Biology of Cox-2: an application in cancer therapeutics.
ABSTRACT Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the conversion of arachidonic acid to prostaglandin and other eicosanoids. Molecular pathology studies have revealed that Cox-2 is over-expressed in cancer and stroma cells during tumor progression, and anti-cancer chemo-radiotherapies induce expression of Cox-2 in cancer cells. Elevated tumor Cox-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. Several experimental and clinical studies have established potent anti-cancer activity of NSAID (Non-steroidal anti-inflammatory drugs) and other Cox-2 inhibitors such as celecoxib. Much attention is being focused on Cox-2 inhibitors as beneficial target for cancer chemotherapy. The mode of action of Cox-2 and its inhibitors remains unclear. Further clinical application needs to be investigated for comprehending Cox-2 biological functions and establishing it as an effective target in cancer therapy.
- [show abstract] [hide abstract]
ABSTRACT: In 2008, 72% of cancer deaths occurred in low-income and middle-income countries, where, although there is a lower incidence of cancer than in high-income countries, survival rates are also low. Many patients are sent home to die, and an even larger number of patients do not have access to treatment facilities. New constraint-adapted therapeutic strategies are therefore urgently needed. Metronomic chemotherapy-the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks-has recently emerged as a potential strategy to control advanced or refractory cancer and represents an alternative for patients with cancer living in developing countries. This low-cost, well-tolerated, and easy to access strategy is an attractive therapeutic option in resource-limited countries. Moreover, combined with drug repositioning, additional anticancer effects can be achieved, ultimately resulting in improved cancer control while maintaining minimum cost of treatment. In this Personal View, we will briefly review the rationale behind the combination of metronomic chemotherapy and drug repositioning-an approach we term metronomics. We assess the clinical experience obtained with this kind of anticancer treatment and describe potential new developments in countries with limited resources. We also highlight the need for adapted clinical study endpoints and innovative models of collaboration between for-profit and non-profit organisations, to address the growing problem of cancer in resource-limited countries.The Lancet Oncology 05/2013; 14(6):e239-48. · 25.12 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Apoptosis resistance in hepatocellular carcinoma (HCC) is one of the most significant factors for hepatocarcinogenesis and tumor progression, and leads to resistance to conventional chemotherapy. It is well known that inhibitor of apoptosis proteins (IAPs) play key roles in apoptosis resistance, it has become an important target for antitumor therapy. In this study, we examined if melatonin, the main secretory product of the pineal gland, targeted IAPs, leading to the inhibition of apoptosis resistance. To accomplish this, we first observed that four members of IAPs (cIAP-1, cIAP-2, Survivin, and XIAP) were overexpressed in human HCC tissue. Interestingly, melatonin significantly inhibited the growth of HepG2 and SMMC-7721 cells and promoted apoptosis along with the downregulation of Survivin and XIAP, but had no effect on the expression of cIAP-1 and cIAP-2. These data suggest that the inhibition of Survivin and XIAP by melatonin may play an important part in reversing apoptosis resistance. Notably, cIAP-1, Survivin and XIAP were significantly associated with the coexpression of COX-2 in human HCC specimens. Melatonin also reduced the expression of COX-2 and inhibited AKT activation in HepG2 and SMMC-7721 cells. Inhibition of COX-2 activity with the selective inhibitor, NS398, and inhibition of AKT activation using the PI3K inhibitor, LY294002, in tumor cells confirmed that melatonin-induced apoptosis was COX-2/PI3K/AKT-dependent, suggesting that the COX-2/PI3K/AKT pathway plays a role in melatonin inhibition of IAPs. Taken together, these results suggest that melatonin overcomes apoptosis resistance by the suppressing Survivin and XIAP via the COX-2/PI3K/AKT pathway in HCC cells.Journal of Pineal Research 04/2013; · 7.30 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: A series of 3,4-diarylpyrazole-1-carboxamide derivatives was designed and synthesized. A selected group of the target compounds was tested for in vitro antiproliferative activities over a panel of 60 cancer cell lines at the National Cancer Institute (NCI, Bethesda, Maryland, USA) at a single-dose concentration of 10 μM, and the four most active compounds 9a, 9l, 9n, and 10o were further tested in a five-dose testing mode to determine their IC50 values over the 60 cell lines. In addition, a selected group of target compounds were tested for inhibitory effect over cyclooxygenase isozymes. Compounds 9a, 9l, 9n, and 10o were also tested for MEK and ERK kinase inhibitory activity using Western Blot assay. Compound 10o was selective towards melanoma cell line subpanel, and its antiproliferative activity may be attributed to selective COX-2 inhibition and ERK pathway inhibition. This article is protected by copyright. All rights reserved.Chemical Biology & Drug Design 07/2013; · 2.47 Impact Factor
1082 Current Drug Targets, 2011, 12, 1082-1093
1389-4501/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
Biology of Cox-2: An Application in Cancer Therapeutics
Zakir Khan*,1,5, Noor Khan2, Ram P. Tiwari3, Nand K. Sah4, GBKS Prasad5 and Prakash S. Bisen5
1INSERM U-955, Team No. 10, Institut Mondor de Recherche Biomédicale, Université Paris Est, 94010 Créteil, Paris,
2Division of Plant-Microbe Interactions, National Botanical Research Institute, Rana Pratap Marg, Lucknow, 226 001,
3Research and Development Centre, Diagnova, RFCL Limited, New Delhi-110020, India
4Department of Botany/Biotechnology, TNB College, T.M. Bhagalpur University, Bhagalpur-812007, India
5School of Studies in Biotechnology, Jiwaji University, Gwalior-474011, India
Abstract: Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the conversion of arachidonic acid to
prostaglandin and other eicosanoids. Molecular pathology studies have revealed that Cox-2 is over-expressed in cancer
and stroma cells during tumor progression, and anti-cancer chemo-radiotherapies induce expression of Cox-2 in cancer
cells. Elevated tumor Cox-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell
resistance to apoptosis. Several experimental and clinical studies have established potent anti-cancer activity of NSAID
(Non-steroidal anti-inflammatory drugs) and other Cox-2 inhibitors such as celecoxib. Much attention is being focused on
Cox-2 inhibitors as a beneficial target for cancer chemotherapy. The mode of action of Cox-2 and its inhibitors remains
unclear. Further clinical application needs to be investigated for comprehending Cox-2 biological functions and
establishing it as an effective target in cancer therapy.
