Cyclooxygenase2 and prostate carcinogenesis

11
Mini-review Cyclooxygenase-2 and prostate carcinogenesis Tajamul Hussain a , Sanjay Gupta b , Hasan Mukhtar a, * a Department of Dermatology, University of Wisconsin, Medical Science Center, 1300 University Avenue, Madison, WI, 53706, USA b Department of Urology, Jim & Eilleen Dicke Research Laboratory, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA Received 23 August 2002; accepted 29 August 2002 Abstract In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti- inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our recently published study (Prostate, 42 2000 73 – 78), we provided the first evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up- regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects against prostate carcinogenesis in humans. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cyclooxygenase enzyme; Prostate cancer; Non-steroidal anti-inflammatory drugs; Inflammation; Prostaglandin 1. Introduction The incidence of prostate cancer has strongly increased during the past decades and it has now become the most common malignancy of men in many Western nations [1]. In the USA, among males, prostate cancer is the second leading cause of cancer- related deaths next only to lung cancer [2]. According to projections by the American Cancer Society, a total of 189 000 men will be diagnosed with prostate cancer in the USA in the year 2002, and 30 200 prostate cancer-related deaths are predicted this year [3]. Of great concern is that fact that more than 50% of prostate cancer patients present with or develop incurable metastatic disease [4]. Although most patients with advanced prostate cancer initially respond to androgen ablation treatment, relapse to an androgen-indepen- 0304-3835/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3835(02)00524-4 Cancer Letters 191 (2003) 125–135 www.elsevier.com/locate/canlet * Corresponding author. Tel.: þ1-608-263-3927; fax: þ 1-608- 263-5223. E-mail address: [email protected] (H. Mukhtar).

Transcript of Cyclooxygenase2 and prostate carcinogenesis

Mini-review

Cyclooxygenase-2 and prostate carcinogenesis

Tajamul Hussaina, Sanjay Guptab, Hasan Mukhtara,*

aDepartment of Dermatology, University of Wisconsin, Medical Science Center, 1300 University Avenue, Madison, WI, 53706, USAbDepartment of Urology, Jim & Eilleen Dicke Research Laboratory, Case Western Reserve University, 10900 Euclid Avenue,

Cleveland, OH, 44106, USA

Received 23 August 2002; accepted 29 August 2002

Abstract

In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and

prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in

the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with

distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is

involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens,

cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large

number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and

progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti-

inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our

recently published study (Prostate, 42 2000 73–78), we provided the first evidence that COX-2 is overexpressed in human

prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2

is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up-

regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors

could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting

corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects

against prostate carcinogenesis in humans.

q 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Cyclooxygenase enzyme; Prostate cancer; Non-steroidal anti-inflammatory drugs; Inflammation; Prostaglandin

1. Introduction

The incidence of prostate cancer has strongly

increased during the past decades and it has now

become the most common malignancy of men in many

Western nations [1]. In the USA, among males,

prostate cancer is the second leading cause of cancer-

related deaths next only to lung cancer [2]. According

to projections by the American Cancer Society, a total

of 189 000 men will be diagnosed with prostate cancer

in the USA in the year 2002, and 30 200 prostate

cancer-related deaths are predicted this year [3]. Of

great concern is that fact that more than 50% of prostate

cancer patients present with or develop incurable

metastatic disease [4]. Although most patients with

advanced prostate cancer initially respond to androgen

ablation treatment, relapse to an androgen-indepen-

0304-3835/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved.

doi:10.1016/S0304-3835(02)00524-4

Cancer Letters 191 (2003) 125–135

www.elsevier.com/locate/canlet

* Corresponding author. Tel.: þ1-608-263-3927; fax: þ1-608-

263-5223.

E-mail address: [email protected] (H. Mukhtar).

dent state occurs shortly leading to tumor outgrowth

[5]. Despite the clinical importance of prostate cancer,

the molecular mechanisms underlying the develop-

ment and progression of this disease are poorly

understood. Therefore, much research is needed

towards understanding the mechanisms involved in

development and progression of prostate cancer and

developing new strategies for its prevention and

treatment. The present article reviews the role of

COX-2 in prostate carcinogenesis. Based on the

evidence available, selective COX-2 inhibitors offer

promise for prevention and therapy of prostate cancer.

