Cyclooxygenase-2 Biology

Cyclooxygenase-2 Biology

Cyclooxygenase-2 Biology


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<strong>Cyclooxygenase</strong>-2 <strong>Biology</strong><br />

Joan Clària*<br />

Current Pharmaceutical Design, 2003, 9, 2177-2190 2177<br />

DNA Unit, Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de<br />

Barcelona, Barcelona 08036, Spain<br />

Abstract: In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2<br />

and the release of arachidonic acid from membrane phospholipids in response to the interaction of a stimulus with a<br />

receptor on the cell surface. Arachidonic acid is subsequently transformed by the enzyme cyclooxygenase (COX) to<br />

prostaglandins (PGs) and thromboxane (TX). The COX pathway is of particular clinical relevance because it is the<br />

major target for non-steroidal anti-inflammatory drugs, which are commonly used for relieving inflammation, pain<br />

and fever. In 1991, it was disclosed that COX exists in two distinct isozymes (COX-1 and COX-2), one of which,<br />

COX-2, is primarily responsible for inflammation but apparently not for gastrointestinal integrity or platelet<br />

aggregation. For this reason, in recent years, novel compounds that are selective for this isozyme, the so-called<br />

selective COX-2 inhibitors or COXIBs, which retain anti-inflammatory activity but minimize the risk of<br />

gastrointestinal toxicity and bleeding, have been developed. This review article provides an overview and an<br />

update on the progress achieved in the area of COX-2 and PG biosynthesis and describes the role of COX-2 in health<br />

and disease. It also discusses some unresolved issues related to the use of selective COX-2 inhibitors as a safe and<br />

promising therapeutic option not only for the treatment of inflammatory states but also for cancer.<br />

Key Words: Eicosanoids, prostaglandins, cyclooxygenase-2, non-steroidal anti-inflammatory drugs, cyclooxygenase-2<br />

inhibitors, gastrointestinal tract.<br />


The history of prostaglandins (PGs) date back in the early<br />

1930´s when Goldblatt and Von Euler who independently<br />

discovered a fatty acid in human seminal fluid with potent<br />

vasoactive properties in rabbits and guinea pigs [1, 2]. von<br />

Euler named this compound prostaglandin because he<br />

assumed it was originated in the prostate gland (it is now<br />

known to be originated in the seminal vesicles) and suggested<br />

that prostaglandins played a role in sperm transport [2].<br />

Thirty years later, Bergstrom and Samuelsson established the<br />

structure of the first two PGs which were termed PGE and<br />

PGF because of their respective partitions into ether and<br />

phosphate buffer (fosfat in Swedish) and demonstrated that<br />

they were produced from the essential fatty acid arachidonic<br />

acid [3]. Today the nomenclature of PGs describes ten<br />

specific molecular groups, designated by the letters A<br />

through J, that are unique by their variation in the functional<br />

groups attached to positions 9 and 11 of the cyclopentane<br />

ring [4]. Each group of PGs consists of three series designated<br />

by the subscript numbers 1, 2 and 3, depending on the<br />

substrate originated: di-homo-γ -linoleic acid, arachidonic<br />

acid, and eicosapentaenoic acid, respectively. Among the<br />

PGs, the most widely distributed and best characterized are<br />

those derived from arachidonic acid (i.e., PGE2, PGD2, PGI2<br />

and PGF2α). For PGF, the additional subscript α or β<br />

denotes the spatial configuration of the carbon 9 hydroxyl<br />

group. Special mention should be given to the platelet pro-<br />

*Address correspondence to this author at the DNA Unit, Hospital Clínic,<br />

Villarroel 170, Barcelona 08036, Spain; Tel: 34-93-2275400 ext. 2814;<br />

Fax: 34-93-2275454; E-mail: jclaria@clinic.ub.es<br />

aggregatory and vasoconstrictor molecule, thromboxane (TX)<br />

A2, whose structure and biosynthesis was elucidated soon<br />

after the discovery of PGs [4].<br />


In 1971, Vane [5], Ferreira et al. [6] and Smith et al. [7]<br />

published their seminal observations proposing that the<br />

ability of aspirin-like drugs to suppress inflammation rests<br />

primarily on their ability to inhibit the production of PGs.<br />

This work fostered further research with focus on the<br />

elucidation of the pathway leading to the biosynthesis of<br />

PGs in animal cells, which concluded that the synthesis of<br />

PGs from arachidonic acid is initiated by the enzyme<br />

cyclooxygenase (COX). Although in human cells there are at<br />

least two different COX isozymes designated COX-1 and<br />

COX-2 (as discussed below a third COX isoform termed<br />

COX-3 has recently been identified), the basic catalytic<br />

activities of these isozymes are similar enough to treat them<br />

as if they were biochemically identical. Accordingly, the<br />

biochemistry of these COX isozymes is herewith discussed<br />

as one. Moreover, although other names for COX are PG<br />

endoperoxide synthase, PG G/H synthase and PGH synthase,<br />

in this review article this enzyme is referred to as COX.<br />

COX is a membrane-bound byfunctional enzyme that<br />

catalyzes the first two committed steps in the pathway<br />

leading to the formation of PGs and TX, namely<br />

cyclooxygenation and peroxidation. In the first step, COX<br />

cyclizes and adds two molecules of O2 to arachidonic acid to<br />

form the cyclic hydroperoxide PGG2. Subsequently, COX<br />

reduces PGG2 to PGH2 [8, 9]. PGH2 is a highly unstable<br />

endoperoxide, which functions as an intermediate substrate<br />

1381-6128/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd.

