Cyclooxygenase-2 Biology

Cyclooxygenase-2 Biology 

Joan Clària* 

Current Pharmaceutical Design, 2003, 9, 2177-2190 2177 

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

Barcelona, Barcelona 08036, Spain 

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

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

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

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

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

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

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

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

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

gastrointestinal toxicity and bleeding, have been developed. This review article provides an overview and an 

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

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

promising therapeutic option not only for the treatment of inflammatory states but also for cancer. 

Key Words: Eicosanoids, prostaglandins, cyclooxygenase-2, non-steroidal anti-inflammatory drugs, cyclooxygenase-2 

inhibitors, gastrointestinal tract. 

PROSTAGLANDINS 

The history of prostaglandins (PGs) date back in the early 

1930´s when Goldblatt and Von Euler who independently 

discovered a fatty acid in human seminal fluid with potent 

vasoactive properties in rabbits and guinea pigs [1, 2]. von 

Euler named this compound prostaglandin because he 

assumed it was originated in the prostate gland (it is now 

known to be originated in the seminal vesicles) and suggested 

that prostaglandins played a role in sperm transport [2]. 

Thirty years later, Bergstrom and Samuelsson established the 

structure of the first two PGs which were termed PGE and 

PGF because of their respective partitions into ether and 

phosphate buffer (fosfat in Swedish) and demonstrated that 

they were produced from the essential fatty acid arachidonic 

acid [3]. Today the nomenclature of PGs describes ten 

specific molecular groups, designated by the letters A 

through J, that are unique by their variation in the functional 

groups attached to positions 9 and 11 of the cyclopentane 

ring [4]. Each group of PGs consists of three series designated 

by the subscript numbers 1, 2 and 3, depending on the 

substrate originated: di-homo-γ -linoleic acid, arachidonic 

acid, and eicosapentaenoic acid, respectively. Among the 

PGs, the most widely distributed and best characterized are 

those derived from arachidonic acid (i.e., PGE2, PGD2, PGI2 

and PGF2α). For PGF, the additional subscript α or β 

denotes the spatial configuration of the carbon 9 hydroxyl 

group. Special mention should be given to the platelet pro- 

*Address correspondence to this author at the DNA Unit, Hospital Clínic, 

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

Fax: 34-93-2275454; E-mail: jclaria@clinic.ub.es 

aggregatory and vasoconstrictor molecule, thromboxane (TX) 

A2, whose structure and biosynthesis was elucidated soon 

after the discovery of PGs [4]. 

PROSTAGLANDIN BIOSYNTHESIS 

In 1971, Vane [5], Ferreira et al. [6] and Smith et al. [7] 

published their seminal observations proposing that the 

ability of aspirin-like drugs to suppress inflammation rests 

primarily on their ability to inhibit the production of PGs. 

This work fostered further research with focus on the 

elucidation of the pathway leading to the biosynthesis of 

PGs in animal cells, which concluded that the synthesis of 

PGs from arachidonic acid is initiated by the enzyme 

cyclooxygenase (COX). Although in human cells there are at 

least two different COX isozymes designated COX-1 and 

COX-2 (as discussed below a third COX isoform termed 

COX-3 has recently been identified), the basic catalytic 

activities of these isozymes are similar enough to treat them 

as if they were biochemically identical. Accordingly, the 

biochemistry of these COX isozymes is herewith discussed 

as one. Moreover, although other names for COX are PG 

endoperoxide synthase, PG G/H synthase and PGH synthase, 

in this review article this enzyme is referred to as COX. 

COX is a membrane-bound byfunctional enzyme that 

catalyzes the first two committed steps in the pathway 

leading to the formation of PGs and TX, namely 

cyclooxygenation and peroxidation. In the first step, COX 

cyclizes and adds two molecules of O2 to arachidonic acid to 

form the cyclic hydroperoxide PGG2. Subsequently, COX 

reduces PGG2 to PGH2 [8, 9]. PGH2 is a highly unstable 

endoperoxide, which functions as an intermediate substrate 

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

2178 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària 

for the biosynthesis, by specific synthases and isomerases, of 

PGs of the E2, F2 and D2 series and also of PGI2 

(prostacyclin) and TXA2 [4]. Interestingly, the coupling of 

PGH2 synthesis to its transformation to PGs and TX by 

downstream enzymes is intricately orchestrated in a cellspecific 

fashion. That is, any given prostanoid-forming cell 

tends to form only one of these compounds as its major 

product. Thus, for example, in brain and mast cells, PGH2 is 

converted to PGD2 by cytosolic enzyme PGD synthase. 

PGH2 can alternatively be converted to PGF2α by PGF 

synthase, which is mainly expressed in the uterus. Vascular 

endothelial cells produce PGI2 or prostacyclin from PGH2 by 

means of the PGI or prostacyclin synthase, and platelets 

release TXA2 from the same precursor (PGH2) as the PGs 

through the action of the enzyme TX synthase. Both PGI2 

and TXA2, have a very short half-life (30 seconds and 3 

minutes, respectively) and are rapidly hydrolyzed to the 

inactive compounds TXB2 and 6-keto-PGF1α, respectively. 

Finally, PGE2 is formed in many cell types by the enzyme 

PGE synthase. A schematic representation of these pathways 

is shown in Fig. (1). It is important to note that PGE 

synthase is also present in an inducible form (mPGE 

synthase), which is membrane-bound, glutathione-dependent 

and whose expression is induced by proinflammatory 

compounds, such as interleukin-1 β [10, 11]. The coordinate 

induction of multiple enzymes of the prostanoid pathway, 

such as COX-2 and mPGE synthase, during the inflammatory 

response is a concept that is currently evolving. 