2. Cyclooxygenases and prostaglandins

Cyclooxygenase (COX) or prostaglandin (PG)

endoperoxide synthase is a rate limiting enzyme in

the PG biosynthesis [6]. COX is a bi-functional

enzyme containing a COX site that converts arachi-

donic acid to prostaglandin endoperoxide synthases

(PGG)2 and a peroxidase site that reduces PGG2 to

PGH2 (Fig. 1) [7]. The PGs are a diverse group of

autocrine and paracrine hormones that mediate many

cellular and physiological processes [6–8]. COX

exists in two isoforms commonly known as COX-1

and COX-2, the order in which they were identified

[8–10]. Although both isoforms catalyze the same

enzymatic reactions and have similar Km and Vmax

values for arachidonic acid, significant differences

exist between them [11]. COX-1 is constitutively

expressed in majority of the cells performing the house

keeping functions that require immediate generation of

prostanoids related to vascular homeostasis, water

reabsorption, gastric acid secretion, platelet aggrega-

tion and renal blood flow [10,11]. COX-1 is located on

human chromosome 9q32-q33.3 spanning 25 kb in size

containing 11 exons and produces 2.8 kb mRNA which

synthesizes about 68 kDa protein [10,11]. In contrast,

COX-2 is a pro-inflammatory and inducible enzyme

Fig. 1. Bi-functional role of the COX enzyme in the biosysnthesis of prostaglandins, prostacyclins and thromboxanes and their physiological

and pathophysiological effects.

T. Hussain et al. / Cancer Letters 191 (2003) 125–135126

which can be induced by mitogens, tumor promoters,

cytokines and growth factors in different cell types and

controlled at both the transcriptional and post-transla-

tional levels [10–12]. COX-2 in involved in differ-

entiative processes, such as inflammation, ovulation,

and labor, in situation where only transient PG

production is required [9–11]. COX-2 is an 8 kb

gene with 10 exons located on human chromosome

1q25.2–q25.3 and transcribes a 4.1–4.5 kb mRNA

which encodes a protein of about 68 kDa [9–11].

Although, genes for COX-1and COX-2 are located on

two separate chromosomes but they are highly related

at the DNA, RNA, and protein level. COX-1 and COX-

2 consist of 576 and 587 amino acids, respectively, and

they share approximately 60% primary sequence

homology [12,13]. Both these enzymes exist as

integral membrane glycoprotein homodimers and are

found on the luminal surfaces of the endoplasmic

reticulum and nuclear envelop [14,15].

3. COX-2 and cancer

In recent years, overexpression of COX-2 has been

implicated in the progression of cancer [16,17].

Aberrant or increased expression of COX-2 has been

found in most of the cancers of the body sites [9,

16–18]. Compelling evidence from genetic and

clinical studies indicates that COX-2 upregulation is

one of the key steps in carcinogenesis [19]. Recent

studies have shown that overexpression of COX-2 is

sufficient to cause tumorigenesis in animal models and

subsequently inhibition of the COX-2 pathway results

in reduction in tumor incidence and progression (Fig.

2) [20]. There are some exceptions to this generally

accepted observation. One recent study has shown that

COX-2 overexpression in the skin of transgenic mice

results in suppression of tumor development [21]. In

sharp contrast, another recent study has shown that

deficiency of COX-2 reduces mouse skin tumorigen-

esis [22]. Based on these observations it is clear that

much additional work with targeted tissue specific over

and under expression of COX-2 is required to firmly

establish the role of this enzyme in target organ

carcinogenesis. However, based on these evidences the

potential application of non-steroidal anti-inflamma-

tory drugs (NSAIDs) as well as recently developed

COX-2 specific inhibitors in cancer clinical practice

has drawn tremendous attention in the past few years as

inhibition of COX-2 offers an effective approach in the

prevention and treatment of cancer [23,24].