2178 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària<br />

for the biosynthesis, by specific synthases and isomerases, of<br />

PGs of the E2, F2 and D2 series and also of PGI2<br />

(prostacyclin) and TXA2 [4]. Interestingly, the coupling of<br />

PGH2 synthesis to its transformation to PGs and TX by<br />

downstream enzymes is intricately orchestrated in a cellspecific<br />

fashion. That is, any given prostanoid-forming cell<br />

tends to form only one of these compounds as its major<br />

product. Thus, for example, in brain and mast cells, PGH2 is<br />

converted to PGD2 by cytosolic enzyme PGD synthase.<br />

PGH2 can alternatively be converted to PGF2α by PGF<br />

synthase, which is mainly expressed in the uterus. Vascular<br />

endothelial cells produce PGI2 or prostacyclin from PGH2 by<br />

means of the PGI or prostacyclin synthase, and platelets<br />

release TXA2 from the same precursor (PGH2) as the PGs<br />

through the action of the enzyme TX synthase. Both PGI2<br />

and TXA2, have a very short half-life (30 seconds and 3<br />

minutes, respectively) and are rapidly hydrolyzed to the<br />

inactive compounds TXB2 and 6-keto-PGF1α, respectively.<br />

Finally, PGE2 is formed in many cell types by the enzyme<br />

PGE synthase. A schematic representation of these pathways<br />

is shown in Fig. (1). It is important to note that PGE<br />

synthase is also present in an inducible form (mPGE<br />

synthase), which is membrane-bound, glutathione-dependent<br />

and whose expression is induced by proinflammatory<br />

compounds, such as interleukin-1 β [10, 11]. The coordinate<br />

induction of multiple enzymes of the prostanoid pathway,<br />

such as COX-2 and mPGE synthase, during the inflammatory<br />

response is a concept that is currently evolving.<br />

Both cyclooxygenase and peroxidase activities of COX<br />

are associated with a single protein molecule and use a single<br />

heme moiety within the enzyme [9]. However, the active<br />

sites for the cyclooxygenase and peroxidase activities of<br />

COX have been shown to be distinct and independent in<br />

pharmacological and in vitro mutagenesis studies [9]. Hence,<br />

the two active sites for cyclooxygenase and peroxidase<br />

probably overlap [9]. The cyclooxygenase active site is<br />

proposed to be a long hydrophobic channel, which extends<br />

from the membrane binding domain to near the heme group.<br />

This hydrophobic channel has been shown to bind<br />

arachidonate and also other fatty acids as substrates. Thus, in<br />

addition to the 20-carbon arachidonate (20:4 ω6), COX also<br />

uses di-homo-γ -linolenate (20:3 ω6), 5,8,11,14,17-eicosapentanoic<br />

acid (EPA), γ -linolenic acid, α-linolenic acid and<br />

linolenic acid. EPA is subsequently converted to PGH3<br />

whereas the 18-carbon fatty acids are converted into monohydroxy<br />

acids. Although COX-1 and COX-2 oxygenate<br />

arachidonate with almost identical kinetics, in general, COX-<br />

2 is much more efficient with alternative substrates. For<br />

instance, COX-2 utilizes both fatty acids and endocannabinoids,<br />

including 2-archidonylglycerol and anandamide, as<br />

substrates. COX-2 action on 2-archidonylglycerol and<br />

anandamide generates endocannabinoid-derived prostanoids,<br />

among them PG glycerol esters and ethanolamides [12]. In<br />

addition, aspirin-acetylated COX-2 converts arachidonic acid<br />

to 15R-hydroxyeicosatetraenoic acid (15R-HETE), which is<br />

further transformed into 15-epi-lipoxins [13]. Moreover,<br />

when exposed to aspirin, COX-2-expressing cells enzymatically<br />

transform omega-3 docosaexaenoic acid (DHA) to<br />

previously unrecognized compounds, i.e., a novel 17R series<br />

of hydroxy-DHAs [14]. Both 15-epi-lipoxins and hydroxy-<br />

DHAs bear potent anti-inflammatory properties and play a<br />

key role in the resolution of inflammation.<br />

COX is an integral membrane protein found mainly in<br />

microsomal membranes. Though confocal fluorescence imaging<br />

microscopy and histofluorescence staining techniques<br />

reveal that COX-1 and COX-2 are located in the endoplasmic<br />

reticulum and nuclear envelope, COX-2 is more highly<br />

concentrated in the nuclear envelope [15]. It is unclear why<br />

COX is associated with several different membrane systems<br />

but one possibility may be that PG synthesis at different<br />

subcellular sites is elicited by different stimuli. In any case,<br />

the aspirin acetylation site, the site of trypsin cleavage and<br />

the major antigenic determinants of COX are on the cytoplasmic<br />

side of the endoplasmic reticulum indicating that<br />

PGH2 is generated intracellularly rather than extracellularly.<br />

Most of the synthases, which further metabolize PGH2 also<br />

appear to be localized on the endoplasmic reticulum.<br />


Similar to what occurs with the PGH2 downstream<br />

metabolizing enzymes (i.e., PG synthases and isomerases),<br />

prostanoid receptors are also cell and/or tissue specific. There<br />

are at least 9 known PG receptors as well as several of their<br />

splice variants that belong to a subfamily of the G proteincoupled<br />

receptor (GPCR) superfamily of seven transmembrane<br />

spanning proteins [16]. Four of the receptor subtypes<br />

bind PGE 2 (EP1-EP4), two bind PGD2 (DP1 and DP 2) and the<br />

rest are single receptors for PGF2α, PGI2 and TXA2 (FP, IP<br />

and TP, respectively) [16-18]. IP, DP1, EP2 and EP4<br />

receptors are coupled with the activation of Gs proteins and<br />

linked to increases in intracellular cAMP, whereas EP1, FP<br />

and TP signal through Gq-mediated increases in intracellular<br />

calcium concentration. Exceptionally, the EP3 receptor is<br />

coupled to Gi and decreases cAMP formation. Interestingly,<br />

in addition to signaling through G-protein linked receptors,<br />

PGs generated from COX-2 located in the nuclear envelope<br />

may mediate signals preferentially through a nuclear<br />

pathway, whereas COX-1 derived PGs may mediate signals<br />

solely through cell surface receptors [16]. This emphasizes<br />

the importance of COX-2 and nuclear receptors (i.e.,<br />

peroxisome proliferator-activating receptors, PPARs) in cell<br />

growth and survival.<br />


The understanding that NSAIDs block prostanoid<br />

formation via inhibition of COX explained the antiinflammatory<br />

effects of these drugs. Similarly, prostanoids,<br />

such as PGE2 and prostacyclin, were found to be protective<br />

to the stomach and, therefore, inhibition of their formation<br />

provided an explanation for the gastrointestinal toxicity<br />

associated with prolonged use of NSAIDs (see later in this<br />

review). On the other hand, inhibition of COX in platelets<br />

explained the ability of aspirin to reduce platelet aggregation<br />

and blood clotting. But still a number of questions remained<br />

unanswered; such as why the toxicity of NSAIDs differs in<br />

the gastrointestinal tract when used at similar antiinflammatory<br />

doses? The answer was provided in the early<br />

1990´s when it was established that there are at least two<br />

COX isozymes present in human cells: COX-1, which is<br />

constitutively expressed; and COX-2, which is inducible<br />

[19-21].<br />

COX-1 and COX-2 are the products of two distinct<br />

genes, which in humans are localized on chromosomes 9 and

<strong>Cyclooxygenase</strong>-2 <strong>Biology</strong> Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2179<br />

HO<br />

OH<br />

O<br />

O<br />

O<br />

OH<br />

TXB2 HO<br />

O<br />

OH<br />

TXA2 COX-1<br />

COX-2<br />

COX-3<br />

COOH<br />

OH<br />

PGE2 COOH<br />

Arachidonic Acid<br />

Fig. (1). Enzymatic pathway of prostaglandin (PG) formation from arachidonic acid. <strong>Cyclooxygenase</strong> (COX), which is present in three<br />

different isozymes COX-1, 2 and 3, oxygenates arachidonic acid to form PGG2 which is further reduced to PGH2. PGH2 is a highly<br />

unstable endoperoxide that is rapidly converted by specific synthases to PGs of the E2, F2 and D2 series and also to PGI2<br />