Keywords: Cyclooxygenase-2 (Cox-2), apoptosis, angiogenesis, cancer, prostaglandin, chemotherapy, radiotherapy, celecoxib.
is the key enzyme in prostaglandin (PG), prostacyclin and
thromboxane synthesis from arachidonic acid [1, 2]. Two
Cox isoforms have been described so far. Cox-1 is cons-
titutively expressed in nearly all cells where as Cox-2 is an
inducible gene which is expressed only under influence of
certain oncoproteins, growth factors, cytokines and tumor
promoters but not detectable in most normal tissues [1-6]
and recently the relationship between Cox-2 and cancer has
been projected [1, 5-7]. It has been well established that
Cox-2 promotes overall growth of tumor and gets up-
regulated in a high percentage of common cancers [8-11]
where it is associated with neoplastic transformation, cell
growth, angiogenesis, invasiveness and metastasis [8, 12-
15]. It has been reported that conventional cancer therapies
increase level of Cox-2 in cancer cells which leads to resist-
ance [16-18] and down-regulation of Cox-2 with modern
approaches significantly inducing sensitivity of cancer cells
to these therapies [5, 10, 19, 20]. Molecular studies have
demonstrated induction of apoptosis and angiogenesis by
Cox-2 inhibition, two highly promising cancer therapeutic
Cyclooxygenase (Cox), known as prostaglandin synthase
do not affect Cox-1, but selectively block only Cox-2. The
Cox-2 inhibitor is now in the market as a form of celecoxib
The Cox-2 inhibitors represent a new class of drugs that
*Address correspondence to this author at the INSERM, U955, Team no.
10, Institut Mondor de Recherche Biomédicale, Faculté de Médecine,
Hôpital Henri-Mondor, 8, rue du Général Sarrail 94010 Créteil Cedex, Paris,
France; Tel: (+33) 01 49 81 37 10; Fax: (+33) 01 49 81 36 42; E-mail:
(CelebrexM). It is widely accepted that Cox-2 inhibitors will
be of great value to people with arthritis and variety of pain
conditions. Recently Cox-2 inhibitors and their derivatives in
combination with chemotherapy or radiation therapy are
rapidly emerging as a new generation of therapeutic drug for
the treatment of cancer [25, 26]. However, the mechanisms
underlying its antitumor effects are not fully understood, and
more thorough preclinical trials are needed to determine if
Cox-2 inhibition represents a useful approach for prevention
and treatment of cancer. This review article is focused on the
molecular and clinical aspects of Cox-2 in tumor progression
MOLECULAR CANCER BIOLOGY OF COX-2
Cox-2 and its Inhibitors: Mechanism of Action
arachidonic acid. First step of PGs biosynthesis is the
hydrolysis of phospholipids to produce free arachidonic acid
which is catalyzed by phospholypase-A2 [23, 27, 28]. The
next step is catalyzed by Cox-2 in which molecular oxygen
inserts into arachidonic acid in order to synthesize an un-
stable product PGG2 , and then after peroxidase activity
of Cox-2 converts PGG2 to PGH2 that is the precursor for all
other prostanoids. The production of individual prostanoids
is catalyzed by different specific synthases which may vary
in their expression between different types of cells (Fig. 1).
Analogs of arachidonic acid, NSAID and other Cox-2 spe-
cific inhibitors act as primary substrate for enzyme. There-
fore, it competes for binding to the active site more promptly
than arachidonic acid due to multiple favorable interactions
and thus inhibits PGs synthesis .
Cox-2 is rate-limiting enzyme of PGs biosynthesis from
Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1083
Cox-2 Inhibitors Act beyond Cox-2
ive inhibitors may illustrate anti-proliferative activity in
Cox-2-independent manner [29, 31]. As for example
celecoxib inhibit the growth of various cancer cell lines that
are Cox-2 deficient and also inhibit the growth of Cox-2
deficient colon cancer xenografts in nude mice [32, 33]. The
underlying mechanisms are not well investigated. However,
several molecular targets have been studied which may be
involved in Cox-2-independent mechanisms. 15-lipoxyge-
nase-1 is verified as one of the target enzyme which gets up-
regulated by Cox-2 inhibitors (NS398 and sulindac sulfone)
and is devoid of Cox-2 inhibitory activity . The pro-
duct of 15-lipoxygenase-1 enzyme is 13-S-HODE, which
has both growth inhibitory and pro-apoptotic activities.
Thompson et al. (2000) demonstrated that the anti-cancer
activity of Cox-2 inhibitors may be attributed to the
phosphodiesterase-2 and -5 . It has also been reported
that a product of Cox-2, PGI2 activates PPAR-gamma 
which in turn down-regulates NF-kB transcriptional activity
and activator protein (AP-1) [37-39]. This pathway may
signal growth inhibitory effects in cancer cells. The relation
between Cox-2 inhibitors and classical cell cycle regulatory
molecules has also been established . Precisely, treat-
ment of cancer cells by celecoxib reduces the level of p21
and p27 proteins, which decrease CDKs kinase activity. This
reduction in kinase activity modulates the mechanisms of
their down-stream targets such as pRB, E2F, ultimately
causing cell cycle arrest [21, 40, 41]. Additional studies
delineating the molecular mechanisms by which Cox-2 and
Evidence from the data also suggested that Cox-2 select-
its inhibitors provide important therapeutic implications are
Pathways of Cox-2 Up-Regulation in Cancer Cells
adverse stimuli such as inflammation and physiological
imbalances. It is evident that Cox-2 gets up-regulated in
cancer cells and is likely to be a consequence of multiple
effects. Cox-2 expression can be regulated at several levels
including transcriptional, post-transcriptional, translational
and post-translational levels [3, 42]. The Cox-2 promoters
have several putative regulatory regions that bind trans-
criptional factors viz. CRE (c-AMP response element), NF-
kB and NL-IL6 [43, 44]. These regulatory sites respond
differentially to various stimuli. The NF-IL6 and NF-kB are
required in response to tumor necrosis factor (TNF) in which
MAPK (mitogen activated protein kinase) and c-jun signal-
ing pathways are involved [45-48]. Lipopolysaccharide-
mediated Cox-2 induction involves p38, MAPK and C-ζ
(PKC-ζ) signal transduction pathways in which NF-IL6 and
CRE have been identified as being critical [47, 49-51].