4. Diet and prostaglandins in prostate

carcinogenesis

Epidemiologic studies and nutritional data suggest

that androgens and/or environmental exposures, such

as diet in particular, dietary fat, play an important role

in prostate carcinogenesis [25]. The association

Fig. 2. Possible involvement of COX-2 and their inhibitors in various stages of prostate cancer.

T. Hussain et al. / Cancer Letters 191 (2003) 125–135 127

between diet and prostate cancer has been drawn from

the studies where incidence and mortality rates of

prostate cancer vary widely between different popu-

lations in various regions of the world consuming

more dietary fat [26]. Number of studies have

reported this link; countries such as the USA,

known to have high levels of fat consumption, were

also found to have a high mortality rate for prostate

cancer, whereas a country such as Japan, with one of

the lowest rates of fat consumption in the world, has a

low mortality rate for the disease [27]. In addition,

migratory studies have further confirmed this obser-

vation where it was found that Asian men migrating to

the United States acquire a higher clinical incidence

of prostate cancer, and subsequent generations of

American born Asian men have prostate cancer risks

almost equal to those of white Americans [28]. These

studies suggest that a change in dietary habits can

greatly modify prostate cancer risk. However, the

results of most case-control studies demonstrated a

significant association of prostate cancer risk with

high dietary intake of total fat while some studies did

not find a significant association [29,30].

Laboratory studies with experimental animal

models further suggest a link between fat content in

diet and the risk of prostate cancer [31]. Arachidonic

acid and its precursor, linoleic acid, are major

ingredients of animal fat and many vegetable oils

used in the regions where prostate cancer is more

common [32]. Studies have shown that treatment of

androgen-unresponsive human prostate carcinoma

cells PC-3 with linoleic acid stimulated the growth

of these cells [33].The effects of these fatty acids are

thought to be caused by their effects on PG synthesis.

A study by Hughes-Fulford et al. [34] has demon-

strated that linoleic acid, arachidonic acid and the

arachidonic acid metabolite prostaglandin (PGE)(2)

stimulate prostate tumor growth and alters gene

expression in human prostate carcinoma PC-3 cells.

Treatment of PC-3 cells with arachidonic acid was

shown to result in a dose-dependent increase in the

gene expression of c-fos, and COX-2, while the

constitutive COX-1 message was not increased.

Further effects of dietary fat was examined on the in

vivo models, where transplantation of human prostate

carcinoma cells DU145 to nude mice fed with high fat

diet was shown to result in a significant increase in

tumor growth compared to the control group of

animals fed with regular diet [35]. These studies

suggest a stimulatory effect of dietary n-6 fatty acid on

prostate cancer cell growth which may be critical for

the development and progression of prostate cancer.

Intake of unsaturated dietary fat may affect PG

synthesis, that appear to influence sex hormone levels;

this raises the possibility that increased levels of

androgens could play an important role in the

initiation of prostate cancer [36]. Studies have

shown that testosterone is capable of stimulating

oxidative stress in prostate carcinoma cells that has

been suggested to be a mechanism of initiation of

prostate carcinogenesis [37]. However, there is no

such study indicating that increase in testosterone

levels leads to an increase in COX-2 expression

during the development and progression of prostate

cancer.

5. COX-2 and prostate cancer

Studies on relationship of COX and prostate were

initiated in 1993 by O’Neill and Ford-Hutchinson [38]

who analyzed COX-1 and COX-2 mRNA expression

in various human tissues and reported the highest

levels in the prostate where COX-1 and COX-2

transcripts were found to be present in approximately

equal levels. In the year 2000, we provided the first

evidence that COX-2 is overexpressed in human

prostate adenocarcinoma [39]. Employing 12 pairs of

unique benign and prostate carcinoma tissue from the

same individuals we showed that mean levels of

COX-2 mRNA expression was significantly increased

in prostate adenocarcinoma. These results were

further verified by the COX-2 protein expression,

which was significantly higher in cancer tissue

compared to their benign counterparts. Many other

studies verified our initial observation and reported

that compared to normal tissue, COX-2 is over-

expressed in human prostate cancer.