Both cyclooxygenase and peroxidase activities of COX 

are associated with a single protein molecule and use a single 

heme moiety within the enzyme [9]. However, the active 

sites for the cyclooxygenase and peroxidase activities of 

COX have been shown to be distinct and independent in 

pharmacological and in vitro mutagenesis studies [9]. Hence, 

the two active sites for cyclooxygenase and peroxidase 

probably overlap [9]. The cyclooxygenase active site is 

proposed to be a long hydrophobic channel, which extends 

from the membrane binding domain to near the heme group. 

This hydrophobic channel has been shown to bind 

arachidonate and also other fatty acids as substrates. Thus, in 

addition to the 20-carbon arachidonate (20:4 ω6), COX also 

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

acid (EPA), γ -linolenic acid, α-linolenic acid and 

linolenic acid. EPA is subsequently converted to PGH3 

whereas the 18-carbon fatty acids are converted into monohydroxy 

acids. Although COX-1 and COX-2 oxygenate 

arachidonate with almost identical kinetics, in general, COX- 

2 is much more efficient with alternative substrates. For 

instance, COX-2 utilizes both fatty acids and endocannabinoids, 

including 2-archidonylglycerol and anandamide, as 

substrates. COX-2 action on 2-archidonylglycerol and 

anandamide generates endocannabinoid-derived prostanoids, 

among them PG glycerol esters and ethanolamides [12]. In 

addition, aspirin-acetylated COX-2 converts arachidonic acid 

to 15R-hydroxyeicosatetraenoic acid (15R-HETE), which is 

further transformed into 15-epi-lipoxins [13]. Moreover, 

when exposed to aspirin, COX-2-expressing cells enzymatically 

transform omega-3 docosaexaenoic acid (DHA) to 

previously unrecognized compounds, i.e., a novel 17R series 

of hydroxy-DHAs [14]. Both 15-epi-lipoxins and hydroxy- 

DHAs bear potent anti-inflammatory properties and play a 

key role in the resolution of inflammation. 

COX is an integral membrane protein found mainly in 

microsomal membranes. Though confocal fluorescence imaging 

microscopy and histofluorescence staining techniques 

reveal that COX-1 and COX-2 are located in the endoplasmic 

reticulum and nuclear envelope, COX-2 is more highly 

concentrated in the nuclear envelope [15]. It is unclear why 

COX is associated with several different membrane systems 

but one possibility may be that PG synthesis at different 

subcellular sites is elicited by different stimuli. In any case, 

the aspirin acetylation site, the site of trypsin cleavage and 

the major antigenic determinants of COX are on the cytoplasmic 

side of the endoplasmic reticulum indicating that 

PGH2 is generated intracellularly rather than extracellularly. 

Most of the synthases, which further metabolize PGH2 also 

appear to be localized on the endoplasmic reticulum. 

PROSTAGLANDIN RECEPTORS 

Similar to what occurs with the PGH2 downstream 

metabolizing enzymes (i.e., PG synthases and isomerases), 

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

are at least 9 known PG receptors as well as several of their 

splice variants that belong to a subfamily of the G proteincoupled 

receptor (GPCR) superfamily of seven transmembrane 

spanning proteins [16]. Four of the receptor subtypes 

bind PGE 2 (EP1-EP4), two bind PGD2 (DP1 and DP 2) and the 

rest are single receptors for PGF2α, PGI2 and TXA2 (FP, IP 

and TP, respectively) [16-18]. IP, DP1, EP2 and EP4 

receptors are coupled with the activation of Gs proteins and 

linked to increases in intracellular cAMP, whereas EP1, FP 

and TP signal through Gq-mediated increases in intracellular 

calcium concentration. Exceptionally, the EP3 receptor is 

coupled to Gi and decreases cAMP formation. Interestingly, 

in addition to signaling through G-protein linked receptors, 

PGs generated from COX-2 located in the nuclear envelope 

may mediate signals preferentially through a nuclear 

pathway, whereas COX-1 derived PGs may mediate signals 

solely through cell surface receptors [16]. This emphasizes 

the importance of COX-2 and nuclear receptors (i.e., 

peroxisome proliferator-activating receptors, PPARs) in cell 

growth and survival. 

COX ISOZYMES: COX-1, COX-2 AND NOW COX-3 

The understanding that NSAIDs block prostanoid 

formation via inhibition of COX explained the antiinflammatory 

effects of these drugs. Similarly, prostanoids, 

such as PGE2 and prostacyclin, were found to be protective 

to the stomach and, therefore, inhibition of their formation 

provided an explanation for the gastrointestinal toxicity 

associated with prolonged use of NSAIDs (see later in this 

review). On the other hand, inhibition of COX in platelets 

explained the ability of aspirin to reduce platelet aggregation 

and blood clotting. But still a number of questions remained 

unanswered; such as why the toxicity of NSAIDs differs in 

the gastrointestinal tract when used at similar antiinflammatory 

doses? The answer was provided in the early 

1990´s when it was established that there are at least two 

COX isozymes present in human cells: COX-1, which is 

constitutively expressed; and COX-2, which is inducible 

[19-21]. 

COX-1 and COX-2 are the products of two distinct 

genes, which in humans are localized on chromosomes 9 and

Cyclooxygenase-2 Biology Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2179 

HO 

OH 

O 

O 

O 

OH 

TXB2 HO 

O 

OH 

TXA2 COX-1 

COX-2 

COX-3 

COOH 

OH 

PGE2 COOH 

Arachidonic Acid 

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

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

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

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

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

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

length with 11 exons and is transcribed as a 2.8 kb mRNA 

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

and it is transcribed as 4.6, 4.0 and 2.8 kb mRNAs variants 

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

O 

O 

O 

O 

TX Synthase 

PGE Synthase 

HO 

HO 

COOH 

Phospholipids 

PGF Synthase 

OOH 

PGG2 OH 

PGH2 OH 

PGF 2α 

HO 

O 

COOH 

COOH 

COOH 

PGI Synthase 

PGD Synthase 

COOH 

OH 

O 

HO OH 

PGD 2 

PGI 2 

HO 

HO 

COOH 

has revealed several potential transcription regulatory 

elements, including a TATA box, a NF-IL-6 motif, two AP- 

2 sites, three Sp1 sites, two NF-kB sites a CRE motif and 

an E-box [28]. 