(prostacyclin) and thromboxane (TX) A2. Both PGI2 and TXA2 have a very short half-life (30 seconds and 3 minutes, respectively) and<br />

are rapidly hydrolyzed to the inactive compounds 6-keto-PGF1α and TXB2, respectively.<br />

1, respectively [22, 23]. The COX-1 gene is about 22 kb in<br />

length with 11 exons and is transcribed as a 2.8 kb mRNA<br />

[22, 24]. The COX-2 gene is about 8 kb long with 10 exons<br />

and it is transcribed as 4.6, 4.0 and 2.8 kb mRNAs variants<br />

[25-27]. Sequence analysis of the COX-2 5´-flanking region<br />

O<br />

O<br />

O<br />

O<br />

TX Synthase<br />

PGE Synthase<br />

HO<br />

HO<br />

COOH<br />

Phospholipids<br />

PGF Synthase<br />

OOH<br />

PGG2 OH<br />

PGH2 OH<br />

PGF 2α<br />

HO<br />

O<br />

COOH<br />

COOH<br />

COOH<br />

PGI Synthase<br />

PGD Synthase<br />

COOH<br />

OH<br />

O<br />

HO OH<br />

PGD 2<br />

PGI 2<br />

HO<br />

HO<br />

COOH<br />

has revealed several potential transcription regulatory<br />

elements, including a TATA box, a NF-IL-6 motif, two AP-<br />

2 sites, three Sp1 sites, two NF-kB sites a CRE motif and<br />

an E-box [28].<br />

O<br />

OH<br />

6-Keto-PGF 1α<br />


2180 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària<br />

The amino acid sequences of COX-1 and COX-2 from a<br />

single species are about 60% identical. COX-1 is a<br />

glycoprotein that in its native, processed form has 576<br />

amino acids with an apparent molecular mass of 70 kDa [22,<br />

24]. The cDNA for COX-2 encodes a polypeptide that,<br />

before cleavage of the signal sequence, contains 604 amino<br />

acids with an apparent molecular mass of 70 kDa [25, 26].<br />

The main difference is that the COX-1 protein contains a 17<br />

amino acid sequence near its amino terminus that is not<br />

present in COX-2. In contrast, COX-2 contains a 18 amino<br />

acid sequence near its carboxyl terminus that is not present<br />

in COX-1 [22, 24-26]. However, and as already mentioned,<br />

the two COX isoforms catalyze identical reactions and<br />

exhibit the same kinetic constants for the conversion of<br />

arachidonic acid to prostanoids.<br />

The most striking distinctions between COX-1 and<br />

COX-2 are the differential regulation of their expression and<br />

their tissue distribution (Fig. 2). COX-1 is ubiquitous and is<br />

constitutively expressed throughout the gastrointestinal<br />

system, the kidneys, the vascular smooth muscle and<br />

platelets [28]. COX-1 is presumably involved in the<br />

housekeeping functions of PGs, such as the cytoprotective<br />

effects in the gastric mucosa, the integrity of platelet<br />

function and the maintenance of renal perfusion. Conversely,<br />

COX-2 is undetectable in most tissues, but its expression<br />

can be induced by a variety of stimuli related to<br />

inflammatory response. COX-2 is, therefore, commonly<br />

referred to as the inducible COX isoform because, like other<br />

immediate-early genes, it can be rapidly upregulated in<br />

response to growth factors and cytokines [28]. This has led<br />

to the supposition that the inducible COX-2 isoform is<br />

responsible for the synthesis of PGs involved in<br />

inflammatory response, whereas COX-1-derived PGs are<br />

involved in preserving the physiological functions of these<br />

prostanoids. However, this distinction is not entirely<br />

accurate, since COX-1 can be induced or upregulated under<br />

certain conditions and COX-2 has been consistently shown<br />

to be constitutively expressed in organs, such as the brain<br />

and the kidneys (see later in this review).<br />

Although the discovery of COX-2 was a great<br />

advancement in our understanding of COX biology, it did<br />

not appear to explain everything. In particular, the<br />

mechanism of action of acetaminophen remained a mystery.<br />

Hugely popular and with a history almost as venerable as<br />

that of aspirin, this drug exerts antipyretic and analgesic<br />

effects without displaying anti-inflammatory activity.<br />

Moreover, at therapeutic concentrations, acetaminophen only<br />

weakly inhibits COX-1 and COX-2. Willoughby first<br />

suggested that this is because of the presence of another<br />

COX isozyme, COX-3 [29]. In fact, Dan Simmons´s group<br />

has recently demonstrated the existence of a new COX that is<br />

especially sensitive to acetaminophen and related compounds<br />

(Fig. 2) [30]. This novel COX, termed COX-3, is a splice<br />

variant of COX-1 and in human tissues its mRNA is<br />

expressed as an 5.2-kb transcript, which is most abundant in<br />

cerebral cortex and heart [30].<br />

Fig. (2). Proposed separate functions for prostaglandins (PGs) derived from cyclooxygenase (COX)-1, -2 and -3. While COX-1 is<br />

found in most tissues and is believed to participate in physiologic homeostasis in the stomach, kidneys and platelets, COX-2 is<br />

preferentially expressed in cells that mediate inflammation and in the central nervous system. Therefore, inhibition of COX-2 is<br />

supposed to be responsible for the beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs), whereas inhibition of COX-<br />

1 accounts for the unwanted side-effects of these drugs. A splice variant of COX-1, termed COX-3, that is especially sensitive to<br />

acetaminophen and may explain the antipyretic and analgesic effects of this drug, has been recently identified.

<strong>Cyclooxygenase</strong>-2 <strong>Biology</strong> Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2181<br />



