Potential Role of Selective COX-2 Inhibitors in Cancer Management

Potential Role of Selective COX-2 Inhibitors in Cancer Management

ABSTRACT: Tumorigenesis is a complex process, and understanding the mechanisms behind tumorigenesis is key to identifying effective targeted therapies. Prostaglandins are signaling lipophilic molecules derived from phospholipids that are involved in normal physiologic functions. However, overexpression of prostaglandins has been associated with tumorigenesis. Several epidemiologic studies have shown an inverse correlation between the incidence of colon cancer and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin synthesis. The NSAIDs target cyclooxygenases (COX), essential enzymes in prostaglandin production. Cyclooxygenase-2 (COX-2) is an inducible form of the enzyme that is usually not expressed in normal tissue. Because COX-2 is frequently overexpressed in premalignant lesions and neoplasms, specific COX-2 inhibitors have been investigated as chemoprevention and potential chemotherapeutic agents. There is now preclinical and early clinical data that suggest inhibitors of COX-2 may protect against colon, breast, lung, esophageal, and oral tumors. This paper will discuss evidence addressing the possible mechanistic contribution of COX-2 in tumorigenesis and will explore the link between COX-2 activity and carcinogenesis. The potential role of COX-2 inhibitors in the chemoprevention and treatment of various tumors will also be discussed. Clinical trials using targeted inhibitors of COX-2 will be critical in determining if COX-2 is a viable molecular target in cancer management. [ONCOLOGY 16(Suppl 4):30-36, 2002]

Prostaglandins and their derivatives are
signaling lipophilic molecules that are involved in diverse homeostatic and
reactive functions, including platelet aggregation, clot formation,
vasodilation, and gastric cytotoxic protection, as well as renal sodium and
water balance. The first step in the synthesis of prostaglandins is the
hydrolysis of membrane phospholipids to arachidonic acid by phospholipase A2.
Arachidonic acid is then converted to an unstable product, prostaglandin G2,
which is rapidly converted to prostaglandin H2 by the peroxidase activity of a
cyclooxygenase (COX). Prostaglandin H2 is converted by tissue-specific enzymes
to other prostaglandins and thromboxanes.

There are two isoforms of the COX enzyme encoded by two
different genes. Cyclooxygenase-1 (COX-1) is a constitutive enzyme that is
present in most normal tissues and mediates the synthesis of prostaglandins
required for normal physiologic functions. The gene for COX-1 is on human
chromosome 9.[1] Cyclooxygenase-2 (COX-2) is an inducible form of the enzyme
that is not normally detected in most tissues and is coded by a gene on human
chromosome 1.[2] Cyclooxygenase-2 is induced by cytokines, growth factors, tumor
promoters, and carcinogens.[3] Cyclooxygenase-2 is also induced by several
oncogenes, such as v-Src, v-Ha-ras, HER2/neu and Wnt.[4-7]

Although prostaglandins are involved in many normal physiologic
functions, these molecules—and the COX enzymes involved in prostaglandin
production—may also be involved in tumorigenesis. Indeed, there is evidence
that prostaglandins may contribute to tumorigenesis by inhibiting the immune
system, stimulating cell growth, enhancing angiogenesis, increasing mutagen
production, enhancing cell invasion, or inhibiting apoptosis. In this article,
we will discuss these mechanisms and will explore the role of COX-2 in
tumorigenesis. We will also review clinical trials that have investigated COX-2
inhibitors as chemoprotection agents and will discuss future directions in the
study of COX-2 as a therapeutic target in cancer management.

Mechanisms of Prostaglandins in Carcinogenesis

Immunosuppressive Effects

Prostaglandins have a variety of immunosuppressive effects. For
example, prostaglandin E2 diminishes the cytotoxic activity of natural killer
cells, inhibits T-cell and B-cell growth, and decreases the production of
cytokines including tumor necrosis factor-alpha. Huang et al[8] showed that
pretreatment with a prostaglandin inhibitor prevents an increase in
interleukin-10 synthesis by peripheral blood lymphocytes. Furthermore,
prostaglandins may also interfere with antigen processing by dendritic cells.[9]
The ability of prostaglandins to inhibit the immune system may allow tumors to
grow without surveillance and may contribute to tumorigenesis.