O 

OH 

6-Keto-PGF 1α 

COOH


The amino acid sequences of COX-1 and COX-2 from a 

single species are about 60% identical. COX-1 is a 

glycoprotein that in its native, processed form has 576 

amino acids with an apparent molecular mass of 70 kDa [22, 

24]. The cDNA for COX-2 encodes a polypeptide that, 

before cleavage of the signal sequence, contains 604 amino 

acids with an apparent molecular mass of 70 kDa [25, 26]. 

The main difference is that the COX-1 protein contains a 17 

amino acid sequence near its amino terminus that is not 

present in COX-2. In contrast, COX-2 contains a 18 amino 

acid sequence near its carboxyl terminus that is not present 

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

the two COX isoforms catalyze identical reactions and 

exhibit the same kinetic constants for the conversion of 

arachidonic acid to prostanoids. 

The most striking distinctions between COX-1 and 

COX-2 are the differential regulation of their expression and 

their tissue distribution (Fig. 2). COX-1 is ubiquitous and is 

constitutively expressed throughout the gastrointestinal 

system, the kidneys, the vascular smooth muscle and 

platelets [28]. COX-1 is presumably involved in the 

housekeeping functions of PGs, such as the cytoprotective 

effects in the gastric mucosa, the integrity of platelet 

function and the maintenance of renal perfusion. Conversely, 

COX-2 is undetectable in most tissues, but its expression 

can be induced by a variety of stimuli related to 

inflammatory response. COX-2 is, therefore, commonly 

referred to as the inducible COX isoform because, like other 

immediate-early genes, it can be rapidly upregulated in 

response to growth factors and cytokines [28]. This has led 

to the supposition that the inducible COX-2 isoform is 

responsible for the synthesis of PGs involved in 

inflammatory response, whereas COX-1-derived PGs are 

involved in preserving the physiological functions of these 

prostanoids. However, this distinction is not entirely 

accurate, since COX-1 can be induced or upregulated under 

certain conditions and COX-2 has been consistently shown 

to be constitutively expressed in organs, such as the brain 

and the kidneys (see later in this review). 

Although the discovery of COX-2 was a great 

advancement in our understanding of COX biology, it did 

not appear to explain everything. In particular, the 

mechanism of action of acetaminophen remained a mystery. 

Hugely popular and with a history almost as venerable as 

that of aspirin, this drug exerts antipyretic and analgesic 

effects without displaying anti-inflammatory activity. 

Moreover, at therapeutic concentrations, acetaminophen only 

weakly inhibits COX-1 and COX-2. Willoughby first 

suggested that this is because of the presence of another 

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

has recently demonstrated the existence of a new COX that is 

especially sensitive to acetaminophen and related compounds 

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

variant of COX-1 and in human tissues its mRNA is 

expressed as an 5.2-kb transcript, which is most abundant in 

cerebral cortex and heart [30]. 

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

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

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

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

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

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


INHIBITION OF THE COX PATHWAY: NSAIDS 

AND COXIBS 

COX is the main pharmacological target for NSAIDs. 

The observation that NSAIDs reduce or prevent the 

production of PGs by direct inhibition of COX enzymes was 

first reported by Vane, Ferreira et al. and Smith et al. in 

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

prescribed class of pharmaceutical agents worldwide, having 

broad clinical utility in treating pain, fever and inflammation 

[31, 32]. The most popular NSAID, aspirin, is also sought 

as a potentially viable option in the prevention of sporadic 

colon cancer and neurodegenerative disorders [33, 34]. 

Unfortunately and apart from the beneficial antiinflammatory, 

antipyretic and analgesic effects of NSAIDs, 

COX inhibition also results in unwanted side effects, 

particularly in the gastrointestinal tract [35]. Gastroduodenal 

ulceration is the best-characterized serious adverse event of 

NSAID therapy and is the consequence of inhibiting PGs, 

which are the most important gastric cytoprotective agents 

[36]. On the other hand although the incidence of renal side 

effects in healthy subjects is not significant, adverse renal 

events are frequent in those patients with impaired effective 

arterial blood volume in which renal function is critically 

dependent on PGs, such as decompensated liver cirrhosis 

[37]. Since COX-1-derived PGs are presumably involved in 

housekeeping functions, such as gastrointestinal cytoprotection, 

and COX-2-derived PGs are implicated in inflammation, 

NSAID gastrotoxicity is considered to be the consequence of 

the inhibition of both COX-1 and COX-2 isozymes by 

traditional NSAIDs (i.e., aspirin, indomethacin, ibuprofen, 

meclofenamate, …). That is, at the concentrations required to 

inhibit PG biosynthesis at sites of inflammation (COX-2 

activity), they also elicit a marked suppression of PG 

production in the gastrointestinal and renal systems (COX-1 

activity) jeopardizing the integrity of the gastric mucosa and 

renal and platelet function. 

The discovery of the COX-2 isozyme and the 

characterization of its role in inflammation fostered the 

development of a new class of compounds that selectively 

inhibit COX-2, without affecting the COX-1-dependent PG 

biosynthesis necessary for physiological functions [38-41]. 

This new generation of anti-inflammatory drugs has been 

proven in vitro to selectively inhibit COX-2 activity and to be 

as efficacious as standard NSAIDs in a number of in vivo 

models of inflammation (rat carrageenan-induced foot pad 

edema and rat adjuvant-induced arthritis) and hyperalgesia (rat 

carrageenan-induced hyperalgesia) [40, 41]. Two COXIBS 

(selective COX-2 inhibitors), celecoxib (Celebrex ® ) and 

rofecoxib (Vioxx ® ) have been marketed in the past three years, 

and in clinical trials have proven to provide significant relief of 

the signs and symptoms of osteoarthritis and rheumatoid 

arthritis and in alleviating pain following dental extraction, 

while reducing the incidence of gastrointestinal ulcers and 

erosions seen with standard NSAID therapy [42-47]. 