A study by Yoshimura et al. [40] analyzed tumor

specimens obtained from 28 prostate carcinoma

patients, eight benign prostatic hyperplasia (BPH)

patients, one prostatic intraepithelial neoplasia (PIN)

patient, and eight specimens of normal prostate tissue

and showed very weak expression of COX-1 and

marked expression of immunoreactive COX-2 in

prostate tumor cells. The expression of both COX-

T. Hussain et al. / Cancer Letters 191 (2003) 125–135128

isoforms was found to be very weak in all cases of

BPH and in the normal prostate tissues. Further, the

extent and intensity of immunoreactive COX-2

polypeptides in tumor cells was statistically much

greater than those of cells from BPH. These results

were further confirmed by mRNA analysis, where

enhanced expression of COX-2, but not COX-1, was

observed in prostate cancer tissues. These results lead

to the conclusion that human prostate carcinoma cells

generated COX-2, and that COX-2 might play an

important role in the proliferation of prostate

carcinoma cells. Studies by Kirschenbaum et al. [41]

analyzed thirty-one specimens of prostate carcinoma

and 10 specimens of BPH and showed that COX-1

expression in noncancerous prostatic tissue was

predominantly (90% positive staining) seen in the

basal epithelial cells of BPH. COX-1 expression was

minimal in noncancerous luminal epithelial cells and

was found to be upregulated in prostate cancer

predominantly in the smooth muscle cells of the

prostate. COX-2 was found to be expressed in the

basal epithelial cells with 60% BPH, 94% peripheral

zone, 75% PIN, respectively. The expression of COX-

2 in prostate cancer was found to be intense and

uniform, with 87% of samples demonstrating immu-

noreactivity. The results of this study indicated that

expression of both COX-1 and COX-2 in human

prostate cancer is increased suggesting that COX-1

and COX-2 (and/or their PG products) may play a role

in the malignant transformation of the prostate. In

another study, Madaan et al. [42] have determined

COX-1 and COX-2 expression in 30 BPH and 82

prostate cancer specimens. In this study a significant

COX-2 overexpression in tumor cells was found

compared to benign glands; however, COX-1

expression in tumor cells was similar to benign

glands. A significant positive correlation between

COX-2 expression was found with increasing tumor

grade suggesting that COX-2 may play an important

role in prostate carcinogenesis. These studies are in

agreement with the study by Lee et al. [43] where

COX-2 was found to be over-expressed in 15 out of 18

(83%) prostate cancer samples and was detected in

only 22% (4/18) of paired benign tissues. Further, the

intensity of immunostaining correlated with the tumor

grading of these specimens. Another recent study by

Uotila et al. [44] has compared COX-1 and COX-2

mRNA and protein expression from 12 prostate

cancer specimens and 13 control prostates. The

intensity of COX-2 was found to be significantly

stronger in prostate cancer cells than in the non-

malignant glandular epithelium of the control pros-

tates. COX-2 was found to be clearly expressed in the

lesions of PIN in control prostates and was also

detected in the muscle fibers of the hyperplastic

stroma. No significant difference was found in COX-1

expression between control and prostate cancer. The

results of this study indicated that the expression of

COX-2 is elevated in prostatic adenocarcinoma and in

PIN. These experimental data generated from both

human prostate tumor tissue specimen and from

prostate cancer cell lines demonstrated an up-

regulation of inducible COX-2 expression and

suggested a positive role for COX-2 in prostate

carcinogenesis. However, in contrast to these obser-

vations a recent study performed immunohistochem-

ical analysis of 144 human prostate cancer cases and

found that there was no consistent overexpression of

COX-2 in established prostate cancer or high grade

PIN, as compared with adjacent normal prostate tissue

[45]. Positive staining was only seen in scattered cells

in both tumor and normal tissue regions but was much

more consistently observed in areas of proliferative

inflammatory atrophy, lesions that have been impli-

cated in prostatic carcinogenesis. Studies cited above

clearly point to the need of additional studies to

examine COX-2 expression in diverse population

groups of prostate cancer and in transgenic and

knockout models of COX-2 expression in prostate.

