New insights into COX-2 biology and inhibition

Brain Research Reviews 48 (2005) 352 – 359 www.elsevier.com/locate/brainresrev

Review

New insights into COX-2 biology and inhibition Paola Patrignani*, Stefania Tacconelli, Maria Gina Sciulli, Marta L. Capone Department of Medicine and Center of Excellence on Aging, bG.d’AnnunzioQ University, School of Medicine, and Fondazione Universitaria bGabriele d’AnnnunzioQ, Ce.S.I., Via dei Vestini 31, 66013, Chieti, Italy Accepted 9 December 2004 Available online 2 February 2005

Abstract It is now established that prostanoids play important roles in many cellular responses and pathophysiologic processes including modulation of the inflammatory reaction, erosion of cartilage and juxtaarticular bone, gastrointestinal cytoprotection and ulceration, angiogenesis and cancer, hemostasis and thrombosis, renal hemodynamics, and progression of kidney disease. The initial step in the formation of prostanoids, i.e., the conversion of free arachidonic acid (AA) to prostaglandin (PG)G2 and then to PGH2, is controlled by two PGH synthases (COX-1 and COX-2). Selective inhibitors of COX-2 (coxibs) have established efficacy in the treatment of pain and inflammation comparable to that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) but exhibit enhanced gastrointestinal safety. Several lines of evidence suggest a critical role of COX-2 expression in cancer and selective COX-2 inhibitors may represent novel chemopreventive tools. Moreover, it has been suggested that COX-2 inhibitors may contribute to maintain high levels of chemotherapeutics in tumor tissues by preventing the overexpression of the multidrug resistance protein MDR1/P-gp. The place of COX-2 inhibitors in neurological diseases continues to attract basic and clinical investigation. The possible involvement of COX-2 in neurodegeneration, substained by the results of epidemiological studies with nonselective NSAIDs, has not been confirmed by the results of initial clinical trials with coxibs in Alzheimer’s disease. Recently, the involvement of COX-2 in endogenous cannabinoid system has been suggested. Interestingly, COX-2-mediated oxygenation of arachidonylethanolamide (anandamide, AEA) and 2-arachidonylglycerol (2-AG) provides diverse sets of novel lipids that are structurally related to prostaglandins. D 2004 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Degenerative disease: Alzheimer’s—neuropharmacology and neurotransmitters Keywords: Prostanoids; COX-2; Coxibs; Neurodegeneration; Inflammation

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . 2. First-generation of COX-2 inhibitors. . . . . . . . . 3. Second-generation of COX-2 inhibitors . . . . . . . 4. COX-2 and cancer . . . . . . . . . . . . . . . . . . 5. COX-2 and neurological disease . . . . . . . . . . . 6. COX-2-dependent metabolism of endocannabinoids . 7. Perspectives . . . . . . . . . . . . . . . . . . . . . 8. Note added in proof . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Fax: +39 0871 3556775. E-mail address: [email protected] (P. Patrignani). 0165-0173/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2004.12.024

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1. Introduction Prostanoids are ubiquitous lipid mediators that coordinate a wide variety of physiologic and pathologic processes via membrane receptors on the surface of target cells [18]. Under physiologic conditions, prostanoids play an important role in the cytoprotection of the gastric mucosa, hemostasis, and renal hemodynamics. Prostanoid biosynthesis is induced in different pathologic conditions, including inflammation and cancer [9,17,37,45]. Prostanoids are formed by arachidonic acid (AA) following its mobilization from the sn-2 position of membrane phospholipids by different stimuli (Fig. 1). Since the early 1990s, it has been appreciated that two cyclooxygenase (COX) enzymes, COX-1 and COX-2, are responsible for the production of prostaglandin (PG) H2, the rate-limiting step in prostanoid biosynthesis. The expression of the two COX isozymes is differently regulated: COX-1 gene exhibits the features of a housekeeping gene whereas the gene for COX-2 is a primary response gene with many regulatory sites [45]. Recently, it has been suggested that there is another COX protein formed as a splice variant of COX-1 [7], named COX-3. COX-3 is made from the COX-1 gene but retains intron 1 in its