Moreover, these eagerly awaited highly selective COX-2 

inhibitors are of great interest because they may represent an 

alternative therapeutic option for the treatment of inflammation 

in diseases, such as in cirrhosis with ascites, in which 

renal function is critically dependent on PGs [48, 49]. A 

second-generation of selective COX-2 inhibitors (i.e., 

valdecoxib and etoricoxib) with a higher COX-1 to COX-2 

selectivity ratio than celecoxib and rofecoxib is currently 

under evaluation in patients with osteoarthritis and rheumatoid 

arthritis. Furthermore, the analgesic efficacy and tolerability of 

parecoxib, an injectable prodrug of valdecoxib, is currently 

being tested in postoperative laparotomy and orthopedic knee 

surgery patients [50, 51]. A list of currently available 

NSAIDs and COXIBs is provided in Table 1. 

COX-2 IN HEALTH AND DISEASE 

Activation of prostanoid receptors triggers an astonishing 

array of biological effects (Table 2). The most important 

targets of PGs include the gastrointestinal tract, the 

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

Names are Given in Brackets 

Traditional NSAIDs Preferential COX-2 inhibitors Selective COX-2 inhibitors 

Aspirin Etodolac (Lodine) Celecoxib (Celebrex) 

Diclofenac (Arthrotec, Cataflam, Voltaren) Meloxicam (Mobic) Etoricoxib (Arcoxia) 

Flurbiprofen (Ansaid) Nabumetone (6-MNA) (Relafen) Parecoxib (Dynastat) 

Ibuprofen (Advil, Motrin, Nuprin, Others) Nimesulide (Mesulid, Nexen) Rofecoxib (Vioxx) 

Indomethacin (Indocin, Inacid, Others) Valdecoxib (Bextra) 

Ketoprofen (Orudis, Oruvail) 

Ketorolac (Acular, Toradol) 

Naproxen (Aleve, Naprelan, Naprosyn) 

Piroxicam (Feldene) 

Sulindac (Clinoril) 

Tolmetin (Tolectin)


Table 2. Biological Effects of Cyclooxygenase Products 

cardiovascular system, the central and peripheral nervous 

systems, the renal system and the reproductive organs. A 

detailed discussion of PG actions and the role of COX-2 

under physiologic and pathologic conditions is herewith 

provided. 

COX-2 and the Gastrointestinal Tract 

Gastric Secretion 

Tissue/Organ Mediators Effects 

Female Reproductive Organs PGE2, PGF2α Uterine Contraction, Oxytocic Action 

Male Reproductive Organs PGE2, PGF2α Fertility 

Cardiovascular System TXA2, PGI2 

TXA2 

PGE2, PGI2 

TXA2, PGF2α 

PGE2, PGI2 

Respiratory System PGE2 

PGF2α , TXA2 

Renal System PGE2, PGI2 

PGE2, PGI2 

PGE2 

In human gastric mucosa, PGE2 and PGF2α have been 

reported as the most abundant COX-derived products, with 

low production of PGD2 and PGI2 [52]. In 1967, initial 

observations reported PGE2 to be anti-secretory and antiulcerogenic 

[53]. Subsequently, it was demonstrated that 

intravenous administration of PGE1 or PGE2 inhibits acid 

and pepsin secretion induced by secretagogues, such as 

pentagrastin and histamine [54]. Moreover, PGE2 has been 

shown to inhibit gastric parietal cells and to increase 

bicarbonate secretion, resulting in decreased acidity of gastric 

juice [55]. It must be taken into account that these 

observations on gastric acid secretion were obtained by 

administering PGs at pharmacological doses and that 

establishing the role of endogenously produced PGs in 

gastric acid secretion has proven to be more challenging. In 

this regard, blockade of PG biosynthesis with COX 

inhibitors has yielded disparate and non-conclusive results 

[56]. Moreover, although studies in experimental models 

have shown that animals actively or passively immunized 

with PG-protein conjugates develop gastrointestinal tract 

erosions and ulcerations primarily in the stomach and 

occasionally in the small bowel, in these experiments basal 

and stimulated acid secretion did not differ in the treated 

versus non-treated animals [57]. Therefore, the role of 

endogenous COX-derived products in gastric secretory 

physiology still remains controversial. 

Recently, COX-2 has been reported to be induced in 

human gastric mucosa infected with Helicobacter pylori [58, 

59]. Moreover, the production of PGE2 in gastric mucosa is 

increased in patients with gastritis and infection with H. 

pylori stimulates synthesis of PGE2 in gastric mucosal cells 

in vitro [58, 60]. While H. pylori infection is considered to 

increase acid secretion in duodenal ulcer patients, in severe 

gastritis, acid secretion is generally decreased and basal 

gastrin levels are assumed to be stimulated. In particular, 

acid secretion was significantly reduced in an experimental 

group of mice with H. pylori infection, an effect that was 

restored to the same level as in the control mice following 

COX-2 inhibition [61]. 