Ceramide and platelet derived growth factor induces Cox-2
expression via CRE-mediated activation of either Ras/Raf-
1/MEK/MAPK or Ras/MEKK-1/JNK pathways (Fig. 2) [43,
52]. Reportedly CBP, AP constituents (c-fos and pc-jun),
EGFR and p53 are associated positively with Cox-2 while
the PPAR-gamma are negatively correlated [20, 37, 52].
However, it is suggested that down-regulation of PPAR-
gamma and induction of the CBP transcription co-activator
can augment NF-kB and AP-1 transcriptional activities
In most tissues, Cox-2 expression is largely responsive to
Fig. (1). Biosynthesis of Prostaglandins by cyclooxygenase pathway in vascular smooth muscle cells (VSMC). Membrane phospholipids
are converted to arachidonic acid by phospholipase-A2 action. Cox-2 over-expresses in tumor tissues in response to specific oncogenic
stimuli where its oxygenase activity metabolises arachidonic acid into PGG2, which is thereafter converted to PGH2 by the peroxidase
activity of Cox-2. Several other eicosanoids are further synthesized from PGH2 by tissue specific isomerase.
1084 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al.
leading to up-regulation of Cox-2 in cancer cells [37, 53].
Recently Cox-2 has been identified as a new down-stream
target of p53. Wild type p53 can induce Cox-2 expression
via Ras/Raf/ERK pathway .
revealed that Cox-2 is one of the most consistently up-
regulated gene induced by NFAT, justified by presence of
NFAT binding sites on Cox-2 promoter [55, 56]. In addition,
several post-transcriptional factors also play an important
role in the regulation of Cox-2 in cancer cells. Translation of
immediate early Cox-2 gene is strictly controlled by mRNA
splicing [3, 42]. Aberrant methylation of CpG island and
subsequent silencing of the Cox-2 promoter have also been
observed in colorectal and gastric tumors . Further
studies are needed to elucidate mechanisms of Cox-2 gene
In breast and colon cancer, gene expression profiling
regulation, which will help in designing effective cancer
therapy based on Cox-2.
Cox-2 in Cancer Progression
biological pathways leading to cancer [8, 10, 13-15, 58].
Over-expression of Cox-2 has been reported in majority of
human cancers including colon, breast, lung, head and neck,
cervical, prostate, pancreas and bladder. Existing evidences
suggest that Cox-2 is elevated at early stage of tumor
progression [59-61]. In general Cox-2 gets up-regulated
throughout the tumorigenic process, from premalignant to
malignant condition in human beings. In carcinomas, Cox-2
over-expression is often greater in well and moderately
differentiated tumors as compared to poorly differentiated
Cox-2 is likely to be a key player in a number of
Fig. (2). Proposed signal pathways of Cox-2 gene regulation.
Receptor Tyrosine Kinase
NF-kB NF-IL6 CRE
Modulate Cox-2 gene transcription
Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1085
ones . Induced level of Cox-2 supports overall growth of
tumor and provides resistance against therapies. Cox-2
interferes in several vital processes, as for example, it
inhibits apoptosis, promotes tumor specific angiogenesis and
induces proangiogenic factors such as VEGF, inducible
nitrogen oxide synthase protein IL-6, IL-8 and TIE-2 [23,
involved in carcinogenesis. The malignant tumor cells
constitute the bulk of the cellular mass in the vast majority of
human cancers [71, 72]. Thus, the tumor cell production of
Cox-2 would be predicted to have a great impact on local
PGs production. It is well established that an increased level
of PGs contributes in tumor cell progression. Enhanced PGs
synthesis can directly stimulate mitogenesis which can
induce oncogenesis in osteoblasts, fibroblast and mammary
epithelial cells [73-75]. Certain PGs such as PGE2 have been
shown to promote both cancer cell growth and motility .
Cox-2 expression and consequent PGs production by tumor
endothelium, infiltrating macrophages and other accessory
cells in tumors resulted in paracrine growth stimulatory
effects. However, PGs do not act as mitogens for all cell
types and in fact are known to depress proliferation of some
cells particularly involved in immune system . Over-
production of PGs, locally disrupts immune surveillance by
down-regulating T and B cell proliferation [78, 79], cyto-
toxic activity of natural killer cells , antigen processing
and cytokine synthesis such as IL-12 and TNF-alpha [79-
81]. However, immune suppression by PGs may contribute
Metabolites derived from Cox-2 are reported to be
tase has been established . PGE2 is shown to stimulate
In breast cancer, a correlation between Cox-2 and aroma-
aromatase transcription, leading to supraphysiological local
estrogen levels which subsequently release growth factors
and enhance proliferation [82, 83]. In all cases of human
breast cancer, cytochrome p450 aromatase enzyme and Cox-
2 were co-expressed [82, 84]. Thus there is a possibility that
estrogen over-production mediated by PGs may be an organ
specific consequence of Cox-2 up-regulation in breast
cancer. Another important Cox-2 metabolite which contri-
butes to carcinogenesis is PGH2. By enzymatic and non-
enzymatic reaction, PGH2 isomerizes into a potent mutagen
malondialdehyde which can induce frame shift and base
substitution mutations in target genes . In addition, per-
oxidase activity of Cox-2 can also activate other mutagens
by oxidation of heterocyclic and aromatic amines . Thus
mitogens derived from Cox-2 can induce DNA damages,
thereby contributing to carcinogenesis.
which largely relies on angiogenesis. Ischemia (low nutrition
supply) can induce tumor cell apoptosis, speeding up
necrosis and cell extinction. Many researches verified
relationship between Cox-2 and angiogenesis [8, 14, 23, 63].