COX is the main pharmacological target for NSAIDs.<br />

The observation that NSAIDs reduce or prevent the<br />

production of PGs by direct inhibition of COX enzymes was<br />

first reported by Vane, Ferreira et al. and Smith et al. in<br />

1971 [5-7]. At present, NSAIDs are among the most widely<br />

prescribed class of pharmaceutical agents worldwide, having<br />

broad clinical utility in treating pain, fever and inflammation<br />

[31, 32]. The most popular NSAID, aspirin, is also sought<br />

as a potentially viable option in the prevention of sporadic<br />

colon cancer and neurodegenerative disorders [33, 34].<br />

Unfortunately and apart from the beneficial antiinflammatory,<br />

antipyretic and analgesic effects of NSAIDs,<br />

COX inhibition also results in unwanted side effects,<br />

particularly in the gastrointestinal tract [35]. Gastroduodenal<br />

ulceration is the best-characterized serious adverse event of<br />

NSAID therapy and is the consequence of inhibiting PGs,<br />

which are the most important gastric cytoprotective agents<br />

[36]. On the other hand although the incidence of renal side<br />

effects in healthy subjects is not significant, adverse renal<br />

events are frequent in those patients with impaired effective<br />

arterial blood volume in which renal function is critically<br />

dependent on PGs, such as decompensated liver cirrhosis<br />

[37]. Since COX-1-derived PGs are presumably involved in<br />

housekeeping functions, such as gastrointestinal cytoprotection,<br />

and COX-2-derived PGs are implicated in inflammation,<br />

NSAID gastrotoxicity is considered to be the consequence of<br />

the inhibition of both COX-1 and COX-2 isozymes by<br />

traditional NSAIDs (i.e., aspirin, indomethacin, ibuprofen,<br />

meclofenamate, …). That is, at the concentrations required to<br />

inhibit PG biosynthesis at sites of inflammation (COX-2<br />

activity), they also elicit a marked suppression of PG<br />

production in the gastrointestinal and renal systems (COX-1<br />

activity) jeopardizing the integrity of the gastric mucosa and<br />

renal and platelet function.<br />

The discovery of the COX-2 isozyme and the<br />

characterization of its role in inflammation fostered the<br />

development of a new class of compounds that selectively<br />

inhibit COX-2, without affecting the COX-1-dependent PG<br />

biosynthesis necessary for physiological functions [38-41].<br />

This new generation of anti-inflammatory drugs has been<br />

proven in vitro to selectively inhibit COX-2 activity and to be<br />

as efficacious as standard NSAIDs in a number of in vivo<br />

models of inflammation (rat carrageenan-induced foot pad<br />

edema and rat adjuvant-induced arthritis) and hyperalgesia (rat<br />

carrageenan-induced hyperalgesia) [40, 41]. Two COXIBS<br />

(selective COX-2 inhibitors), celecoxib (Celebrex ® ) and<br />

rofecoxib (Vioxx ® ) have been marketed in the past three years,<br />

and in clinical trials have proven to provide significant relief of<br />

the signs and symptoms of osteoarthritis and rheumatoid<br />

arthritis and in alleviating pain following dental extraction,<br />

while reducing the incidence of gastrointestinal ulcers and<br />

erosions seen with standard NSAID therapy [42-47].<br />

Moreover, these eagerly awaited highly selective COX-2<br />

inhibitors are of great interest because they may represent an<br />

alternative therapeutic option for the treatment of inflammation<br />

in diseases, such as in cirrhosis with ascites, in which<br />

renal function is critically dependent on PGs [48, 49]. A<br />

second-generation of selective COX-2 inhibitors (i.e.,<br />

valdecoxib and etoricoxib) with a higher COX-1 to COX-2<br />

selectivity ratio than celecoxib and rofecoxib is currently<br />

under evaluation in patients with osteoarthritis and rheumatoid<br />

arthritis. Furthermore, the analgesic efficacy and tolerability of<br />

parecoxib, an injectable prodrug of valdecoxib, is currently<br />

being tested in postoperative laparotomy and orthopedic knee<br />

surgery patients [50, 51]. A list of currently available<br />

NSAIDs and COXIBs is provided in Table 1.<br />


Activation of prostanoid receptors triggers an astonishing<br />

array of biological effects (Table 2). The most important<br />

targets of PGs include the gastrointestinal tract, the<br />

Table 1. Classification of Non-Steroidal Anti-Inflammatory Drugs According to their Selectivity Towards COX-2. Brand<br />

Names are Given in Brackets<br />

Traditional NSAIDs Preferential COX-2 inhibitors Selective COX-2 inhibitors<br />

Aspirin Etodolac (Lodine) Celecoxib (Celebrex)<br />

Diclofenac (Arthrotec, Cataflam, Voltaren) Meloxicam (Mobic) Etoricoxib (Arcoxia)<br />

Flurbiprofen (Ansaid) Nabumetone (6-MNA) (Relafen) Parecoxib (Dynastat)<br />

Ibuprofen (Advil, Motrin, Nuprin, Others) Nimesulide (Mesulid, Nexen) Rofecoxib (Vioxx)<br />

Indomethacin (Indocin, Inacid, Others) Valdecoxib (Bextra)<br />

Ketoprofen (Orudis, Oruvail)<br />

Ketorolac (Acular, Toradol)<br />

Naproxen (Aleve, Naprelan, Naprosyn)<br />

Piroxicam (Feldene)<br />

Sulindac (Clinoril)<br />

Tolmetin (Tolectin)

2182 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària<br />

Table 2. Biological Effects of <strong>Cyclooxygenase</strong> Products<br />

cardiovascular system, the central and peripheral nervous<br />

systems, the renal system and the reproductive organs. A<br />

detailed discussion of PG actions and the role of COX-2<br />

under physiologic and pathologic conditions is herewith<br />

provided.<br />

COX-2 and the Gastrointestinal Tract<br />

Gastric Secretion<br />

Tissue/Organ Mediators Effects<br />

Female Reproductive Organs PGE2, PGF2α Uterine Contraction, Oxytocic Action<br />