Gastrointestinal Motility 

Thrombosis, Platelet Aggregation 

Vascular Permeability 

Arterial Vasodilation 

Venous vasoconstriction 

Patency of the Fetal Ductus Arteriosus 

Bronchodilation 

Bronchoconstriction 

Regulation Renal Blood Flow and Glomerular Filtration Rate 

Renin Release 

Inhibition Hydroosmotic Effect of ADH 

Gastrointestinal System PGE2, PGI2 Cytoprotection 

Immune System PGE2, PGI2 Inhibition T and B lymphocyte activation and proliferation 

Central Nervous System PGE2 

PGD2 

PGE2, PGI2 

Fever 

Sleep 

Pain 

Essential to digestion, gastrointestinal motility is a 

complex process regulated by both neural and humoral 

components. Paracrine modulation of normal intestinal 

motility by eicosanoids such as PGs is still a matter of 

debate, but pharmacological doses of certain prostanoids 

have been shown to alter motility both in vivo and in vitro 

[62]. Vascular reactivity studies in isolated intestinal muscle 

show that PGE2 induces contraction of longitudinal muscle 

and relaxation of circular muscle, whereas PGF2α induces 

contraction of both muscles [63]. Isolated colonic 

longitudinal and circular muscle layers respond to PGE2 and 

PGF2α in the same manner as the small intestine, although 

the results obtained preclude any generalization. For 

example, low doses of PGE2 can induce activity in the distal 

colon and be inhibitory in the proximal colon [64]. On the 

other hand, in most animal studies, PGs of the E series relax 

the lower esophageal sphincter whereas PGF2α constricts it 

[55]. In any case, when administered in vivo both PGs 

decrease transit time and produce diarrhea through increased


fluid and electrolyte secretion and/or altered gastrointestinal 

motility [65, 66]. 

Little is known about the roles that COX-1 and COX-2 

may play in the regulation of gastrointestinal motility. 

Although several studies have shown that the non-selective 

NSAIDs indomethacin and aspirin impair intestinal 

peristalsis, which is the most relevant clinical motor pattern 

of the gut, recent findings suggest that this effect is unrelated 

to COX inhibition and have different targets, such as nuclear 

factor-κ B and/or peroxisome proliferator-activated receptors 

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

been shown not to affect gastric motility in rats with 

gastroduodenal ulcerogenic responses induced by 

hypothermic stress [68]. Nevertheless, a role for prostanoids 

derived from COX-2 in postoperative bowel motility has 

been proposed. In this regard, selective inhibition of COX-2 

significantly increases postoperative small bowel transit in 

experimental rodent models of postoperative ileus [69, 70]. 

Gastrointestinal Inflammation 

Eicosanoids along with many other soluble factors, such 

as cytokines, reactive oxygen species, bacterial products and 

lipid mediators, play a critical role in gastrointestinal 

inflammation. Several eicosanoids, including products from 

COX (PGE2 and TXB2) and lipoxygenase (leukotriene (LT) 

B4 and HETEs), are increased in inflamed tissues compared 

with normal mucosa [71]. A positive correlation exists 

between the increase in these eicosanoids and the activity of 

the disease, returning the levels during remission to values 

similar to those from normal colorectal mucosa [55]. An 

increasing body of evidence, especially in animal models of 

inflammatory bowel disease (IBD), indicate that PGs 

counteract the pro-inflammatory activity of LTB4. Indeed, 

the administration of NSAIDs to either patients or animal 

models with IBD does not have a salutary effect but rather is 

associated with flare-ups and colitis [72, 73]. This 

phenomenon is interpreted as NSAIDs suppressing PGE2 

formation thus allowing LTB4 synthesis to proceed toward 

pro-inflammation. 

In experiments using animal models of inflammation, 

such as carrageenan injection into the footpad and the murine 

air pouch model, COX-2 expression and activity is markedly 

upregulated [38, 74]. In these experimental models of acute 

inflammation, selective COX-2 inhibition by inhibiting 

edema at the inflammatory site and being analgesic is 

beneficial [38, 74, 75]. Therefore, because there is increased 

expression of COX-2 in both animal models of colitis and in 

human IBD [76, 77], in theory, selective COX-2 inhibition 

would also likely be beneficial in this disease. Although 

preliminary results suggest that COX-2 inhibitors may be 

safe and beneficial in most patients with IBD [78], other 

investigators do not agree because they have enough evidence 

to support that PGs derived from COX-2 are important in 

promoting the healing of mucosal injury, in protecting 

against bacterial invasion, and in down-regulating the 

mucosal immune system [79]. Indeed, in experimental 

models, suppression of COX-2 in a setting of 

gastrointestinal inflammation and ulceration has been shown 

to result in the impairment of healing and exacerbation on 

inflammation-mediated injury [76, 79]. In humans, clear 

cases of exacerbation of IBD have been reported with the use 

of a selective COX-2 inhibitor [80]. Therefore, the use of 

COX-2 selective inhibitors in patients with IBD should be 

viewed with the same caution as the use of traditional 

NSAIDs. 

COX-2 and Colon Cancer 

The most solid, unequivocal and well-established role of 

COX-2 in the gastrointestinal system is its participation in 

colon cancer [81-84]. 

Early observations in this field were obtained in studies 

comparing the levels of PGs in colon tumors with those of 

normal colon tissue. The concentration of PGs, in particular 

of PGE2, was found increased in human colorectal cancer 

tissue when compared with normal colonic mucosa [85-87]. 

Similar findings were reported in experimental models of 

colonic carcinogenesis [88]. These early investigations also 

established which PG series is involved in colon cancer. 

Rigas et al. compared the levels of different PGs in colon 

tumors with those of normal colon tissue and found that 

PGE2 was elevated about two-fold in the cancer samples [86]. 

In contrast, no significant changes were found in the levels 

of PGF2α and TXA2, and, even, PGI2 was reduced about 

three-fold in tumors [86]. Therefore, because both human and 

experimental colonic tumors produce increased amounts of 

this particular PG, PGE2 appears to be the eicosanoid 

involved in colon carcinogenesis. 