Mitogenic Effects

Enhanced prostaglandin synthesis may also contribute to
tumorigenesis by direct stimulation of cell growth. Data have shown that
prostaglandin E2 and prostaglandin F2-alpha can be mitogenic in BALB/c3T3
fibroblasts in the presence of epidermal growth factor.[10] Furthermore,
proliferation of mammary epithelial cells can be stimulated in the presence of
epidermal growth factor by prostaglandin E1 and prostaglandin E2.[11] In breast
tissue, prostaglandins may stimulate cell growth by stimulating the aromatase
gene, CYP19, and thus enhancing estrogen synthesis.[12,13] Interestingly,
enhanced expression of CYP19 and COX has been found in human breast cancer

Inhibition of Apoptosis

Prolonged survival of abnormal cells favors the accumulation of
genetic changes that may result in tumor formation. Therefore, inhibition of
apoptosis may increase the tumorigenic potential of initiated cells. Sheng et
al[15] demonstrated that prostaglandin E2 may inhibit apoptosis by inducing
bcl-2. Recently it was shown that inhibition of COX-2 by celecoxib (Celebrex), a
selective COX-2 inhibitor, resulted in a decrease of production of prostaglandin
E2 and TXB2, and was associated with an increase in apoptosis in vivo.[16]

Mechanisms of Cyclooxygenase in Carcinogenesis

Effects on Metastatic Potential

Enhanced COX-2 expression may also contribute to tumorigenesis
by increasing cell invasiveness. DuBois et al[17] showed that COX-2
overexpression in rat intestinal epithelial cells increases cell adhesion to the
extracellular matrix. Recently, Stockton and Jacobson[18] demonstrated that
COX-2 is required for NIH3T3 cell migration in a process that appears to be
regulated by the extracellular signal-regulated kinase 1/2. Furthermore, the
activity of enzymes responsible for digesting cellular basement membrane is
enhanced by COX-2 overexpression in the breast cancer cell line Hs578T and colon
cancer cells, which likely contributes to the increased ability of these cells
to invade through a layer of Matrigel.[19,20]

Increased Production of Mutagens

Another mechanism by which COX-2 overexpression may play a role
in carcinogenesis is an increase in the production of mutagens. One such potent
mutagen is malondialdehyde, which can be produced by isomerization of
prostaglandin H2. Malondialdehyde acts by forming adducts with deoxynucleotides,
which cause frame-shifts and base-pair substitutions.[21] In addition, Wiese et
al[22] showed that the peroxidase activity of cyclooxygenases can catalyze the
formation of mutagens by the oxidation of aromatic amines, heterocyclic amines,
and dihydrodiol derivatives of polycyclic hydrocarbons. Thus, COX-2
overexpression may lead to DNA damage that may eventually lead to


Cyclooxygenase-2 has also been implicated in enhanced
angiogenesis, which plays a role in carcinogenesis. Tumor growth depends on
increased blood supply via secretion of angiogenic promoters such as vascular
endothelial growth factor. Cyclooxygenase-2 overexpression in colon cancer cells
is correlated with increased production of vascular growth factors and formation
of capillary networks.[23] This angiogenic effect of COX-2 can be blocked by
NS398, a selective COX-2 inhibitor. Williams et al[24] demonstrated that tumor
formation is markedly decreased in COX-2 knockout mice compared with wild-type
mice. Furthermore, the pharmacologic inhibition of COX-2 leads to a decrease in
vascular endothelial growth factor production that may contribute to a decrease
in tumor formation. Masferrer et al[25] showed that celecoxib, a selective COX-2
inhibitor, blocks corneal blood vessel formation in a rat model. Thus, COX-2
overexpression may increase tumor blood supply and may contribute to tumor

Further Links Between COX-2 and Tumorigenesis

Cyclooxygenase-2 is upregulated in multiple human premalignant
and malignant conditions, including tumors of the colon, breast, stomach, lung,
pancreas, cervix, prostate, bladder, liver, skin, head and neck, and esophagus (Table
).[26-40] There are multiple lines of evidence suggesting a link between
levels of COX-2 and tumorigenesis. Increased levels of COX-2 are detected in
premalignant intestinal tumors in experimental animal models.[41] The knockout
of the COX-2 gene led to a marked reduction in the size and number of polyps in
APCD716 mice. In addition, APCD716 mice treated with a selective COX-2 inhibitor
had reduced adenoma formation.[42] Further, COX-2 knockout mice develop fewer
skin papillomas than control mice.[43] Taken together, these results suggest
that inhibition of COX-2 could be important in the prevention of a variety of
epithelial tumors.