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mRNA; it was initially reported to be expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed [7]. Although canine COX-3 expressed by transfected insect cells can be inhibited by therapeutic concentrations of analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, recently, it has been reported that this COX-1 variant is not expressed in human, rat, or mouse as the corresponding additional intron 1 sequence in the mRNA transcript spans 94 (human) or 98 (rat and mouse) nucleotides, thus shifting the coding sequence out of frame [11,43]. Prostanoid biosynthesis is inhibited by nonsteroidal antiinflammatory drugs (NSAIDs) that are widely prescribed as analgesics and anti-inflammatory agents. Their mechanism of action includes inhibition of both the COX-1 and COX-2 isoenzymes [26,28,37,38] (Fig. 2). COX-2, but not COX-1, is characterized by an accessible side pocket that is an extension to the hydrophobic channel [44,48]. The inhibition of COX-2 is thought to mediate the therapeutic actions of NSAIDs, while the inhibition of COX-1 results in unwanted side-effects, particularly at the gastrointestinal (GI) tract (Fig. 2) [17,37,56]. In fact, COX-1 is the major COX isoform expressed in platelets and gastric mucosa of normal humans. NSAID toxicity in the GI mucosa leading to ulceration, bleeding, perforation, and obstruction is the result of inhibition of COX-1 activity in platelets that increases the tendency of bleeding and in gastric mucosa where prostanoids play an important role in protecting the stomach from erosion and ulceration [17,37,56]. However, this simplified paradigm of constitutive COX-1 and inducible COX-2 has many exceptions: COX-1 can be regulated during development [41,45], whereas COX-2 is constitutively expressed in the brain [59], reproductive tissues [21] and kidney [15,19].

2. First-generation of COX-2 inhibitors

Fig. 1. Pathway of prostanoid biosynthesis and their specific receptors. Arachidonic acid (AA), a 20-carbon fatty acid containing four double bonds, is released from the sn2 position in membrane phospholipids by phospholipases and is metabolized enzymatically into the prostanoids, i.e., prostaglandin(PG)E2, PGF2a, PGD2, prostacyclin (PGI2), and thromboxane(TX)A2. The coordinate activity of 3 consecutive enzymatic steps is involved in prostanoid biosynthesis: (1) the release of AA from membrane phospholipids carried out by phospholipase A2, (2) the transformation of AA to the unstable endoperoxide PGH2 by PGH-synthases (COX-1 and COX2), and (3) its metabolization to the different prostanoids by isomerases which have different structures and exhibit a cell- and tissue-specific distribution. The different prostanoids activate specific cell-membrane receptors that belong to the G-protein-coupled rhodopsin-type family.

The discovery of COX-2 [28,58] has provided the rationale for the development of a new class of NSAIDs, denominated coxibs, with the aim of reducing the GI toxicity associated with the administration of nonselective NSAIDs, by virtue of COX-1 sparing [17,37,56] (Fig. 2). The first selective COX-2 inhibitors approved by FDA and EMEA for the treatment of rheumatoid arthritis (RA), osteoarthritis (OA), and for relief of acute pain associated with dental surgery and primary dysmenorrhea, rofecoxib and celecoxib, are diaryleterocyclic derivatives containing a phenylsulphone and a phenylsulphonamide moiety (Table 1), respectively, that interact with COX-2 side-pocket through slow, tight-binding kinetics [26,37]. Sparing of COX-1 is presumably involved in halving the incidence of GI perforation, GI hemorrhage, or symptomatic peptic ulcer in patients with RA treated with rofecoxib vs. naproxen in a large randomized, double-blind GI outcomes study (the VIGOR study) [3]. In contrast, detectable

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Fig. 2. Pharmacological effects of COX-1 and COX-2 inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) in different sites. GI, gastrointestinal; GFR, glomerular filtration rate; RBF, renal blood flow; PGI2, prostaglandin I2.

inhibition of COX-1 by celecoxib at 800 mg/day (51) (i.e., 2-fold higher than the maximal chronic dose recommended in RA) may have contributed, at least in part, to its failure in reducing the incidence of GI end-points vs. diclofenac or ibuprofen administered to OA patients in the CLASS study [20,44]. Table 1 Pharmacodynamic and pharmacokinetics of coxibs