Since PGE2 levels are increased in tumors, COX is 

suspected to play a key role in the progression of colon 

cancer. The relative levels of COX-1 and COX-2 expression 

in colorectal cancers were evaluated by a number of 

independent laboratories. All the investigations reported 

increased expression of COX-2, but not COX-1, in colorectal 

carcinomas [89-91]. Published reports indicate that roughly 

85% of adenocarcinomas exhibit a two- to fifty-fold increase 

in COX-2 expression at both mRNA and protein levels 

compared with matched, macroscopically normal, colonic 

mucosa from the same patient [89-92]. Both carcinogeninduced 

(azoxymethane-induced colonic tumors in rats) and 

genetic (Min mice with multiple intestinal neoplasia) animal 

models of colon cancer have confirmed the existence of an 

increased expression of COX-2 in tumors [92-94]. 

Nevertheless, although COX-2 is differentially expressed in 

various regions of the colon in human colorectal cancer, with 

the COX-2 protein being greatly over-expressed in tumors 

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

still debated. Cancer cells, nontransformed epithelial cells, 

stromal cells, vascular endothelial cells and inflammatory 

infiltrates are constituents of colon tissue and all of these cell 

types are reported to have elevated levels of COX-2 

compared with the normal colon tissues [95]. On the 

contrary, subsequent studies have demonstrated that the 

increased expression of COX-2 in colon cancer originates 

mainly from the interstitial cells (i.e., macrophages), whereas 

little COX-2 expression is found in epithelial cancer cells 

[96, 97]. 

Several mechanisms have been suggested for the 

enhanced COX-2 gene expression in colon cancer, including 

mutations of APC and ras, activation of EGF receptor and 

IGF-I receptor pathways and heregulin/HER-2 receptor 

pathway, direct induction by the Epstein-Barr virus 

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


instance, Oshima et al. assessed the development of 

intestinal adenomas in APC Δ716 knockout mice (a model in 

which a targeted truncation deletion in the tumor suppressor 

gene APC causes intestinal polyposis) in a wild type and 

homozygous null COX-2 genetic background. The number 

and size of polyps were dramatically reduced (six to eightfold) 

in the COX-2 null mice compared with COX-2 wildtype 

mice [101]. 

In vitro, the functional consequences of COX-2 overexpression 

have been analyzed in the rat intestinal cell line 

(RIE cells), the gastrocolonic cell lines HT-29 and HCA-7 

and in the human colon cell line Caco-2 transfected with 

COX-2. Overall, these experiments have revealed that cells 

over-expressing COX-2 undergo phenotypic changes that 

could enhance their tumorigenic potential, such as exhibition 

of an increased adhesion to extracellular matrix proteins and 

resistance to apoptosis [102, 103]. The proliferative activity 

of COX-2 is believed to be primarily mediated by PGs. 

Along these lines, the human gastrocolonic cancer cell line, 

HT-29, shows increased proliferation in the presence of PGs 

in the culture medium [104]. Moreover, in vivo, colonocyte 

proliferation is significantly stimulated by the injection of 

the stable derivative of PGE2, dimethyl PGE2, into normal 

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

growth is provided by the use of selective COX-2 inhibitors. 

The effects of the highly selective COX-2 inhibitor, SC- 

58125, was tested in two different cell lines, only one of 

which had a high level of COX-2 expression and activity. It 

was observed that SC-58125 decreased cell growth only in 

the COX-2 expressing cell line [105]. 

In vivo, in human and experimental animals, a body of 

evidence support the concept that inhibition of COX, and, in 

particular COX-2, protects against colon cancer. 

Epidemiological studies have demonstrated the association 

between regular long-term consumption of NSAIDs, in 

particular aspirin, and reduced incidence of colon cancer [33, 

106-108]. Aspirin and sulindac have also been shown to 

reduce the number and size of its nonmalignant precursor, 

the adenomatous colonic polyp, in patients with familial 

adenomatous polyposis (FAP) [109, 110]. Moreover, a 

recent paper provides evidence of a protective association 

between aspirin and NSAIDs and esophageal cancer [111]. 

These epidemiological data are considered robust, because 

separate studies differing in locale, design and population 

have consistently yielded similar results. Parallel studies in 

animal models of colon carcinogenesis have also proven that 

aspirin, as well as other traditional NSAIDs, such as 

piroxicam, indomethacin, sulindac, ibuprofen and 

ketoprofen, inhibit chemically-induced colon cancer in rats 

and mice [33]. The mechanism by which NSAIDs reduce the 

risk of cancer is likely related to the inhibition of COX-2. In 

fact, a randomized clinical trial has shown that the selective 

COX-2 inhibitor, celecoxib, effectively inhibits the growth 

of adenomatous polyps and causes regression of existing 

polyps in patients with hereditary FAP [112]. Studies in 

rodents have also demonstrated that selective 

pharmacological inhibition of COX-2 activity prevents 

chemically-induced carcinogenesis and intestinal polyp 

formation in an experimental model of FAP [113-115]. In 

Min mice and rats exposed to chemical carcinogens, selective 

COX-2 inhibitors induce apoptosis as well as stimulate 

apoptosis and suppress growth in many carcinomas, 

including cultured human cancers of the stomach, esophagus, 

tongue, brain, lung and pancreas [116]. 

Recent studies indicate that angiogenesis, which is the 

development of new blood vessels and an essential step in 

tumor growth, requires COX-2 [84]. In fact, COX-2 

overexpressing cells produce large amounts of vascular 

endothelial growth factor (VEGF), a key proangiogenic 

factor, which stimulates both endothelial migration and in 

vitro angiogenesis [102]. These effects may be blocked by 

selective COX-2 inhibitors, highlighting the potential 

application of these compounds in blocking developing 

tumors [113]. On the other hand, mice lacking the COX-2 

gene have deficient VEGF expression, reduced tumor 

angiogenesis and decreased tumor growth [117]. Moreover, 

selective inhibition of COX-2, but not COX-1, suppresses 

the growth of corneal capillary blood vessels in rats exposed 

to basic fibroblast growth factor and inhibits the growth of 

several human tumors implanted in mice [117, 118]. Taken 

together, these results support the notion of the benefit of 

selective COX-2 inhibition as an anti-angiogenic therapy. 