Synthetic and naturally occurring inhibitors of COX (eg,
sulindac [Clinoril], ibuprofen, flurbiprofen [Ansaid], indomethacin [Indocin])
have also been shown to protect against mammary, colon, oral, and esophageal
cancer in experimental animals.[44-50] For example, studies have shown that
flurbiprofen, an inhibitor of COX-1 and COX-2, can inhibit the growth of
transplanted mammary tumors[51] and increase the mean survival duration in
mice.[52] In addition to having therapeutic activity against established mammary
tumors, flurbiprofen inhibits mammary carcinogenesis induced by a low dose of
N-methyl-N-nitrosourea in rats.[46] Other data have also demonstrated that
indomethacin, another inhibitor of both COX-1 and COX-2, has significant
chemoprotective activity in rats when administered during either the early or
late stage of mammary tumorigenesis.[47] Importantly, epidemiologic studies have
shown that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs)
reduces the incidence of various human cancers, including cancers of the colon,
breast, lung, esophagus, stomach, and bladder.[53-60]

Celecoxib has been evaluated as a possible chemopreventive agent
for the inhibition of tumorigenesis. In a study to evaluate the inhibitory
activity of celecoxib against azoxymethane-induced aberrant crypt foci formation
in the colon of rats, celecoxib significantly suppressed the total number of
aberrant crypt foci in rats compared with placebo.[61] In a second study of
azoxymethane-treated rats, celecoxib reduced the incidence of colon cancer by
93% and tumor multiplicity by 97%.[62] These animal data provide strong evidence
that celecoxib has cancer activity in the prevention of cancer when tested in a
defined model of tumorigenesis.

Recently, Harris et al[63] compared the chemoprevention effects
of celecoxib with ibuprofen and placebo in the development and growth of
7,12-dimethyl-benz(a)anthracene (DMBA)-induced rat mammary tumors. Seven days
prior to receiving a single dose of 15 mg of DMBA by intubation, rats were fed
either a control diet or diets containing 1,500 ppm of celecoxib or 1,500 ppm of
ibuprofen. Both celecoxib and ibuprofen significantly increased tumor latency,
reduced tumor burden, and prevented tumor formation compared with placebo.
However, celecoxib was more potent than ibuprofen. At 105 days after DMBA
treatment, tumor incidence was 100% in control rats compared with 32% and 60% in
rats fed either celecoxib (P < .001) or ibuprofen (P < .001),
respectively. The control rats had an average of 3.2 tumors compared with 0.4
and 1.5 tumors in rats treated with celecoxib (P < .001) and ibuprofen
< .001), respectively. Additionally, the average tumor volume was 1.5 cm³ in
control rats vs 0.3 cm³ and 0.6 cm³ in rats treated with celecoxib (P < .001)
or ibuprofen (P < .001), respectively. The higher potency of celecoxib
suggests that this agent may have an in vivo advantage over other NSAIDs as a
chemoprevention agent.[63]

The DMBA-induction model was also used to evaluate celecoxib for
efficacy against established tumors. Alshafie et al[64] examined the effect of
celecoxib, given as a daily diet (1,500 ppm), on the growth of established DMBA-induced
tumors in rats over a 6-week treatment period. Tumors in the control group
continued to grow; whereas tumors in the celecoxib group markedly decreased in
size. The average reduction in tumor volume relative to baseline was
approximately 32% (P < .04). At the end of the 6-week treatment period,
average tumor volume was 1.45 cm³ and 0.13 cm³ in the control and celecoxib
groups, respectively. Tumor volume regression occurred in 90% of rats treated
with celecoxib.[64] These results suggest that celecoxib has potent antitumor
activity and chemoprevention activity in this rat mammary carcinoma model.


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