3. Second-generation of COX-2 inhibitors Novel COX-2 inhibitors with improved biochemical selectivity over that of commercially available coxibs have been recently developed, i.e., etoricoxib [36], valdecoxib [33], parecoxib (the prodrug of valdecoxib, it is the first

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injectable COX-2 inhibitor) [52], and lumiracoxib [49,51]. As shown in Table 1, they are characterized by different pharmacodynamic and pharmacokinetic features. Whether this will translate into different clinical efficacy and safety profile remains to be verified in comparative clinical trials. Highly selective COX-2 inhibitors may have the potential advantage to lead to a clear-cut separation of COX-2- from COX-1-dependent effects by virtue of maximizing the likelihood of exposed patients being in the 80–100% range of COX-2 inhibition and in the 0–20% range of COX-1 inhibition throughout the dosing interval [17,37]. This will translate into reduced probability of experiencing a clinically relevant inhibition of platelet COX-1 even in the presence of the reported intersubject pharmacodynamic and pharmacokinetic variability in response to coxibs [30]. The potential use of highly selective COX-2 inhibitors at supratherapeutic doses, to improve clinical efficacy, is limited by the apparent dose-dependence of renal side-effects reported for rofecoxib and celecoxib [10,16]. The improved GI safety profile of the novel selective COX-2 inhibitors vs. nonselective NSAIDs, extrapolated from clinical efficacy trials [6,49,51], should be confirmed in large-size randomized clinical trials with serious upper GI events as primary end-points. Recently, the results of the TARGET study designed to evaluate the safety and efficacy of lumiracoxib 400 mg once daily compared with ibuprofen 800 mg t.i.d. and naproxen 500 mg b.i.d. in 18,000 patients with OA over 12 months, have shown that the selective COX2 inhibitor is associated with improved gastrointestinal safety compared with nonselective NSAIDs, but this benefit is countered by the coadministration of low-dose aspirin [42].

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COX-2 inhibition reverses the tumor-induced increase in the immunosuppressive cytokine IL-10 from lymphocytes and macrophage and the suppression of the production of macrophage immune activator cytokine IL-12 [50]. COX-2 may be involved in the resistance of tumors to chemotherapeutic drugs through the enhancement of expression of the ATP binding cassette (ABC) transporter MDR1, also termed P-glycoprotein (P-gp) [47]. Recently, it has been reported that in patients with gastric cancer, high levels of COX-2 and inducible PGE synthase (mPGES1) are associated with enhanced expression of P-gp and Bcl-xL (an anti-apoptotic protein) [32]. Thus, the use of COX-2 inhibitors might decrease resistance of tumors to chemotherapeutic drugs [35,47]. These studies suggest that NSAIDs and selective COX-2 inhibitors are promising as anticancer drugs. Several clinical trials with coxibs are ongoing to verify their clinical efficacy in this setting [54]. Celecoxib has been approved for the treatment of familiar adenomatous polyposis (FAP) by the US FDA on the basis of its superiority to placebo in causing polyp regression [48]. However, many questions remain still open. In fact, both population-based and randomized studies have shown a protection associated with aspirin doses and dosing intervals recommended for the anti-thrombotic therapy that are inconsistent with COX-2 inhibition. This raises the intriguing possibility that permanent inactivation of platelet COX-1 restores antitumor reactivity. Whether COX-2 inhibition offers any advantage over inhibition of COX-1 or of both isozymes together, it should be verified in head-to-head comparative clinical trials.