In addition to the well-documented implication of COX- 

2 in colon cancer, several investigations have recently 

examined its potential role in other epithelial cancers. These 

studies have provided strong evidence that COX-2 may also 

be implicated in breast, head and neck, lung, pancreatic and 

gastric cancers and suggest that the beneficial effects of 

COX-2 inhibitors may extend to these other cancers [119- 

122]. Indeed, celecoxib consistently and dose-dependently 

inhibits tumor growth and the number of lung metastasis in 

the syngenic Lewis lung carcinoma model [116]. 

Interestingly, in animal studies, celecoxib has been shown to 

potentiate the antitumor activity of conventional 

chemotherapy and radiation [123, 124]. 

COX-2 and the Kidney 

PGs play multiple roles in the adult kidney. PGE2 and 

PGI2 are powerful renal vasodilators that modulate intrarenal 

vascular tone and influence glomerular hemodynamics and 

renal perfusion [125, 126]. Moreover, PGE2 modulates renal 

sodium through direct inhibition of sodium reabsorption in 

tubular epithelial cells [125, 126]. PGE2 also modulates 

renal water homeostasis by antagonizing the hydroosmotic 

effect of antidiuretic hormone in the collecting duct [125, 

126]. Finally, PGs are involved in the renal responses to 

loop diuretics and in the regulation of renin secretion [126, 

127]. Since PG synthesis is initiated by COX-1 and COX-2, 

and both COX isoforms are constitutively expressed in the 

kidneys [128, 129], it was of interest to establish which 

COX isoform is involved in the maintenance of renal 

function under normal conditions. The distribution of COX- 

1 in the renal area differs significantly from that of COX-2. 

In this regard, COX-1 is preferentially expressed in the renal 

vasculature and in the medullary and papillary collecting 

ducts in humans, monkeys, dogs, rabbits and rats, whereas 

COX-2 expression is consistently focal, and limited to the 

macula densa of the juxtaglomerular apparatus, epithelial 

cells of the thick ascending limb and papillary interstitial 

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

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


endothelial and smooth muscle cells of arteries and veins, 

and intra-glomerularly in podocytes, but not in macula densa 

cells [130]. 

At present, it is hypothesized that only PGs derived from 

COX-1 are involved in normal renal function. The marketed 

selective COX-2 inhibitors, rofecoxib and celecoxib, have 

been evaluated in randomized controlled trials in terms of 

their effects on renal PGs, renal function and occurrence of 

adverse renal events. Most of the studies have reported that 

selective COX-2 inhibition does not significantly impair 

renal function in healthy subjects [131]. Nevertheless, it is 

worthy to note that in healthy elderly patients, a population 

more susceptible to renal NSAID-damaging effects, both 

celecoxib and rofecoxib induce a reduction in urinary sodium 

excretion similar to that of indomethacin and naproxen [132, 

133]. Although the role of COX-2-derived PGs in the kidney 

is still under debate, the finding that mice lacking the COX- 

2 gene develop mild to severe nephropathy during the first 

weeks after birth [134, 135], supports the eventuality that 

COX-2-derived PGs may play a physiological role in the 

kidney other than maintenance of circulatory and excretory 

functions. 

The incidence of renal side effects secondary to NSAID 

treatment is low, and the role of PGs in renal homeostasis is 

hardly noticeable in healthy subjects. In contrast, 

administration of NSAIDs to patients with unbalanced 

effective arterial blood volume represents a major clinical 

problem since renal function in these patients is critically 

dependent on PGs [37]. In these circumstances, which 

include low sodium diet, hemorrhagic hypovolemia and 

edematous conditions associated with congestive heart 

failure, nephrotic syndrome and decompensated liver 

cirrhosis, NSAIDs induce a pronounced impairment in renal 

plasma flow, glomerular filtration rate, urine volume and 

urinary sodium excretion. Since selective COX-2 inhibitors 

have been developed to effectively inhibit COX-2 while 

sparing physiologic PG production from COX-1, these novel 

compounds could potentially be the anti-inflammatory of 

choice in these patients. In this regard, in recent studies in 

rats with carbon tetrachloride-induced cirrhosis and ascites, an 

experimental model that closely reproduces human liver 

disease, selective COX-2 inhibition with celecoxib did not 

seriously compromise renal function [48, 49]. Interestingly, 

in these animals COX-1 protein expression was found to be 

unchanged whereas COX-2 protein levels were consistently 

upregulated [49]. Therefore, these results indicate that despite 

abundant renal COX-2 protein expression, the maintenance of 

renal function in altered effective arterial blood volume 

conditions, such as liver cirrhosis is mainly dependent on 

COX-1-derived PGs. 

COX-2 and the Brain 

PGs have long been recognized as mediators of fever. 

Fever is produced by PGE2, acting on temperature-sensing 

neurons in the preoptic area [136]. The endogenous feverproducing 

PGE2 is thought to originate from COX-2 induced 

by lipopolysaccharide or interleukin-1 in endothelial cells 

lining the cerebral blood vessels [137]. In fact, 

intraperitoneal injection of lipopolysaccharide to rats induces 

COX-2 in brain endothelial cells in parallel with the 

appearance of fever [138]. Moreover, selective inhibitors of 

COX-2 are potent antipyretic agents [139]. 

PGs are also now recognized as mediators of 

inflammatory reactions in neural tissue and more recently of 

brain function. Constitutive COX-2 immunoreactivity and 

COX-2 mRNA expression have been detected in neurons and 

specially in the forebrain [140]. The expression of COX-2 in 

the brain is particularly high in neonates [141]. Since brains 

of neonates have higher levels of cerebral PGs than those of 

adults [141], and since these PGs are involved in the 

regulation of blood flow in the newborn [142], this 

phenomenon suggests that COX-2 is likely to be important 

in the modulation of blood flow at this stage of life. 