Cox-2 derived PGE2 can promote angiogenesis and helps in
tumor growth and metastasis [64, 67, 86]. Over-expression
of Cox-2 can induce secretion of several angiogenic factors
such as VEGF, TGF-1 and bFGF [87, 88]. These factors
specially stimulate vascular tube formation and support
tumor growth due to sufficient nutrition supply. Anti-
angiogenic activity of Cox-2 inhibitors is an important
mechanism by which they suppress tumor growth. Celecoxib
inhibits angiogenesis by complete inhibition of angiogenic
factors in tumor cells . In an important study, Darmond
et al. (2001) demonstrated that inhibition of Cox-2 in
Overall growth of tumor depends on nutrition supply
Fig. (3). Role of PGE2 and other down-stream mediators of Cox-2 in tumor development. Primary signal of PGE2 in (1) an autocrine or
paracrine (2) manner to tumor cell, promotes cell proliferation and survival. Another paracrine signaling pathway involves in production of
PGE2 by tumor cells, which in turn acts in an autocrine/paracrine fashion to promote synthesis of angiogenic growth factors such as VEGF
by tumor cell. These factors act in a paracrine fashion (3, 4) to promote proliferation, migration and tube formation. PGE2 also increase
invasiveness by EGFR-P13K-Akt pathway.
Proangiogenic Proliferation, migration
Invasiveness Factor (VEGF) and tube formation
1086 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al.
endothelial cells by NSAID suppresses Alpha-V-beta-3-
dependent activation of cdc42 and Rac resulting in inhibition
of spreading and migration of endothelial cells and sup-
pression of angiogenesis . PGE2 can increase invasive-
ness and motility that is predominantly mediated by EGFR-
phosphotidylenositol-3-kinase-Akt pathway [86, 90, 91]. In
brief the mechanisms of Cox-2 inhibition resisting the
growth of cancer might prevent angiogenesis and weaken
invasiveness which further enhances its potential in anti-
cancer therapy (Fig. 3).
investigated [24, 92]. Over-expression of Cox-2 and its end
point metabolite, PGE2, protected cells against apoptosis and
majority of Cox-2 inhibitors enhance apoptotic cell death
[20, 23, 24, 76, 93, 94]. Till date mechanism of apoptosis
inhibition by Cox-2 is poorly understood. Cox-2 products
have influence on both extrinsic (receptor mediated) and
intrinsic (mitochondrial mediated) apoptotic pathways [93,
95, 96]. Many researches have demonstrated that Cox-2
directly or indirectly changes the ratio of pro-apoptotic and
anti-apoptotic proteins toward anti-apoptosis. Over-expres-
sion of Cox-2 reduced the levels of bax and bclxl (pro-
apoptotic)  and induced the levels of bcl2 and survivin
(anti-apoptotic) proteins [67, 76, 95-97]. Survivin is one of
the key anti-apoptotic proteins which is over-expressed in
most of the human cancers [98, 99] and provides resistance
to conventional cancer therapies including chemotherapy and
radiotherapy [100, 101]. Cox-2 stabilizes survivin due to
ubiquitination levels which provide resistance to apoptosis
. Above findings suggested that Cox-2 inhibiting apop-
tosis might be through the regulation of proteins that are
predominantly involved in mitochondrial-mediated apop-
tosis. PGE2 appears to have an inhibitory effect on Fas-me-
diated apoptosis also [23, 93]. PGE2 over-production repress-
ses expression of DR-4 and DR-5 receptors consequently
inhibiting recruitment of the intracellular adaptor molecules
for Fas-associated death domain and thus attenuating caspase
activation [103, 104]. It is interesting to note that inhibition
of Cox-2 by a Cox-2 inhibitor sulindac sulfide restored
expression of DR-4,5 and augmented Fas-mediated cell
Correlation between apoptosis and Cox-2 has also been
understood. However, a possibility is that wild type of p53 in
cancer cells decreases Cox-2 expression while mutation in
p53 gene contributes in Cox-2 induction consequently result-
ing in anti-apoptosis . In an important study, Han et al.
(2002) demonstrated that oxidative and genotoxic effects
induced expression of Cox-2 in p53-dependent manner and
inhibition of Cox-2 potentiates DNA damage/p53-mediated
apoptosis . Interaction between Cox-2 and apoptotic
protein may represent additional mechanisms by which Cox-
2 expression interferes with tumor growth (Fig. 4).
Role of p53 in Cox-2-mediated apoptosis is poorly
CLINICAL CANCER THERAPEUTICS OF COX-2
Pioneer Studies Associating Cox-2 with Cancer
Several in vivo studies have been conducted to evaluate the
role of Cox-2 in tumorigenesis. In a frontline research,
Oshima et al. (1996) engineered an Apc716 Cox-2 null mice
and got up to 86% reduction in intestinal adenoma, thus
providing for the first time definitive evidence of the role of
Cox-2 in tumorigenesis . Many of the same molecular
and biochemical changes underlying human colon cancer
were observed in the azoxymethane (AOM)-induced rat
colon cancer model, in which Cox-2 down-regulation
effectively prevented development of colon tumors by 93%
and inhibited tumor initiation by approximately 80% [106,
107]. Similar trend was observed in 7,12-dimethyl-benz(a)
anthracene (DMBA)-treated animal model, which is well
suited for breast cancer studies [108, 109]. A significant
correlation between Cox-2 and HER-2 expression was
reported in mammary tumors expressing HER-2/neu gene in
mice and consistently these findings have also been estab-
lished in human breast cancer [110-112]. Interestingly,
epidemiological researches also suggest a reduction in the
risk of cancer development and cancer-related deaths by
administration of Cox-2 inhibitors [113, 114].
Cox-2 Inhibitors in Cancer Prevention and Treatment
progression, researches conducted using a variety of Cox-2
specific inhibitors demonstrate a decrease in cancer
incidence in many animal models [106, 109, 115]. Celecoxib
(CelebrexTM) is a well known Cox-2 inhibitor, approved by
the U.S. Food and Drug Administration (FDA) for the
treatment of arthritis. Since many prior studies suggested
potential of Cox-2 inhibitors in cancer prevention, the
National Cancer Institute (NCI) conducted many laboratory
studies and clinical trials for the validation of Cox-2
inhibitors in the prevention and treatment of a variety of
cancers including bladder, breast, cervical, colorectal, oeso-
phageal, head and neck, lung, and prostate cancers at differ-
ent research organizations. As of now NCI continues to test
celecoxib in more than 50 clinical trials for the prevention
and treatment of cancer.