The expression of COX-2 in human prostate

carcinoma cells remains controversial. Either rela-

tively down modulated or undetectable levels of

COX-2 expression was observed in prostate cancer

cell lines by several investigators. For example in

LNCaP, PC-3, DU145 and tumor necrosis factor

(TSU) prostate cancer cell lines, COX-2 expression

was undetectable under basal conditions but was

found to be transiently induced in PC-3 and TSU cells

when they were subjected to phorbol ester treatment

[45]. Interestingly, in another study basal COX-2

mRNA and protein expression was found to be higher

in normal prostate epithelial cells compared to its

level of expression in PC-3, LNCaP and DU145

prostate carcinoma cells [46]. Similarly, in one study

COX-2 transcripts were found to be absent in LNCaP

and PC-3 cells [47]. In another study LNCaP and PC-

T. Hussain et al. / Cancer Letters 191 (2003) 125–135 129

3 prostate carcinoma cells were shown to exhibit trace

amounts of COX-1 and COX-2 expression as

measured by reverse transcription-polymerase chain

reaction and immunoblot analysis [48]. Therefore,

there are two significantly contrasting observations

exist, one endorsing the marked up regulation of

COX-2 and its possible involvement in prostate

cancer development and progression, while the

other, promoting a COX-2-independent mechanisms

for prostate tumor development.

6. Role of COX-2 in prostate carcinogenesis

There are multiple mechanisms through which

COX-2 may play a role in carcinogenesis and some or

all of these may be involved in prostate cancer

development and progression [49]. Number of these

mechanisms are likely to result from COX-2-induced

increase in PG synthesis. Evidence that increased PG

synthesis has both growth-promoting and positive

feedback effects in prostate cancer was provided in a

study by Tjandrawinata et al. [50] where treatment of

prostate carcinoma cells PC-3 with exogenous PGE2

wasfound to result in increasedmitogenesisandCOX-2

up-regulation. Further, treatment of PC-3 cells with 5

mM flurbiprofen in the presence of exogenous PGE2

inhibited the up-regulation of COX-2 mRNA and cell

growth. Another study has demonstrated that PGE2

stimulates PIN cell growth through activation of the

interleukin (IL)-6/GP130/signal transducers and acti-

vators of transcription (STAT)-3 signaling pathway

[51].PGE2 wasfound tostimulate soluble IL-6 receptor

(sIL-6R) release, gp130 dimerization, STAT-3 protein

phosphorylation, and DNA binding activity which led

to increased PIN cell growth. This study provides

mechanistic evidence that increased expression of

COX-2/PGE2 contributes to prostate cancer develop-

ment and progression via activation of the IL-6

signaling pathway.

COX-2 over-expression has been shown to upregu-

late Bcl2 expression with an associated decrease in

apoptosis [52]. Accordingly, in a recent study, the

human prostate carcinoma LNCaP cells, which over-

expresses COX-2, exhibits apoptosis induction and

Bcl2 down-modulation when treated with NS398, a

selective inhibitor of COX-2 enzyme function [53].