Male Reproductive Organs PGE2, PGF2α Fertility<br />

Cardiovascular System TXA2, PGI2<br />

TXA2<br />

PGE2, PGI2<br />

TXA2, PGF2α<br />

PGE2, PGI2<br />

Respiratory System PGE2<br />

PGF2α , TXA2<br />

Renal System PGE2, PGI2<br />

PGE2, PGI2<br />

PGE2<br />

In human gastric mucosa, PGE2 and PGF2α have been<br />

reported as the most abundant COX-derived products, with<br />

low production of PGD2 and PGI2 [52]. In 1967, initial<br />

observations reported PGE2 to be anti-secretory and antiulcerogenic<br />

[53]. Subsequently, it was demonstrated that<br />

intravenous administration of PGE1 or PGE2 inhibits acid<br />

and pepsin secretion induced by secretagogues, such as<br />

pentagrastin and histamine [54]. Moreover, PGE2 has been<br />

shown to inhibit gastric parietal cells and to increase<br />

bicarbonate secretion, resulting in decreased acidity of gastric<br />

juice [55]. It must be taken into account that these<br />

observations on gastric acid secretion were obtained by<br />

administering PGs at pharmacological doses and that<br />

establishing the role of endogenously produced PGs in<br />

gastric acid secretion has proven to be more challenging. In<br />

this regard, blockade of PG biosynthesis with COX<br />

inhibitors has yielded disparate and non-conclusive results<br />

[56]. Moreover, although studies in experimental models<br />

have shown that animals actively or passively immunized<br />

with PG-protein conjugates develop gastrointestinal tract<br />

erosions and ulcerations primarily in the stomach and<br />

occasionally in the small bowel, in these experiments basal<br />

and stimulated acid secretion did not differ in the treated<br />

versus non-treated animals [57]. Therefore, the role of<br />

endogenous COX-derived products in gastric secretory<br />

physiology still remains controversial.<br />

Recently, COX-2 has been reported to be induced in<br />

human gastric mucosa infected with Helicobacter pylori [58,<br />

59]. Moreover, the production of PGE2 in gastric mucosa is<br />

increased in patients with gastritis and infection with H.<br />

pylori stimulates synthesis of PGE2 in gastric mucosal cells<br />

in vitro [58, 60]. While H. pylori infection is considered to<br />

increase acid secretion in duodenal ulcer patients, in severe<br />

gastritis, acid secretion is generally decreased and basal<br />

gastrin levels are assumed to be stimulated. In particular,<br />

acid secretion was significantly reduced in an experimental<br />

group of mice with H. pylori infection, an effect that was<br />

restored to the same level as in the control mice following<br />

COX-2 inhibition [61].<br />

Gastrointestinal Motility<br />

Thrombosis, Platelet Aggregation<br />

Vascular Permeability<br />

Arterial Vasodilation<br />

Venous vasoconstriction<br />

Patency of the Fetal Ductus Arteriosus<br />

Bronchodilation<br />

Bronchoconstriction<br />

Regulation Renal Blood Flow and Glomerular Filtration Rate<br />

Renin Release<br />

Inhibition Hydroosmotic Effect of ADH<br />

Gastrointestinal System PGE2, PGI2 Cytoprotection<br />

Immune System PGE2, PGI2 Inhibition T and B lymphocyte activation and proliferation<br />

Central Nervous System PGE2<br />

PGD2<br />

PGE2, PGI2<br />

Fever<br />

Sleep<br />

Pain<br />

Essential to digestion, gastrointestinal motility is a<br />

complex process regulated by both neural and humoral<br />

components. Paracrine modulation of normal intestinal<br />

motility by eicosanoids such as PGs is still a matter of<br />

debate, but pharmacological doses of certain prostanoids<br />

have been shown to alter motility both in vivo and in vitro<br />

[62]. Vascular reactivity studies in isolated intestinal muscle<br />

show that PGE2 induces contraction of longitudinal muscle<br />

and relaxation of circular muscle, whereas PGF2α induces<br />

contraction of both muscles [63]. Isolated colonic<br />

longitudinal and circular muscle layers respond to PGE2 and<br />

PGF2α in the same manner as the small intestine, although<br />

the results obtained preclude any generalization. For<br />

example, low doses of PGE2 can induce activity in the distal<br />

colon and be inhibitory in the proximal colon [64]. On the<br />

other hand, in most animal studies, PGs of the E series relax<br />

the lower esophageal sphincter whereas PGF2α constricts it<br />

[55]. In any case, when administered in vivo both PGs<br />

decrease transit time and produce diarrhea through increased

<strong>Cyclooxygenase</strong>-2 <strong>Biology</strong> Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2183<br />