On the confirmation of Cox-2 involvement in cancer
Adenoma Prevention with Celecoxib (APC) Trial
Polyps Trials conducted on more than 3500 patients
demonstrated the successful use of celecoxib [116, 117]. It is
important to note that celecoxib was more effective against
advance stage lesions and in patients at a greater risk for
colorectal cancer. Despite reducing the adenoma recurrence
in a dose-dependent manner, the cardiovascular risk posed
on administration of celecoxib (400 mg/day) drew the
attention. Furthermore, an adverse dose-response effect was
observed, with higher toxicity in patients receiving higher
dose. However, ongoing clinical trials (NCT00005094) with
altered dose and time schedules of celecoxibs may provide
better results with reduced side effects.
In Adenoma and Colorectal Sporadic Adenomatous
Cox-2 Clinical Studies in Breast Cancer
2. Several preclinical studies on breast tumor mice model
showed involvement of Cox-2 and its metabolites at many
key points throughout tumorigenesis, including premalignant
hyperproliferation, transformation, tumor viability, growth,
invasion and metastatic spread [118, 119].
Breast tumor is well reported for over-expression of Cox-
capecitabine are considered an active treatment strategy for
breast tumor [120, 121]. A pilot study was conducted to
Conventional therapeutic drugs such as trastuzumab and
Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1087
determine if the addition of celecoxib is useful in improving
the response rate of breast cancers to neoadjuvant cytotoxic
treatment . It was followed by a phase-II study of
celecoxib and trastuzumab in patients with HER-2/neu-over-
expressing metastatic breast cancer which had progressed
while receiving trastuzumab . In this trial, an improved
response rate of 20% was recorded as compared to trastuzu-
mab alone. One more phase-II trial of celecoxib in combi-
nation with capecitabine was conducted on advanced meta-
static breast cancer patients . This combination was
found to be very effective with a response rate of 20-30%.
Interestingly lower toxicity was observed in combination as
compared to capecitabine alone. Currently this trial is
moving in its further stage with larger series of patients.
Additionally, in both the mentioned trials, the Cox-2 level
was significantly higher in tumors that showed a clinical
response to the addition of celecoxib as compared to non-
responders whereas this was not observed in patients treated
with chemotherapy alone. Moreover, both regimens were
well tolerated and there were no clinical signs and symptoms
of cardiac failure.
Importantly, as we described above, Cox-2 and aromitase
expressed in a significantly positive manner in human breast
cancer, suggest the involvement of autocrine and paracrine
mechanisms in hormone-dependent breast cancer develop-
ment via growth stimulation from local estrogen biosynthesis
Endocrine therapy is another treatment for breast cancer.
[82-84, 125]. Induced vascularization and estrogen synthesis
adversely affect the endocrine therapy and this portrays Cox-
2 blocking as an important remedy to combine with hormone
therapy. A successful preclinical study was conducted to test
the potential of celecoxib and exemestane combination on
DMBA rat model [108, 109]. Then after a CAAN (Celecoxib
anti-aromatase neoadjuvant) trial was conducted to investi-
gate the efficacy combining aromatase inhibitors with Cox-2
inhibitor in postmenopausal hormone sensitive breast cancer
patients [126, 127]. The preliminary results of these trials
show that celecoxib and anti-aromatase combination therapy
works well in breast cancer.
Cox-2 in Head and Neck Cancer
2 as a therapeutic target in head and neck cancer prevention
and treatment. Pathological studies indicate a higher
expression of Cox-2 in head and neck cancer tissues [128,
129]. Treatment of head and neck cancer cell lines with
celecoxib induced cell death in vitro and suppressed the in
vivo tumor growth in animal model . NCI and other
Cancer Research Centers across the world have started
clinical trials of celecoxib alone and in combination with
other drugs to treat head and neck cancer. It is well known
that celecoxib suppresses tumor growth by reducing blood
supply. However, NCI started a phase-I/II trial in year 2008
(NCT00357617) to determine, if celecoxib could be useful in
Several studies have been undertaken to investigate Cox-
Fig. (4). Schematic representation of Cox-2 apoptotic targets. Elevated Cox-2 level has influence on both mitochondrial and receptor-
mediated apoptosis. Cox-2 over expression induces apoptotic resistance in cancer cells by increasing anti-apoptotic and suppressing pro-
apoptotic proteins involved in both apoptotic pathways. In mitochondrial pathway Cox-2 showed negative effect on bcl-xl and Bax (pro-
apoptotic) and positive effect on bcl2 and survivin (anti-apoptotic) and in receptor mediated pathway Cox-2 over expression constrains
formation of death domain complex by decreasing DR-4 and DR-5 receptor proteins. It is hypothesized that anti-cancer therapies can induce
Cox-2 expression in p53-dependent manner, which in turn attenuate p53-mediated apoptosis by regulating pro and anti-apoptotic proteins.
Complex Fas Receptor
Apaf1 Casp-3, 6
1088 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al.
reducing the amount of normal tissues that need to be
removed by surgery. The results of this ongoing trial could
be useful for doctors in learning more about the cancer and
predict how well patients will respond to treatment with
celecoxib. NCI had also conducted a phase-II trial in order to
check the molecular effects of short-term celecoxib treatment
on head and neck squamous cell carcinoma (HNSCC)
(NCT00596219). This study aims to measure how celecoxib
affects those chemicals, which can be found in the tumor,
blood and urine of patients with head and neck cancer. Cox-
2 inhibitors are also testing in combination with other key
therapeutic targets of head and neck cancer. A clinical trial is
going on at Winship Cancer Institute of Emory University to
test the feasibility and efficacy of Cox-2 inhibitor
(celecoxib), EGFR inhibitor (ZD1839) and Tyrosine Kinase
Inhibitor (OSI-774) in Early Stage (Stage I/II) of HNSCC
(NCT00400374). Preliminary reports of these trials showed
chemopreventive effect of Cox-2 inhibition in head and
cancer. Upcoming data may help in the treatment of head
and neck cancer in clinical settings.
and cell lines of neuroblastoma also. Inhibition of Cox-2 by
celecoxib significantly induced apoptosis of neuroblastoma
cell lines and suppressed in vivo tumor growth [7, 131].
Furthermore, use of NSAID was found to be effective in
treating paediatric neuroblastoma . All together, these
findings suggest that Cox-2 inhibitors may be a novel
adjuvant therapy for neuroblastoma.