5. COX-2 and neurological disease 4. COX-2 and cancer Several lines of evidence suggest the critical role of COX2 in tumorigenesis [5,12,14,39]. In mouse and human adenomatous polyps of the colon, the earliest expression of COX-2 is detected in stromal cells, but in several types of cancers, COX-2 is found in multiple cells, i.e., epithelial, endothelial, stromal, and inflammatory cells [39]. Metastatic tumors in bone and various other organs express COX-2 in metastatic cells and surrounding cells of tumor [39]. Angiogenesis, the development of new blood vessels, is an essential step in the growth of tumors, since the growth of the malignant cells is limited by the availability of nutrients. COX-2 inhibitors have been shown to block neovascularization and COX-2 may enhance basic fibroblast cell growth factor-induced angiogenesis through induction of vascular endothelial growth factor in a rat sponger implant model [29]. Several lines of evidence suggest that COX-2 overexpression in tumor cells is associated with inhibition of apoptosis and that COX-2 inhibitors induce the apoptotic response. In addition, it is known that PGE2 can have immunosuppressive properties allowing tumor to escape host surveillance mechanisms [39]. It has been reported that

The neuropathologic features of Alzheimer’s disease (AD) include the accumulation of microglia around plaques, a local cytokine-mediated acute-phase response, and activation of the complement cascade [1]. This inflammatory response may damage neurons and exacerbate the pathologic processes underlying the disease [4,31]. A large number of epidemiological studies have indicated that the use of NSAIDs may prevent or delay the clinical features of AD [55]. Moreover, a large epidemiologic study using computerized medical records to accurately indicate drug use in subjects who had taken NSAIDs for a cumulative period of 24 months or more evidenced that the use of NSAIDs sharply reduces AD risk [55]. Since COX-2 expression in the brain and PGE2 content in the cerebrospinal fluid have been reported to be elevated in AD together with the finding that COX-2 protein levels in the brain correlate with the severity of amyloidosis and clinical dementia, it has been suggested that COX-2 inhibition by NSAIDs might be involved in the apparent protection in this setting. However, the results of the a recent randomized, double-blind clinical trial of rofecoxib vs. naproxen have failed to demonstrate a significant slowing of cognitive decline in patients with

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mild-to-moderate Alzheimer’s disease over 12 months [2]. Several factors might have contributed to the failure of this trial. In particular, the selection of patients with advanced neuropathology and the short period of exposure to treatment may have played a role. Alternatively, COX-independent mechanisms of NSAIDs may have contributed to the apparent protection demonstrated in epidemiological studies. It has been reported that NSAIDs may activate peroxisome proliferator-activated receptor (PPAR) [27,34,40]. In fact, PPARg activation leads to the inhibition of microglial expression of a broad range of pro-inflammatory molecules (Fig. 3). Moreover, some NSAIDs have been reported to alter the 42-residue isoform of amyloid h peptide cleavage and the subsequent species of Ah produced potentially in a novel and direct interaction with the g-secretase complex (Fig. 3), causing a subtle conformational change of the enzyme that leads to the reduction of brain levels of Ah42. In view of the evidence from cell culture and animal studies suggesting the reduction of amyloid generation with other NSAIDs, such as ibuprofen (but not naproxen or selective COX-2 inhibitors) [8,13,57], further clinical trials using other NSAIDs might be performed. However, it should be pointed out that no evidence is available to correlate these alternative mecha-

nisms of NSAIDs with their clinical benefit reported in population-based studies. It has been shown that NSAIDs reduce dopaminergic neuron degeneration in animal models of Parkinson disease (PD) [16], but no epidemiological data are available on NSAID use and the risk of PD. However, it has been shown that COX-2 is up-regulated in brain dopaminergic neurons of both PD postmortem specimens and in the 1-methyl-4phenyl-1,2,3,6-tertrahydropyridine (MPTP) mouse model of PD, and COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone involved in the pathogenesis of PD, suggesting that the inhibition of COX-2 may be a valuable target for the development of new therapies for PD aimed at slowing the progression of the neurodegenerative process [53].

6. COX-2-dependent metabolism of endocannabinoids There is increasing evidence that endocannabinoids play a role in a number of physiological and pathological processes. In fact, they are involved in central and peripheral nervous functions (pain perception, motor behavior, cognition,

Fig. 3. Possible molecular mechanisms involved in the control of neuroinflammation by NSAIDs. (A) NSAIDs may influence the inflammatory response by inhibiting COX-2 and/or COX-1; in vitro studies have reported that NSAIDs can activate the peroxisome proliferator activated receptor g (PPAR g). (B) Studies performed in vitro and in experimental animal models have reported that NSAIDs directly bind to the g-secretase complex and alter h-amyloid precursor protein processing decreasing Ah42 production and also changing production of other Ah species.