fluid and electrolyte secretion and/or altered gastrointestinal<br />

motility [65, 66].<br />

Little is known about the roles that COX-1 and COX-2<br />

may play in the regulation of gastrointestinal motility.<br />

Although several studies have shown that the non-selective<br />

NSAIDs indomethacin and aspirin impair intestinal<br />

peristalsis, which is the most relevant clinical motor pattern<br />

of the gut, recent findings suggest that this effect is unrelated<br />

to COX inhibition and have different targets, such as nuclear<br />

factor-κ B and/or peroxisome proliferator-activated receptors<br />

γ [67]. In fact, the selective COX-2 inhibitor NS-398 has<br />

been shown not to affect gastric motility in rats with<br />

gastroduodenal ulcerogenic responses induced by<br />

hypothermic stress [68]. Nevertheless, a role for prostanoids<br />

derived from COX-2 in postoperative bowel motility has<br />

been proposed. In this regard, selective inhibition of COX-2<br />

significantly increases postoperative small bowel transit in<br />

experimental rodent models of postoperative ileus [69, 70].<br />

Gastrointestinal Inflammation<br />

Eicosanoids along with many other soluble factors, such<br />

as cytokines, reactive oxygen species, bacterial products and<br />

lipid mediators, play a critical role in gastrointestinal<br />

inflammation. Several eicosanoids, including products from<br />

COX (PGE2 and TXB2) and lipoxygenase (leukotriene (LT)<br />

B4 and HETEs), are increased in inflamed tissues compared<br />

with normal mucosa [71]. A positive correlation exists<br />

between the increase in these eicosanoids and the activity of<br />

the disease, returning the levels during remission to values<br />

similar to those from normal colorectal mucosa [55]. An<br />

increasing body of evidence, especially in animal models of<br />

inflammatory bowel disease (IBD), indicate that PGs<br />

counteract the pro-inflammatory activity of LTB4. Indeed,<br />

the administration of NSAIDs to either patients or animal<br />

models with IBD does not have a salutary effect but rather is<br />

associated with flare-ups and colitis [72, 73]. This<br />

phenomenon is interpreted as NSAIDs suppressing PGE2<br />

formation thus allowing LTB4 synthesis to proceed toward<br />

pro-inflammation.<br />

In experiments using animal models of inflammation,<br />

such as carrageenan injection into the footpad and the murine<br />

air pouch model, COX-2 expression and activity is markedly<br />

upregulated [38, 74]. In these experimental models of acute<br />

inflammation, selective COX-2 inhibition by inhibiting<br />

edema at the inflammatory site and being analgesic is<br />

beneficial [38, 74, 75]. Therefore, because there is increased<br />

expression of COX-2 in both animal models of colitis and in<br />

human IBD [76, 77], in theory, selective COX-2 inhibition<br />

would also likely be beneficial in this disease. Although<br />

preliminary results suggest that COX-2 inhibitors may be<br />

safe and beneficial in most patients with IBD [78], other<br />

investigators do not agree because they have enough evidence<br />

to support that PGs derived from COX-2 are important in<br />

promoting the healing of mucosal injury, in protecting<br />

against bacterial invasion, and in down-regulating the<br />

mucosal immune system [79]. Indeed, in experimental<br />

models, suppression of COX-2 in a setting of<br />

gastrointestinal inflammation and ulceration has been shown<br />

to result in the impairment of healing and exacerbation on<br />

inflammation-mediated injury [76, 79]. In humans, clear<br />

cases of exacerbation of IBD have been reported with the use<br />

of a selective COX-2 inhibitor [80]. Therefore, the use of<br />

COX-2 selective inhibitors in patients with IBD should be<br />

viewed with the same caution as the use of traditional<br />

NSAIDs.<br />

COX-2 and Colon Cancer<br />

The most solid, unequivocal and well-established role of<br />

COX-2 in the gastrointestinal system is its participation in<br />

colon cancer [81-84].<br />

Early observations in this field were obtained in studies<br />

comparing the levels of PGs in colon tumors with those of<br />

normal colon tissue. The concentration of PGs, in particular<br />

of PGE2, was found increased in human colorectal cancer<br />

tissue when compared with normal colonic mucosa [85-87].<br />

Similar findings were reported in experimental models of<br />

colonic carcinogenesis [88]. These early investigations also<br />

established which PG series is involved in colon cancer.<br />

Rigas et al. compared the levels of different PGs in colon<br />

tumors with those of normal colon tissue and found that<br />

PGE2 was elevated about two-fold in the cancer samples [86].<br />

In contrast, no significant changes were found in the levels<br />

of PGF2α and TXA2, and, even, PGI2 was reduced about<br />

three-fold in tumors [86]. Therefore, because both human and<br />

experimental colonic tumors produce increased amounts of<br />

this particular PG, PGE2 appears to be the eicosanoid<br />

involved in colon carcinogenesis.<br />

Since PGE2 levels are increased in tumors, COX is<br />

suspected to play a key role in the progression of colon<br />

cancer. The relative levels of COX-1 and COX-2 expression<br />

in colorectal cancers were evaluated by a number of<br />

independent laboratories. All the investigations reported<br />

increased expression of COX-2, but not COX-1, in colorectal<br />

carcinomas [89-91]. Published reports indicate that roughly<br />

85% of adenocarcinomas exhibit a two- to fifty-fold increase<br />

in COX-2 expression at both mRNA and protein levels<br />

compared with matched, macroscopically normal, colonic<br />

mucosa from the same patient [89-92]. Both carcinogeninduced<br />

(azoxymethane-induced colonic tumors in rats) and<br />

genetic (Min mice with multiple intestinal neoplasia) animal<br />

models of colon cancer have confirmed the existence of an<br />

increased expression of COX-2 in tumors [92-94].<br />

Nevertheless, although COX-2 is differentially expressed in<br />

various regions of the colon in human colorectal cancer, with<br />

the COX-2 protein being greatly over-expressed in tumors<br />

located in the rectum [89-92], at present its cellular origin is<br />

still debated. Cancer cells, nontransformed epithelial cells,<br />

stromal cells, vascular endothelial cells and inflammatory<br />

infiltrates are constituents of colon tissue and all of these cell<br />

types are reported to have elevated levels of COX-2<br />

compared with the normal colon tissues [95]. On the<br />

contrary, subsequent studies have demonstrated that the<br />

increased expression of COX-2 in colon cancer originates<br />

mainly from the interstitial cells (i.e., macrophages), whereas<br />

little COX-2 expression is found in epithelial cancer cells<br />

[96, 97].<br />

Several mechanisms have been suggested for the<br />

enhanced COX-2 gene expression in colon cancer, including<br />

mutations of APC and ras, activation of EGF receptor and<br />

IGF-I receptor pathways and heregulin/HER-2 receptor<br />

pathway, direct induction by the Epstein-Barr virus<br />

oncoprotein and latent membrane protein 1 [98-100]. For

2184 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària<br />

instance, Oshima et al. assessed the development of<br />

intestinal adenomas in APC Δ716 knockout mice (a model in<br />