Inhibition of COX-2 by celecoxib has been shown to

induce apoptosis in both androgen-responsive LNCaP

and androgen-unresponsive PC-3 cells by blocking

Akt phosphorylation which is independent of Bcl2

[54]. In addition, COX-2 was found to be induced by

TNF-a, which underlines the inducibility of COX-2 in

response to pro-inflammatory stimulus [46]. These

experimental data demonstrate the inflammatory, anti-

apoptotic and growth stimulating nature of COX-2 in

prostate cancer and therefore suggest a positive role for

COX-2 in prostate cancer development and pro-

gression in humans. Further, Bcl2 expression has

been shown to be closely associated with the androgen-

independent prostate cancer phenotype and represents

a potential pathway through which COX-2 may induce

prostate cancer progression to an androgen-indepen-

dent state [55]. Contrary to well established exper-

imental data that NSAIDs and other COX-2 specific

inhibitors exert their chemopreventive action by

specific inhibition of COX-2 activity, several recent

studies have proposed the existence of COX-2-

independent mechanism as a mode of action of these

agents in their ability to prevent cancer. For example, it

has been shown that sulindac derivatives inhibit cell

growth and induce apoptosis in prostate cancer cells

PC-3 and LNCaP with similar sensitivity despite these

cells express COX-2 at varying levels [48]. This

similarity in sensitivity to apoptosis by sulindac

compounds led to the prediction of involvement of

COX-2-independent pathway. Similarly celecoxib, a

selective COX-2 inhibitor was reported to induce

apoptosis by interfering with functioning of Akt,

extracellular-regulated kinases and endoplasmic reti-

culum Ca2þ-adenosine triphosphatases [54,56]. Dis-

ruption of these signaling pathways led to rapid

apoptosis which was distinct from the one induced by

NSAIDs, suggesting the COX-2-independent mech-

anism in celecoxib induced apoptosis. In a recent

study, using Tet-On antisense COX-2 clones it was

demonstrated that celecoxib-induced apoptosis in PC-

3 and LNCaP prostate carcinoma cells is independent

of COX-2 inhibition [57]. Although there is a

correlation between the use of NSAIDs and the anti-

carcinogenic effects, the direct demonstration that

these agents inhibit COX-2 activity in their action both

in vitro and in vivo remains to be established.

Other effects of COX-2 overexpression that may

contribute to the malignant phenotype include

decreased E-cadherin expression with consequent

T. Hussain et al. / Cancer Letters 191 (2003) 125–135130

loss of cell-to-cell adhesion, matrix-metalloproteinase

overexpression with an associated increase in inva-

siveness, and modulated production of angiogenic

factors by cancer cells [58,59]. A correlation was

found between hypoxia-induced COX-2 expression

and up regulation of vascular endothelial growth

factor (VEGF) in PC-3 and LNCaP prostate carci-

noma cells [60]. Moreover, the COX-2-dependent

effect on VEGF up-regulation was found to be

inhibited by treatment with COX-2 specific inhibitor

NS398 and this inhibitory effect was reversed by

PGE2 treatment [61]. Since VEGF plays an important

role in angiogenesis, its up-regulation by COX-2

expression and inhibition by COX-2 specific inhibitor

suggests a positive role of COX-2 in angiogenesis, an

important event in prostate metastasis [61]. In another

study, PC-3 tumor growth in nude mice was shown to

be regressed by administration of COX-2 specific

inhibitor and the regression was found to be

associated with a significant decrease in VEGF

suggesting a role for COX-2 in prostate cancer

angiogenesis [62]. Aimed at understanding the role

of PG in invasive potential of prostate carcinoma

cells, it was been demonstrated that inhibitors of PG

synthesis inhibit invasiveness and the secretion of

matrix metalloproteinase (MMPs) [63]. This inhi-

bition of prostaglandin biosynthesis has been shown

to alter the balance between MMPs and tissue specific

inhibitors of matrix metalloproteinases thereby inhi-

biting tumor invasion in prostate cancer.

Since COX-2 reactions involve production of

reactive oxygen radicals that can potentially damage

biological macromolecules, in another study [64] the

possibility that DNA and/or nucleosides can be

oxidized during COX reactions was examined. DNA

or nucleosides incubated with COX-2 and arachidonic

acid resulted in a significant increase in the amount of

8-oxo-2’-deoxyguanosine. This increase was found to

be enzyme-dependent and could be prevented by

COX-2 inhibitors as well as by antioxidants. These

data for the first time indicated that peroxyl radicals or

other oxidized species formed during conversion of

arachidonic acid to PGG2 might be responsible for

increased oxidation of DNA bases. These results

suggested that overexpression of COX-2 in inflamma-

tory diseases like prostate cancer places an additional

burden on antioxidative defenses of the cell, which

might contribute to DNA oxidation and the induction

of mutations. Further, studies have also shown that

overexpression of COX-2 in cancer cells inhibit

immune surveillance and increase metastatic potential

[65]. These studies need validation in prostate cancer.