Cox-2 was found highly up-regulated in primary tumors
Cox-2 in Lung Cancer
expression of Cox-2 [132, 133]. The level of Cox-2 in both
types of non-small cell lung carcinomas (NSCLC: adenocar-
cinomas and squamous cell carcinomas) was significantly
higher than in normal lung tissues. In vitro cell studies have
demonstrated that over-expression of Cox-2 stabilizes anti-
apoptotic genes and induces invasiveness in NSCLC
(Dohadwala M et al. 2001, Krysan K et al. 2004) leading to
resistance of NSCLC against chemotherapy and radiotherapy
[134, 135]. Preclinical studies on NSCLC animal models
have shown that treatment with either NSAID or celecoxib
reduced tumor growth by acting on multiple tumor-progres-
sion targets such as angiogenesis, tumor invasion, resistance
to apoptosis, and suppression of antitumor immunity via
Lung cancer tissues were also identified with high
both Cox-2-dependent and-independent pathways . In
sync with preclinical studies, epidemiological evidence has
shown a decreased incidence of lung cancer in patients who
used cox-2 inhibitor. Based on these observations, many
clinical studies have been initiated to evaluate the effect of
celecoxib in combination with chemotherapy and radio-
therapy [137, 138]. Phase I/II, III/IV clinical trials in colla-
boration with NCI and University of California are in prog-
ress to test celecoxib on NSCLC patients (NCT00104767,
NCT00055978). A combination trial of celecoxib, paclitaxel
and carboplatin is being conducted by Bimodality Lung
Oncology Team (BLOT).
correlation with EGFR. Preclinical studies have demons-
trated successful use of Cox-2 inhibitors with EGFR inhi-
bition . Ongoing clinical trials are also evaluating the
combination of celecoxib with epidermal growth factor
receptor inhibitors (ZD1839) of NSCLC (NCT00068653).
Initial trends of these clinical studies have shown that cele-
coxib can be safely administered alone and in combination
with other chemoradiotherapeutic agents in NSCLC patients.
In NSCLC, Cox-2 has shown a significant positive
Cox-2 Clinical Studies in Other Cancers
2 was significantly associated with poor prognosis and
shorter patient’s survival in cervical, prostate, skin and
bladder cancers [139-141]. In addition, high levels of Cox-2
have also been found in gastric, liver, pancreatic and biliary
tumors . Cox-2 inhibitors are already in clinical trials
for the prevention of skin cancers and for the treatment of
cervical and prostate cancer (Table 1).
Like various mentioned cancers, high expression of Cox-
different cancers, celecoxib was promisingly shown to
reduce tumorigenesis alone and in combination with other
conventional chemoradiotherapies. It is interesting to note
that celecoxib is effective in the advanced stages of cancer.
Overall clinical successes of trials are stepping stones to
progress. Further studies are warranted to clarify if Cox-2-
inhibition has an impact in clinical settings.
In the above preclinical and clinical studies regarding
unknown variables and might be much more complex than
Role of Cox-2 in tumor progression still has many
Table 1. Clinical Trials of Celecoxib in Skin, Cervical and Prostate Cancer
Prevention Trial Phase Number of Patients Participants
Skin II 36 Basal cell nevus syndrome 
Skin II, III 240 Actinic keratoses 
Skin II, III 240 No elevated risk 
Cervical I, II 62 Radiation, 5-FU, cisplatin, NCT00023660
Cervical II/III 130 Intraepithelial neoplasia, placebo, NCT00081263
Prostate I 60–70 Surgery, NCT00022399
Prostate II, III 85 Recurrent, placebo, NCT00136487
Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1089
currently believed. It is a key challenge to researchers and
scientists across the world for better understanding of
argument as regarding their mode of action throughout the
body and, therefore, an improved strategy based on Cox-2
needs to be designed for treating cancer. Since it is well
established that most of the tumors produce high levels of
Cox-2, investigations are being directed towards elucidating
the role of Cox-2 inhibitors in preventing cancer. An anti-
cancer effect of Cox-2 inhibitors is widely accepted but its
utilization is controversial due to side effects including
cardiovascular risk . It is important to note that only
high dose (400 mg/d) of celecoxib showed this side effect in
colon cancer trial. Researchers may investigate giving lower
doses of celecoxib or different dose regimens to determine if
this causes less cardiovascular risk. Still it is unclear whether
cardiovascular side effects are a class effect or all Cox-2
inhibitors exhibit the same behavioral pattern. More resear-
ches in this direction will assist in the development of novel
drugs with lesser side effects once the mechanisms through
which Cox-2 inhibitors reduce tumor progression are
understood. Many clinical trials from phase-I to IV are still
in progress with most of the cancers to test celecoxib alone
and in combination with other chemoradiotherapeutic agents
in different doses and time schedules. The preliminary
results are very exciting to carry on further study with
celecoxib with fewer side effects. It is interesting to mention
that Cox-2 inhibitors have shown good results in personal
medication according to the status of Cox-2 expression. For
example, celecoxib used in combination with ZD1839
(EGFR inhibitor), which is an excellent therapeutic target in
head and neck and lung cancer (NCT00068653). Many more
studies are needed to test the feasibility and efficacy of
celecoxib with other specific tumor marker inhibitors in
particular cancer. As it is reported that Cox-2 inhibitors have
capacity to reduce tumorigenesis even without involving
Cox-2 [33, 131]. Now researchers are being initiated in order
to unravel other targets for Cox-2 inhibitors in cancers. This
will aid in the construction of innovative derivatives of Cox-
2 inhibitors to enhance effectiveness with reduce side effects
in cancer cure.
over-expression is found in many cancers including head and
neck, lung, colon and breast. Cox-2 generated biomarkers
such as PGs or other down-stream mediators have an
important role in regulating cell proliferation and survival.
Elevated level of Cox-2 gives anti-apoptotic and angiogenic
signals thus resisting cancer cells to conventional cancer
therapies. Hence it is becoming interestingly evident that
selective Cox-2 inhibitors have a growing potential as a
beneficial target for chemopreventive and tumor regression
for many cancers.
Cox-2 is an inducible isoform of cyclooxygenase and its
Industrial Research (CSIR), New Delhi for the award of
Emeritus Scientist to Prof. P.S. Bisen.