which a targeted truncation deletion in the tumor suppressor<br />

gene APC causes intestinal polyposis) in a wild type and<br />

homozygous null COX-2 genetic background. The number<br />

and size of polyps were dramatically reduced (six to eightfold)<br />

in the COX-2 null mice compared with COX-2 wildtype<br />

mice [101].<br />

In vitro, the functional consequences of COX-2 overexpression<br />

have been analyzed in the rat intestinal cell line<br />

(RIE cells), the gastrocolonic cell lines HT-29 and HCA-7<br />

and in the human colon cell line Caco-2 transfected with<br />

COX-2. Overall, these experiments have revealed that cells<br />

over-expressing COX-2 undergo phenotypic changes that<br />

could enhance their tumorigenic potential, such as exhibition<br />

of an increased adhesion to extracellular matrix proteins and<br />

resistance to apoptosis [102, 103]. The proliferative activity<br />

of COX-2 is believed to be primarily mediated by PGs.<br />

Along these lines, the human gastrocolonic cancer cell line,<br />

HT-29, shows increased proliferation in the presence of PGs<br />

in the culture medium [104]. Moreover, in vivo, colonocyte<br />

proliferation is significantly stimulated by the injection of<br />

the stable derivative of PGE2, dimethyl PGE2, into normal<br />

mice [104]. A conclusive proof of the role of COX-2 in cell<br />

growth is provided by the use of selective COX-2 inhibitors.<br />

The effects of the highly selective COX-2 inhibitor, SC-<br />

58125, was tested in two different cell lines, only one of<br />

which had a high level of COX-2 expression and activity. It<br />

was observed that SC-58125 decreased cell growth only in<br />

the COX-2 expressing cell line [105].<br />

In vivo, in human and experimental animals, a body of<br />

evidence support the concept that inhibition of COX, and, in<br />

particular COX-2, protects against colon cancer.<br />

Epidemiological studies have demonstrated the association<br />

between regular long-term consumption of NSAIDs, in<br />

particular aspirin, and reduced incidence of colon cancer [33,<br />

106-108]. Aspirin and sulindac have also been shown to<br />

reduce the number and size of its nonmalignant precursor,<br />

the adenomatous colonic polyp, in patients with familial<br />

adenomatous polyposis (FAP) [109, 110]. Moreover, a<br />

recent paper provides evidence of a protective association<br />

between aspirin and NSAIDs and esophageal cancer [111].<br />

These epidemiological data are considered robust, because<br />

separate studies differing in locale, design and population<br />

have consistently yielded similar results. Parallel studies in<br />

animal models of colon carcinogenesis have also proven that<br />

aspirin, as well as other traditional NSAIDs, such as<br />

piroxicam, indomethacin, sulindac, ibuprofen and<br />

ketoprofen, inhibit chemically-induced colon cancer in rats<br />

and mice [33]. The mechanism by which NSAIDs reduce the<br />

risk of cancer is likely related to the inhibition of COX-2. In<br />

fact, a randomized clinical trial has shown that the selective<br />

COX-2 inhibitor, celecoxib, effectively inhibits the growth<br />

of adenomatous polyps and causes regression of existing<br />

polyps in patients with hereditary FAP [112]. Studies in<br />

rodents have also demonstrated that selective<br />

pharmacological inhibition of COX-2 activity prevents<br />

chemically-induced carcinogenesis and intestinal polyp<br />

formation in an experimental model of FAP [113-115]. In<br />

Min mice and rats exposed to chemical carcinogens, selective<br />

COX-2 inhibitors induce apoptosis as well as stimulate<br />

apoptosis and suppress growth in many carcinomas,<br />

including cultured human cancers of the stomach, esophagus,<br />

tongue, brain, lung and pancreas [116].<br />

Recent studies indicate that angiogenesis, which is the<br />

development of new blood vessels and an essential step in<br />

tumor growth, requires COX-2 [84]. In fact, COX-2<br />

overexpressing cells produce large amounts of vascular<br />

endothelial growth factor (VEGF), a key proangiogenic<br />

factor, which stimulates both endothelial migration and in<br />

vitro angiogenesis [102]. These effects may be blocked by<br />

selective COX-2 inhibitors, highlighting the potential<br />

application of these compounds in blocking developing<br />

tumors [113]. On the other hand, mice lacking the COX-2<br />

gene have deficient VEGF expression, reduced tumor<br />

angiogenesis and decreased tumor growth [117]. Moreover,<br />

selective inhibition of COX-2, but not COX-1, suppresses<br />

the growth of corneal capillary blood vessels in rats exposed<br />

to basic fibroblast growth factor and inhibits the growth of<br />

several human tumors implanted in mice [117, 118]. Taken<br />

together, these results support the notion of the benefit of<br />

selective COX-2 inhibition as an anti-angiogenic therapy.<br />

In addition to the well-documented implication of COX-<br />

2 in colon cancer, several investigations have recently<br />

examined its potential role in other epithelial cancers. These<br />

studies have provided strong evidence that COX-2 may also<br />

be implicated in breast, head and neck, lung, pancreatic and<br />

gastric cancers and suggest that the beneficial effects of<br />

COX-2 inhibitors may extend to these other cancers [119-<br />

122]. Indeed, celecoxib consistently and dose-dependently<br />

inhibits tumor growth and the number of lung metastasis in<br />

the syngenic Lewis lung carcinoma model [116].<br />

Interestingly, in animal studies, celecoxib has been shown to<br />

potentiate the antitumor activity of conventional<br />

chemotherapy and radiation [123, 124].<br />

COX-2 and the Kidney<br />

PGs play multiple roles in the adult kidney. PGE2 and<br />

PGI2 are powerful renal vasodilators that modulate intrarenal<br />

vascular tone and influence glomerular hemodynamics and<br />

renal perfusion [125, 126]. Moreover, PGE2 modulates renal<br />

sodium through direct inhibition of sodium reabsorption in<br />

tubular epithelial cells [125, 126]. PGE2 also modulates<br />

renal water homeostasis by antagonizing the hydroosmotic<br />

effect of antidiuretic hormone in the collecting duct [125,<br />

126]. Finally, PGs are involved in the renal responses to<br />

loop diuretics and in the regulation of renin secretion [126,<br />

127]. Since PG synthesis is initiated by COX-1 and COX-2,<br />

and both COX isoforms are constitutively expressed in the<br />

kidneys [128, 129], it was of interest to establish which<br />

COX isoform is involved in the maintenance of renal<br />

function under normal conditions. The distribution of COX-<br />

1 in the renal area differs significantly from that of COX-2.<br />

In this regard, COX-1 is preferentially expressed in the renal<br />

vasculature and in the medullary and papillary collecting<br />

ducts in humans, monkeys, dogs, rabbits and rats, whereas<br />

COX-2 expression is consistently focal, and limited to the<br />

macula densa of the juxtaglomerular apparatus, epithelial<br />

cells of the thick ascending limb and papillary interstitial<br />

cells of rats, rabbits and dogs [128, 129]. In the adult human<br />

kidney, expression of COX-2 protein has been observed in

<strong>Cyclooxygenase</strong>-2 <strong>Biology</strong> Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2185<br />