7. NSAIDs and prostate cancer

NSAIDs have long been known for their analgesic,

antipyretic and anti-inflammatory function [66,67].

Since inflammation is closely related to tumor pro-

motion, agents with potent anti-inflammatory activities

are anticipated to exert chemopreventive effects. These

observations led to a wide variety of investigations to

determine whether or not these drugs have an ability to

reduce the riskofprogressionof several humancancers.

NSAIDs and their mode of action in cancer chemopre-

ventionhasbeen the focusofmanyepidemiologicaland

experimental studies, which support the importance of

these drugs in cancer chemoprevention [68]. Epide-

miological studies have shown a decreased risk of some

cancers in people who regularly take aspirin or other

NSAIDs [68,69]. Many subsequent studies in several

human cancers have established the anti-tumorigenic

effectof thesedrugs.Thesestudieshaveshownthatanti-

tumorigenic action of NSAIDs is mediated by selective

inhibition of COX, particularly COX-2. Non-specific

NSAIDs such as aspirin, sulindac and indomethacin

inhibit not only the enzymatic action of inducible and

pro-inflammatory COX-2, but also the constitutively

expressed, cytoprotective COX-1 as well. Conse-

quently, non-selective NSAIDs can cause platelet

dysfunction, gastrointestinal ulceration, and kidney

damage [70–72]. For this reason, selective inhibition of

COX-2 to treatneoplasticproliferation ispreferred over

non-selective inhibition. Selective COX-2 inhibitors

such as melaxicam, celecoxib and rofecoxib are

NSAIDs that have been modified chemically to

preferentially inhibit COX-2 without affecting COX-1

[73].

The epidemiological evidence for a protective

effect of NSAIDs in prostate cancer development and

progression is equivocal. A population-based, case-

controlled study from New Zealand, reported a trend

towards reduced risk of advanced prostate cancer

associated with regular use of NSAIDs while these

associations failed to reach statistical significance [74].

Another study by Nelson and Harris [75] has demon-

T. Hussain et al. / Cancer Letters 191 (2003) 125–135 131

strated that regular daily use of ibuprofen or aspirin

was associated with a 66% reduction in prostate cancer

risk (odds ratio ¼ 0.34, 95% confidence

interval ¼ 0.23–0.58, P , 0:01). The risk of prostate

cancer was also significantly reduced in men who were

reported to be taking prescription NSAIDs (odds

ratio ¼ 0.35, 95% confidence interval ¼ 0.15–0.84,

P , 0:05). Another recent study [76] employing 1362

white men ranging from 50–79 year-old from the

Olmsted County, Minnesota using prescription and

nonprescription NSAIDs has shown that daily use of

NSAIDs may be associated with a lower incidence of

prostate cancer in men aged 60 years or older. The

stronger effect among older men suggests that NSAIDs

may prevent the progression rather than early stages of

prostate cancer from latent to clinical disease. Overall,

these results suggest that NSAIDs may have value in

the chemoprevention of prostate cancer.

Experimental studies on animal models of prostate

cancer have shown that NSAIDs exert chemopreven-

tive as well as therapeutic effects. In a study by

Pollard and Luckert [77] where treatment of trans-

plantable rat prostate adenocarcinoma III cells which

produce local tumors and osteolytic and osteoplastic

lesions and metastasize through defined lymphatic

channels to the lungs, with NSAID piroxicam resulted

in suppression of tumor growth, bone destruction, and

metastasis. In chemically-induced prostate carcino-

genesis F344 rat model supplementation with indo-

methacin in drinking water, exhibited tumor

suppressive effects and significant decrease in tissue

PGE2 levels [78]. Noble prostate cancer-bearing rats

treated with PG modulators viz. indomethacin (a

general COX inhibitor), UK 38485 (thromboxane

synthase inhibitor), and nafazatron (anti-thrombotic

agent which increases prostacyclin), had significantly

lower pulmonary metastasis than untreated controls

[79,80]. In a rat model, COX-2 inhibitors increased

tumor response to radiation treatment without increas-

ing the radiation effects on normal tissues [81].