Authors are thankful to Council of Scientific and
GRB = Growth Factor Receptor-Bound Protein
SOS = Son-of-sevenless
MAPK = Mitogen-Activated Protein Kinase
ERK = Extracellular Signal-Regulated Kinase
MEK = MAPK/Erk kinase
MEKK = MAPK/Erk Kinase Kinase
JNK = Jun N-terminal kinase
PKC = Protein Kinase C
EGFR = Epidermal Growth Factor Receptor
PI3K-Akt = Phosphatidylinositol-3-Kinase and Protein
VEGF = Vascular Endothelial Growth Factor
 Kawahito SH, Wilder Y, Hasiramoto RL, et al. Expression of
cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res
1995; 55: 3785-9.
Sellers RS, Radi ZA, Khan
cyclooxygenases in cardiovascular homeostasis. Vet Pathol 2010;
Smith WL, Garavito RM, Dewitt DL. Prostaglandin endoperoxide
H synthases (cyclooxigenases)-1 and -2. J Biol Chem 1996; 271:
Wu KK. Cyclooxigenase-2 induction: molecular mechanism and
pathophysiologic roles. J Lab Clin Med 1996; 128: 242-5.
Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The
role of cyclooxygenase-2 in cell proliferation and cell death in
human malignancies. Int
Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular
target for cancer prevention and treatment. Trends Pharmacol Sci
2003; 24: 96-102.
Johnsen JI, Lindskog M, Ponthan F, et al. Cyclooxygenase-2 is
expressed in neuroblastoma, and nonsteroidal anti-inflammatory
drugs induce apoptosis and inhibit tumor growth in vivo. Cancer
Res 2004; 64: 7210-15.
Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN.
Cyclooxygenase regulates angiogenesis induced by colon cancer
cells. Cell 1998; 93: 705-16.
de Heer P, Gosens MJ, de Bruin EC, et al. Cyclooxygenase 2
expression in rectal cancer is of prognostic significance in patients
receiving preoperative radiotherapy. Clin Cancer Res 2007; 13:
Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of
cyclooxygenase (COX)-2 in human skin epidermal cancer cells:
evidence for growth suppression by inhibiting COX-2 expression.
Int J Cancer 2000; 86: 667-71.
Farooqui M, Li Y, Rogers T, et al. COX-2 inhibitor celecoxib
prevents chronic morphine-induced promotion of angiogenesis,
tumour growth, metastasis and mortality, without compromising
analgesia. Br J Cancer 2007; 97: 1523-31.
Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S,
DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in
human colorectal adenomas
Gastroenterology 1994; 107: 1183-8.
Fujita H, Koshida K, Keller ET, et al. Cyclooxygenase-2 promotes
prostate cancer progression. Prostate 2002; 53: 232-240.
Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan
OC. Role of prostaglandin E-2-dependent angiogenic switch in
cyclooxygenase-2-induced breast cancer progression. Proc Natl
Acad Sci 2004; 101: 591-6.
 NK. Pathophysiology of
J Cell Biol 2010;
1090 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al.
 Pai R, Nakamura T, Moon WS, Tarnawski AS. Prostaglandins
promote colon cancer cell invasion; signaling by cross-talk between
two distinct growth factor receptors. FASEB J 2003; 17: 1640-7.
Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of
tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res
2000; 60: 1326-31.
Petersen C, Petersen S, Milas L, Lang FF, Tofilon PJ.
Enhancement of intrinsic tumor cell radiosensitivity induced by a
selective cyclooxygenase-2 inhibitor. Clin Cancer Res 2000; 6:
Singh B, Cook KR, Vincent L, Hall CS, Martin C, Lucci A. Role of
COX-2 in tumorospheres derived from a breast cancer cell line. J
Surg Res 2010; DOI:10.1016/j.jss.2010.03.003.
Sminia P, Kuipers G, Geldof A, Lafleur V, Slotman B. Cox-2
inhibitors act as radiosensitizers in tumor treatment. Biomed
Pharmacother 2005; 59: 272-5.
Song YC, Kim SH, Juhnn YS, Song YS. Apoptotic effect of
celecoxib dependent upon p53 status in human ovarian cancer cells.
Ann N Y Acad Sci 2007; 1095: 26-34.
Chang H, Leng J, Demetris AJ, Wu T. Cyclooxygenase-2 promotes
human colengiocarcinoma growth: Evedence for cyclooxygenase-
2-independent mechanism in celecoxib-mediated Induction of p21
and p27 and cell cycle arrest. Cancer Res 2004; 64: 1369 76.
Suo-Lin F, Yun-Lin W, Young-Ping Z, Min-Min Q, Chen Y. Anti-
cancer effects of Cox-2 inhibitors and their correlation with
angiogenesis and invasion in gastric cancer. World J Gastroentorol
2004; 10: 1971-4.
Casado M, Molla B, Roy R, et al. Protection against Fas-induced
liver apoptosis in transgenic mice expressing cyclooxygenase 2 in
hepatocytes. Hepatology 2007; 45: 631-8.
Patsos HA, Greenhough A, Hicks DJ, et al. The endogenous
cannabinoid, anandamide, induces COX-2-dependent cell death in
apoptosis-resistant colon cancer cells. Int J Oncol 2010; 37: 187-
Lanza-Jacoby S, Dicker AP, Miller S, et al. Cyclooxygenase
(COX)-2-dependent effects of the inhibitor SC236 when combined
with ionizing radiation in mammary tumor cells derived from
HER-2/neu mice. Mol Cancer Ther 2004; 3: 417-24.
Hasegawa K, Ohashi Y, Ishikawa K, et al. Expression of
cyclooxygenase-2 in uterine endometrial cancer and antitumor
effects of a selective COX-2 inhibitor. Int J Oncol 2005; 26: 1419-
Dong M, Johnson M, Rezaie A, et al. Cytoplasmic phospholipase
A2 levels correlate with apoptosis in human colon tumorigenesis.
Clin Cancer Res 2005; 11: 2265-71.
Vecchio AJ, Simmons DM, Malkowski MG. The structural basis of
fatty acid substrate binding to cyclooxygenase-2. J Biol Chem.
2010; 285: 22152-63.
Praveen Rao PN, Knaus EE. Evolution of Nonsteroidal Anti-
Inflammatory Drugs (NSAIDs):Cyclooxygenase (COX) Inhibition
and Beyond. J Pharm Pharm Sci 2008; 11: 81-110.