endothelial and smooth muscle cells of arteries and veins,<br />

and intra-glomerularly in podocytes, but not in macula densa<br />

cells [130].<br />

At present, it is hypothesized that only PGs derived from<br />

COX-1 are involved in normal renal function. The marketed<br />

selective COX-2 inhibitors, rofecoxib and celecoxib, have<br />

been evaluated in randomized controlled trials in terms of<br />

their effects on renal PGs, renal function and occurrence of<br />

adverse renal events. Most of the studies have reported that<br />

selective COX-2 inhibition does not significantly impair<br />

renal function in healthy subjects [131]. Nevertheless, it is<br />

worthy to note that in healthy elderly patients, a population<br />

more susceptible to renal NSAID-damaging effects, both<br />

celecoxib and rofecoxib induce a reduction in urinary sodium<br />

excretion similar to that of indomethacin and naproxen [132,<br />

133]. Although the role of COX-2-derived PGs in the kidney<br />

is still under debate, the finding that mice lacking the COX-<br />

2 gene develop mild to severe nephropathy during the first<br />

weeks after birth [134, 135], supports the eventuality that<br />

COX-2-derived PGs may play a physiological role in the<br />

kidney other than maintenance of circulatory and excretory<br />

functions.<br />

The incidence of renal side effects secondary to NSAID<br />

treatment is low, and the role of PGs in renal homeostasis is<br />

hardly noticeable in healthy subjects. In contrast,<br />

administration of NSAIDs to patients with unbalanced<br />

effective arterial blood volume represents a major clinical<br />

problem since renal function in these patients is critically<br />

dependent on PGs [37]. In these circumstances, which<br />

include low sodium diet, hemorrhagic hypovolemia and<br />

edematous conditions associated with congestive heart<br />

failure, nephrotic syndrome and decompensated liver<br />

cirrhosis, NSAIDs induce a pronounced impairment in renal<br />

plasma flow, glomerular filtration rate, urine volume and<br />

urinary sodium excretion. Since selective COX-2 inhibitors<br />

have been developed to effectively inhibit COX-2 while<br />

sparing physiologic PG production from COX-1, these novel<br />

compounds could potentially be the anti-inflammatory of<br />

choice in these patients. In this regard, in recent studies in<br />

rats with carbon tetrachloride-induced cirrhosis and ascites, an<br />

experimental model that closely reproduces human liver<br />

disease, selective COX-2 inhibition with celecoxib did not<br />

seriously compromise renal function [48, 49]. Interestingly,<br />

in these animals COX-1 protein expression was found to be<br />

unchanged whereas COX-2 protein levels were consistently<br />

upregulated [49]. Therefore, these results indicate that despite<br />

abundant renal COX-2 protein expression, the maintenance of<br />

renal function in altered effective arterial blood volume<br />

conditions, such as liver cirrhosis is mainly dependent on<br />

COX-1-derived PGs.<br />

COX-2 and the Brain<br />

PGs have long been recognized as mediators of fever.<br />

Fever is produced by PGE2, acting on temperature-sensing<br />

neurons in the preoptic area [136]. The endogenous feverproducing<br />

PGE2 is thought to originate from COX-2 induced<br />

by lipopolysaccharide or interleukin-1 in endothelial cells<br />

lining the cerebral blood vessels [137]. In fact,<br />

intraperitoneal injection of lipopolysaccharide to rats induces<br />

COX-2 in brain endothelial cells in parallel with the<br />

appearance of fever [138]. Moreover, selective inhibitors of<br />

COX-2 are potent antipyretic agents [139].<br />

PGs are also now recognized as mediators of<br />

inflammatory reactions in neural tissue and more recently of<br />

brain function. Constitutive COX-2 immunoreactivity and<br />

COX-2 mRNA expression have been detected in neurons and<br />

specially in the forebrain [140]. The expression of COX-2 in<br />

the brain is particularly high in neonates [141]. Since brains<br />

of neonates have higher levels of cerebral PGs than those of<br />

adults [141], and since these PGs are involved in the<br />

regulation of blood flow in the newborn [142], this<br />

phenomenon suggests that COX-2 is likely to be important<br />

in the modulation of blood flow at this stage of life.<br />

Furthermore, COX-2 is thought to play a key role in the<br />

final stages of development and brain modeling when COX-<br />

2 becomes active in a manner that coincides with the<br />

imprinting of environmental influences [143].<br />

Intense nerve stimulation, leading to seizures, induces<br />

COX-2 mRNA in discrete neurons of the hippocampus,<br />

whereas acute stress raises levels in the cerebral cortex [140,<br />

144]. The actual role of COX-2 and PGs in these sites is not<br />

understood, but associations between COX-2 induction and<br />

neural degeneration after glutamate stimulation, seizures and<br />

spreading depression waves suggest that COX-2 may play<br />

more of a role in the selective loss of neural connections than<br />

in their formation [145]. Finally, current studies show that<br />

COX-2 potentiates brain parenchymal amyloid plaque<br />

formation leading to Alzheimer’s disease, thus supporting a<br />

therapeutic potential for NSAIDs and COXIBs in the<br />

treatment of this neurological disease [146].<br />

COX-2 and the Reproductive Function<br />

PGs are important for inducing uterine contractions<br />

during labor. NSAIDs, such as indomethacin, delay<br />

premature labor by inhibiting the production of PGs [147].<br />

However, the inhibition of PGs with indomethacin led to a<br />

high mortality among infants because of premature closure of<br />

the ductus arteriosus, a circulatory shunt maintained by PGs<br />

that allows the output of the left ventricle to bypass the fetal<br />

lungs [147, 148]. PGs originating from COX-2 may play a<br />

role in the birth process because COX-2 mRNA in the<br />

amnion and placenta increases markedly immediately before<br />

and after the initiation of labor [149]. Theoretically, selective<br />

inhibitors of COX-2 are able to reduce PG synthesis in fetal<br />

membranes and could be useful in delaying premature labor<br />

without the unwanted side effects of traditional NSAIDs.<br />

However, COX-2 also plays a role in ovulation, the<br />

successful rupture of the follicle and in the implantation of<br />

the embryo in the uterine endometrium [150]. Indeed, COX-<br />

2 null mice show multiple failures in reproductive function,<br />

including ovulation, fertilization, implantation and<br />

decidualization [151].<br />

COX-2 and Inflammation and Arthritis<br />

The most important action of PGs is their role in<br />

inflammation [4]. In response to an inflammatory insult, the<br />

release of PGs, and more importantly PGE2, constitutes a<br />

key event in the development of the three cardinal signs of<br />

inflammation: swelling/redness, pain and fever. Given its

2186 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària<br />

potent vasodilatory properties, PGE2 increases tissue blood<br />

flow, which results in the characteristic erythema (redness) of<br />

inflammation [4]. On the other hand, together with other<br />

soluble factors including bradykinin, histamine and<br />

leukotrienes, PGE2 increases vascular permeability<br />

contributing to fluid extravasation and the appearance of<br />

edema (swelling) [4]. PGE2 also sensitizes afferent nerve<br />

fibers acting both at peripheral sensory neurons and at central<br />

sites within the spinal cord and brain to evoke hyperalgesia<br />

(pain) [4]. Finally PGE2 is a potent pyretic mediator<br />

involved in the appearance of fever [136]. Moreover, PGs<br />

also contribute to the amplification of the inflammatory<br />

response by enhancing and prolonging signals produced by<br />

pro-inflammatory agents, such as bradykinin, histamine,<br />

neurokinins and complement.<br />

Although the importance of COX and PGs in<br />

inflammation has been known for years, the inducibility of<br />

COX and PG formation has only fully been appreciated<br />

recently with the uncovering of the properties of COX-2.<br />

COX-2 was originally discovered as a transcript that was<br />

upregulated during inflammation and cellular transformation<br />

[19-21]. Animal models of inflammatory arthritis provided<br />

the first available information regarding expression of COX-<br />

2 in acute and chronic inflammation, indicating that<br />

increased expression of COX-2 is responsible for the<br />

increased PG production seen in inflamed joint tissues [75].<br />

COX-2 induction was observed in both human osteoarthritisaffected<br />

cartilage as well as in synovial tissue taken from<br />

patients with rheumatoid arthritis [152, 153]. The critical<br />

role of COX-2 in inflammation led to the rational design of<br />

the first clinical trials for selective COX-2 inhibitors in<br />

patients with osteoarthritis and rheumatoid arthritis [42-45].<br />

The results of these drug-screening studies are sufficient to<br />

guarantee that COX-2 inhibitors achieve the same antiinflammatory<br />

efficacy as traditional NSAIDs [42-45].<br />

COX-2 and the Cardiovascular System<br />

The major effects of PGs on the cardiovascular system are<br />

on the smooth muscle cells and platelets where prostacyclin<br />

(PGI2) has opposite biologic properties to those of TXA2.<br />

Thus, on the vasculature and especially on veins, PGI2<br />

mainly promotes vasorelaxation while TXA2 acts as a<br />

vasoconstrictor [4]. It was classically considered that PGI2<br />

produced by vascular endothelial and smooth muscle cells<br />

was formed via COX-1. However, recent work has<br />

demonstrated that PGI2 in vascular cells is produced by<br />

COX-2 as well as COX-1 [28]. Treatment of volunteers with<br />

a selective COX-2 inhibitor decreased urinary excretion of<br />

PGI2 without affecting TXA2 [132]. These results raised the<br />

possibility of an increased risk of cardiovascular events<br />

associated with COXIBs. However, two major randomized<br />

trials have recently shown that the relative risk of a<br />

cardiovascular event with selective COX-2 inhibitors is<br />

similar to that of traditional NSAIDs [154, 155]. On the<br />

other hand, in platelets, TXA2 induces platelet aggregation<br />

whereas PGI2 strongly inhibits aggregation. It is widely<br />

recognized that platelets express only COX-1. Nevertheless,<br />

in certain stages of megakaryogenesis, COX-2, as well as<br />

COX-1 are detected [156]. The biological significance of this<br />

phenomenon is, at present, unclear.<br />


COX = <strong>Cyclooxygenase</strong><br />

COXIBs = Selective COX-2 inhibitors<br />

FAP = Familial adenomatous polyposis<br />

LT = Leukotrienes<br />

NSAIDs = Non-steroidal anti-inflammatory drugs<br />

PGs = Prostaglandins<br />

TX = Thromboxane<br />

VEGF = Vascular endothelial growth factor<br />


References 157-159 are related articles recently published in<br />

Current Pharmaceutical Design.<br />

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