Therefore, the role of COX-2 inhibitors in prostate

cancer prevention and treatment either alone or in

combination with chemotherapy or radiotherapy is

worthy for further exploration.

In a recent study [82] from our group we investigated

the effect of human recommended dose of celecoxib, a

specific COX-2 inhibitor against prostate carcinogen-

esis in a transgenic adenocarcinoma of the mouse

prostate (TRAMP) model. In TRAMP, expression of

theSV40earlygenes (Tandtantigen,Tag)aredrivenby

theprostate-specificpromoterprobasin that leads tocell

transformation within the prostate that histologically

resembles to human prostate cancer. The basal enzyme

activity and protein expression of COX-2 was found to

be significantly higher (,3.2-fold) in the dorso-lateral

prostate of TRAMP mice compared to their non-

transgenic littermates. This suggested that COX-2

may have a causative role in prostate cancer develop-

ment in this model. We employed 8 week old TRAMP

mice and randomly divided them in groups consuming

control diet (AIN 76A) or a custom prepared AIN 76A

diet containing 1500 ppm celecoxib ad libitum for 24

weeks. The animals fed control diet developed palpable

tumors at 12–14 weeks while at these times no palpable

tumors were observed in animals fed celecoxib-

supplemented diet. Sequential magnetic resonance

imaging analysis of celecoxib-fed mice at 16, 24, and

32 weeks of age suggested that each time point prostate

volume was lower in celecoxib-fed group compared to

control group. These results were consistent with

significant decrease in prostate and genito-urinary-

weight in celecoxib-fed mice at the termination of the

experiment. Feeding celecoxib in the diet was found to

result in significant inhibition of distant site metastases

to lymph nodes and lungs. These results were further

confirmed by the histopathological examination of the

tissue. Compared to animals consuming control diet,

celecoxib supplemented animals showed reduced

proliferation, and down-modulation of COX-2 in the

dorso-lateral prostate. Furthermore, celecoxib sup-

plementation resulted in enhanced in vivo apoptosis in

the dorso-lateral prostate. Taken together, these studies

suggest that NSAIDs and other selective COX-2

inhibitors possess chemopreventive activity against

prostate carcinogenesis.

8. Conclusions

There is ample evidence that COX-2 and its PG

products may play a critical role in prostate cancer

development and progression. Significant advances

have been made in the past 5 years in understanding

the COX-pathway in prostate, however, the relation-

ship between COX-2 and prostate carcinogenesis

remains to be more clearly elucidated. Animal models

T. Hussain et al. / Cancer Letters 191 (2003) 125–135132

of COX-2 overexpression and knockouts specifically

in prostate needs to be developed. It will be useful to

study the downstream signaling pathways and apop-

totic response for the preventive role of COX-2

inhibitors in mouse models of prostate cancer. It will

be of great interest to examine if COX-2 is sufficient

or need cooperation with other factors to induce

prostate carcinogenesis. It will be important to study

the specific roles that COX-1 and COX-2 plays during

the development of prostate cancer and to examine the

key modulator(s) for development of prostate adeno-

carcinoma: total PG production or the different PG

products derived from the COX-1 and COX-2 path-

way. Lastly, unraveling the COX-2-dependent versus

COX-2-independent effects of the COX-2 inhibitors

in prostate cancer may reveal the cellular mechanisms

of COX-2 action and its role in prostate cancer

development. Answers to these questions will provide

a molecular basis for understanding the contributing

role of COX-2 in mechanism of prostate carcinogen-

esis and the effectiveness of the use of COX-2 specific

and non-specific inhibitors in different stages of

prostate cancer treatment. However, based on avail-

able information it appears that COX-2 plays an

important role in prostate cancer development and

progression and therefore selective COX-2 inhibitors

may have promise in prostate cancer management.

Acknowledgements

Original work from authors laboratory cited in this

review is supported by the funds from United States

Public Health Service RO3 CA 89739 (to H.M. and

S.G.) and Cancer Research Foundation of America (to

S.G.).

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