Furthermore, COX-2 is thought to play a key role in the 

final stages of development and brain modeling when COX- 

2 becomes active in a manner that coincides with the 

imprinting of environmental influences [143]. 

Intense nerve stimulation, leading to seizures, induces 

COX-2 mRNA in discrete neurons of the hippocampus, 

whereas acute stress raises levels in the cerebral cortex [140, 

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

understood, but associations between COX-2 induction and 

neural degeneration after glutamate stimulation, seizures and 

spreading depression waves suggest that COX-2 may play 

more of a role in the selective loss of neural connections than 

in their formation [145]. Finally, current studies show that 

COX-2 potentiates brain parenchymal amyloid plaque 

formation leading to Alzheimer’s disease, thus supporting a 

therapeutic potential for NSAIDs and COXIBs in the 

treatment of this neurological disease [146]. 

COX-2 and the Reproductive Function 

PGs are important for inducing uterine contractions 

during labor. NSAIDs, such as indomethacin, delay 

premature labor by inhibiting the production of PGs [147]. 

However, the inhibition of PGs with indomethacin led to a 

high mortality among infants because of premature closure of 

the ductus arteriosus, a circulatory shunt maintained by PGs 

that allows the output of the left ventricle to bypass the fetal 

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

role in the birth process because COX-2 mRNA in the 

amnion and placenta increases markedly immediately before 

and after the initiation of labor [149]. Theoretically, selective 

inhibitors of COX-2 are able to reduce PG synthesis in fetal 

membranes and could be useful in delaying premature labor 

without the unwanted side effects of traditional NSAIDs. 

However, COX-2 also plays a role in ovulation, the 

successful rupture of the follicle and in the implantation of 

the embryo in the uterine endometrium [150]. Indeed, COX- 

2 null mice show multiple failures in reproductive function, 

including ovulation, fertilization, implantation and 

decidualization [151]. 

COX-2 and Inflammation and Arthritis 

The most important action of PGs is their role in 

inflammation [4]. In response to an inflammatory insult, the 

release of PGs, and more importantly PGE2, constitutes a 

key event in the development of the three cardinal signs of 

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


potent vasodilatory properties, PGE2 increases tissue blood 

flow, which results in the characteristic erythema (redness) of 

inflammation [4]. On the other hand, together with other 

soluble factors including bradykinin, histamine and 

leukotrienes, PGE2 increases vascular permeability 

contributing to fluid extravasation and the appearance of 

edema (swelling) [4]. PGE2 also sensitizes afferent nerve 

fibers acting both at peripheral sensory neurons and at central 

sites within the spinal cord and brain to evoke hyperalgesia 

(pain) [4]. Finally PGE2 is a potent pyretic mediator 

involved in the appearance of fever [136]. Moreover, PGs 

also contribute to the amplification of the inflammatory 

response by enhancing and prolonging signals produced by 

pro-inflammatory agents, such as bradykinin, histamine, 

neurokinins and complement. 

Although the importance of COX and PGs in 

inflammation has been known for years, the inducibility of 

COX and PG formation has only fully been appreciated 

recently with the uncovering of the properties of COX-2. 

COX-2 was originally discovered as a transcript that was 

upregulated during inflammation and cellular transformation 

[19-21]. Animal models of inflammatory arthritis provided 

the first available information regarding expression of COX- 

2 in acute and chronic inflammation, indicating that 

increased expression of COX-2 is responsible for the 

increased PG production seen in inflamed joint tissues [75]. 

COX-2 induction was observed in both human osteoarthritisaffected 

cartilage as well as in synovial tissue taken from 

patients with rheumatoid arthritis [152, 153]. The critical 

role of COX-2 in inflammation led to the rational design of 

the first clinical trials for selective COX-2 inhibitors in 

patients with osteoarthritis and rheumatoid arthritis [42-45]. 

The results of these drug-screening studies are sufficient to 

guarantee that COX-2 inhibitors achieve the same antiinflammatory 

efficacy as traditional NSAIDs [42-45]. 

COX-2 and the Cardiovascular System 

The major effects of PGs on the cardiovascular system are 

on the smooth muscle cells and platelets where prostacyclin 

(PGI2) has opposite biologic properties to those of TXA2. 

Thus, on the vasculature and especially on veins, PGI2 

mainly promotes vasorelaxation while TXA2 acts as a 

vasoconstrictor [4]. It was classically considered that PGI2 

produced by vascular endothelial and smooth muscle cells 

was formed via COX-1. However, recent work has 

demonstrated that PGI2 in vascular cells is produced by 

COX-2 as well as COX-1 [28]. Treatment of volunteers with 

a selective COX-2 inhibitor decreased urinary excretion of 

PGI2 without affecting TXA2 [132]. These results raised the 

possibility of an increased risk of cardiovascular events 

associated with COXIBs. However, two major randomized 

trials have recently shown that the relative risk of a 

cardiovascular event with selective COX-2 inhibitors is 

similar to that of traditional NSAIDs [154, 155]. On the 

other hand, in platelets, TXA2 induces platelet aggregation 

whereas PGI2 strongly inhibits aggregation. It is widely 

recognized that platelets express only COX-1. Nevertheless, 

in certain stages of megakaryogenesis, COX-2, as well as 

COX-1 are detected [156]. The biological significance of this 

phenomenon is, at present, unclear. 

ABBREVIATIONS 

COX = Cyclooxygenase 

COXIBs = Selective COX-2 inhibitors 

FAP = Familial adenomatous polyposis 

LT = Leukotrienes 

NSAIDs = Non-steroidal anti-inflammatory drugs 

PGs = Prostaglandins 

TX = Thromboxane 

VEGF = Vascular endothelial growth factor 

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Cyclooxygenase-2 Biology

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