glyceryl esters appears to be unique. No meaningful interaction with natural or recombinant prostanoid receptors is apparent. Nevertheless, in certain cells and tissues, prostamides and PG-glyceryl esters exert potent effects. The recent discovery of selective antagonists for the putative prostamide receptor has been a major advance in further establishing prostamide pharmacology as an entity distinct from prostanoid receptors. Since discovery of the prototype prostamide antagonist (AGN 204396), rapid progress has been made. The latest prostamide antagonists (AGN 211334-6) are 100 times more potent than the prototype and are, therefore, sufficiently active to be used in living animal studies. These compounds will allow a full evaluation of the role of prostamides in health and disease. To date, the only therapeutic application for prostamides is in glaucoma. The prostamide analog, bimatoprost, being the most effective ocular hypotensive drug currently available. Interestingly, PGE(2)-glyceryl ester and its chemically stable analog PGE(2)-serinolamide also lower intraocular pressure in dogs. Nevertheless, the therapeutic future of PGE(2)-glyceryl ester is more likely to reside in inflammation.     

The choice of selective COX-2 inhibitors

Non-steroidal anti-inflammatory drug (NSAID) has been widely prescribed as a useful antifebrile or painkiller. But, gastrointestinal injury as a side effect of NSAIDs has been a big social probrem. NSAID-induced gastric damage has been shown to be induced by the inhibition of both cyclooxygenase (COX)-1 and 2. Thus, selective COX-2 inhibitors are expected to induce less gastric injury and to be safe as compared to traditional NSAIDs. But in certain situations such as gastric ulcer or H. pylori-induced gastritis, selective COX-2 inhibitors may delay ulcer healing or repair processes. Previous reports have shown that COX-2 inhibitors increase cardiovascular (CV) events as compared with placebo and recent studies further suggest that all NSAIDs might also be involved in increases in CV events. Therefore, any NSAIDs must be carefully used when they are prescribed for patients with CV risks.     

Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception

The present study is the first to investigate the participation of central cyclooxygenase (COX) pathways in modulating the antinociceptive effects of intracisternally administered cannabinoid on nociception induced by inflammation of the temporomandibular joint (TMJ) in freely moving rats. Following intra-articular injection of 5% formalin in the TMJ, nociceptive scratching behavior was recorded for nine successive 5-min intervals in Sprague-Dawley rats. Intracisternal injection of 30 microg of WIN 55,212-2, a synthetic non-subtype-selective CB1/2 agonist, administered 20 min prior to formalin injection significantly reduced the number of scratches and duration of scratching induced by formalin compared with the vehicle-treated group. Antinociceptive effect of WIN 55,212-2 was blocked by intracisternal injection of 10 microg of AM251, a CB1 receptor-selective antagonist, but not by AM630, a CB2 receptor-selective antagonist. A 10 microg dose of WIN 55,212-2 that was ineffective in producing antinociception became effective following intracisternal administration of NS-398, a selective COX-2 inhibitor; indomethacin, a non-selective COX 1/2 inhibitor; acetaminophen, a putative COX-3 inhibitor, but not following pretreatment with the selective COX-1 inhibitor, SC-560. The ED(50) value of WIN 55,212-2 in the NS-398-treated group was significantly lower than that in the vehicle-treated group. Importantly, administration of low doses of COX inhibitors alone did not attenuate nociception. These results indicate that inhibition of central COX pathways, presumably via COX-2 inhibition, reduces inflammatory pain by enhancing the cannabinoid-induced antinociceptive effect. Based on our observations, combined administration of cannabinoids with COX inhibitors may hold a therapeutic promise in the treatment of inflammatory TMJ pain.     

局灶性鼠脑缺血脑组织环氧酶-2的表达与细胞凋亡的关系

目的探讨环氧酶-2蛋白与细胞DNA损伤的关系 .方法采用大鼠大脑中动脉阻塞脑缺血模型,应用HE染色观察缺血损伤的演变,免疫组化染色观察环氧酶-2蛋白的表达 ,DNA末端标记法(TUNEL)法观察细胞DNA损伤.结果环氧酶-2蛋白的表达与TUNEL阳性细胞在时程上一致,解剖部位上重叠.结论环氧酶-2是诱导细胞凋亡的重要因素,脑缺血后环氧酶 -2的高度表达促进了梗死范围的扩大.     

COX-2-selective inhibitors in the treatment of arthritis

Therapy with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has long been the cornerstone of pharmacologic management of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Many patients with OA or RA, however, are at increased risk of developing clinically significant adverse events associated with NSAID therapy, particularly upper gastrointestinal (GI) complications including symptomatic and complicated ulcers. The introduction of cyclooxygenase (COX)-2-selective inhibitors (coxibs) represents a major advance in the pharmacologic approach to the signs and symptoms of arthritis. In addition to the first two members of this class, celecoxib and rofecoxib, other coxibs have been introduced or are in development (valdecoxib, etoricoxib). In numerous clinical trials, coxibs have been shown to be as effective as nonselective NSAIDs in relieving pain and inflammation associated with OA and RA, and notably, with a significantly lower risk of NSAID-type adverse events. The use of coxibs to treat OA and RA is recommended as first-line therapy when symptoms of pain and inflammation are present in patients vulnerable to potential NSAID-associated GI toxicity.