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reward and drug or alcohol addiction, and hypothalamic function). Moreover, endocannabinoids play role in peripheral effects, such as reproduction, immune response, gastrointestinal, and cardiovascular function. In addition to the well-studied hydrolytic mode of endocannabinoid metabolism, these lipids are also susceptible to oxidative metabolism by a number of fatty acid oxygenases. These include the cyclooxygenases, lipoxygenases, and cytochrome P450s known to be involved in eicosanoid production from arachidonic acid [25]. COX-2 selectively oxygenates the endocannabinoids 2-arachidonylglycerol (2-AG) and anandamide (AEA) [22,23,46,60]. AEA oxygenation has been demonstrated with purified human COX-2 as well as cells expressing human COX-2 [46,60]. In contrast, partially purified human COX-1 or the enzyme expressed in human promonocytic THP cells does not oxygenate AEA [60]. Endocannabinoids bind in productive conformation in COX2 and similarly to arachidonic acid are oxygenated by wildtype COX-2 to provide prostaglandin-like lipids and by aspirin-acetylated COX-2 to provide 15-HETE derivatives [24]. Despite the rapidly expanding understanding of endocannabinoid oxidative metabolism, the biological significance of these pathways has only begun to be addressed. Oxygenation of AEA or 2-AG by any or all of the enzymes may represent a simple endocannabinoid inactivation pathway. In contrast, oxidative metabolism would represent an activation pathway, and certain oxygenation reactions might produce cannabimimetic agents with enhanced metabolic stability when compared to the parent endocannabinoid. Moreover, oxygenated products might represent unique signal mediators with potent activities distinct from their cannabimimetic precursors. Finally, oxidized endocannabinoids may serve as pro-drugs for the well-known arachidonate-derived eicosanoids subject to bioactivation by an appropriate amidase or esterase. Both 2-AG- and AEAderived prostanoids are significantly more stable metabolically than free-acid PGs, suggesting that COX-2 action on endocannabinoids may provide oxygenated lipids with sufficiently long half-lives to act as systemic mediators or pro-drug [25]. These studies raise the attractive possibility that COX-2-generated PG esters or amides exert biological actions thereby extending the range of action of this class of eicosanoids.

7. Perspectives The enhanced GI safety of highly selective COX-2 inhibitors vs. conventional NSAIDs has been accompanied by the prospect of additional efficacy in preventing and delaying the progression of colon cancer and perhaps also Alzheimer’s disease. Despite the failure of rofecoxib in an initial clinical trial in Alzheimer’s disease, the possible clinical benefit of other coxibs should be verified in further studies. However, it should be underlined that the available clinical end points of progression of Alzheimer’s disease

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may represent a constraint on the fine assessment of actual progression of this disease. Finally, the benefit of coxibs vs. nonselective NSAIDs in this setting remains to be evaluated in primary prevention trials.

8. Note added in proof Rofecoxib was withdrawn from the market (September 30, 2004) by Merck because of a significant increase (by a factor of 1.9) in the incidence of serious thromboembolic adverse events versus placebo in the Adenomatous Polyp Prevention On Vioxx (APPROVe) study which was designed to determine the drug’s effect on benign sporadic colonic adenomas (http://www.fda.gov/bbs/topics/news/ 2004/NEW01122.html). In the VIGOR trial, the drug was reported as well to cause an increased risk of myocardial infarction (by a factor of 5) versus the comparator naproxen in patients with rheumatoid arthritis [3]. Recently released data from controlled clinical trials have shown that other COX-2 selective agents (celecoxib and valdecoxib) may be associated with an increased risk of serious cardiovascular events (heart attack and stroke) especially when they are used for long periods of time or in very high risk settings (immediately after heart surgery) (http://www.fda.gov/bbs/ topics/ANSWERS/2004/ANS/01336.html). Selective inhibitors of COX-2 depress prostacyclin (PGI2), an atheroprotective agent, but not COX-1 derived thromboxane (TX)A2, a proaggregatory and vasoconstrictor mediator, which might predispose patients to heart attack and stroke.

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