Hawkey C J. Cox-2 inhibitors. Lancet 1999; 353: 307-14.
Patel MI, Subbaramaiah K, Du B, et al. Celecoxib inhibits prostate
cancer growth: evidence of a cyclooxygenase-2-independent
mechanism.Clin Cancer Res 2005; 11: 1999-2007.
Waskewich C, Blumenthal RD, Li H, Stein R, Goldenberg DM,
Burton J. Celecoxib exhibits the greatest potency amongst
cyclooxygenase (Cox) inhibitors for growth inhibition of Cox-2-
negative hematopoietic and epithelial cell lines. Cancer Res 2002;
Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G.
COX-2 independent induction of cell cycle arrest and apoptosis in
colon cancer cells by the selective COX-2 inhibitor celecoxib.
FASEB J 2001; 155: 2742-4.
Shureiki D, Chen D, Lotan R, et al. 15-Lipoxygenase-1 mediates
independently of cyclooxygenase-2 in colon cancer cells. Cancer
Res 2000; 60: 6846-50.
Thompson WJ, Piazza GA, Li H, et al. Exisulind induction of
apoptosis involves guanosine
phosphodiesterase inhibition, protein kinase-G acticvation and
attenuated B-catenin. Cancer Res 2000; 60: 6846-50.
drug induced apoptosis
 Lim H, Gupta RA, Ma WG, et al. Cyclooxigenase-2 derived
prostaglandin mediates embryo implantation in the mouse via
PPAR-delta. Genes Dev 1999; 13: 1561-74.
Konstantinopoulos PA, Vandoros GP, Sotiropoulou-Bonikou G,
Kominea A, Papavassiliou AG. NF-kB/PPAR-gamma and/or AP-
1/PPAR-gamma ‘on/off’switches and induction of CBP in colon
adenocarcinomas: correlation with Cox-2 expression. Int J
Colorectal Dis 2007; 22: 57-68.
Elstne E, Muller C, Koshizuka K, et al. Ligands for peroxisome-
proliferator-activated receptor inhibits growth and induce apoptosis
of human breast cancer cells in vitro and in BNX mice. Proc Nat
Acad Sci 1998; 95: 8806-11.
He TC, Chan TA, Vogelstein B, Kinzler KW. PPAR is an APC
regulated target of nonsteroidal anti-inflammatory drugs. Cell
1999; 99: 335-40.
Mineo TC, Ambrogi V, Cufari ME, Pompeo E. May
cyclooxygenase-2 (COX-2), p21 and p27 expression affect
prognosis and therapeutic strategy of patients with malignant
pleural mesothelioma? Eur J Cardiothorac Surg. 2010; 38: 245-52.
Yim HW, Jong SH, Kim TY, et al. Cyclooxygenase-2 inhibits
novel ginseng metabolite-mediated apoptosis. Cancer Res 2005;
Ishikawa TO, Jain N, Herschman HR. Feedback regulation of
cyclooxygenase-2 transcription ex vivo and in vivo. Biochem
Biophys Res Commun 2009; 378: 534-8.
Subbaramaiah K, Chung WJ, Dannenberg AJ. Ceramide regulates
the transcription of cyclooxygenase-2. Evidence for involvement of
extracellular signal regulated kinase/c-jun N-terminal kinase and
p38 mitogen-activated potein kinase pathways. J Biol Chem 1998;
Liu YW, Wang SA, Hsu TY, Chen TA, Chang WC, Hung JJ.
Inhibition of LPS-induced C/EBPdelta by Trichostatin a has a
positive effect on LPS-induced Cyclooxygenase 2 expression in
RAW264.7 cells. J Cell Biochem 2010; 110(6): 1430-8.
Wang Y, Yin B, Liu S, Xue S. Cardioprotective effect by tumor
necrosis factor-alpha and interleukin-6 through late preconditioning
in unstable angina patients. Arch Med Res 2007; 38: 80-5.
Ke J, Long X, Liu Y, et al. Role of NF-kappaB in TNF-alpha-
induced COX-2 expression in synovial fibroblasts from human
TMJ. J Dent Res 2007; 86: 363-7.
Hsieh HL, Wu CB, Sun CC, Liao CH, Lau YT, Yang CM.
Sphingosine-1 phosphate induces Cox-2 expression via P13K/Akt
and p42/p44 MAPK pathways in rat vascular smooth muscle cells.
J Cell Physiol 2006; 207: 757-66.
Båge T, Lindberg J, Lundeberg J, Modéer T, Yucel-Lindberg T.
Signal pathways JNK and NF-kappaB, identified by global gene
expression profiling, are involved in regulation of TNFalpha-
induced mPGES-1 and COX-2 expression in gingival fibroblasts.
BMC Genomics. 2010; 11:241, DOI: 10.1186/1471-2164-11-241.
Chen P, Cai Y, Yang ZG, et al. Involvement of PKC, p38, MAPK
and AP-2 in IL-B-induced expression of cycloxygenase-2 in human
pulmonary epithelial cells. Respirology 2006; 11: 18-23.
Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T. Transcriptional
regulation of human prostaglandinendoperoxide synthase-2 gene by
lipopolysaccharide and phorbol ester in vascular endothelial cells.
Involvement of both nuclear factor for interleukin-6 expression site
and cAMP response element. J Biol Chem 1995; 270: 24965-71.
Wadleigh DJ, Reddy ST, Kopp E, Ghosh S, Herschman HR.
Transcriptional activation of the cyclooxygenase-2 gene in
endotoxin-treated RAW 264.7 macrophages. J Biol Chem 2000;
Weilin Xie, Harvey R. Herschman. V-src Induces Prostaglandin
Synthase 2 Gene Expression by Activation of the c-Jun N-terminal
Kinase and the c-Jun Transcription Factor. J Biol Chem 1995; 270:
Jing Chen, Min Zhao, Reena Rao, Hiroyasu Inoue, Chuan-Ming
Hao. C/EBP and Its Binding Element Are Required for NFkB-
induced Cox-2 Expression Following Hypertonic Stress. J Biol
Chem 2005; 280: 16354-9.
Han JA, Kim J, Ongusaha PP, et al. p53 mediated induction of
Cox-2 counteracts p53- or genotoxic stress-induced apoptosis. The
EMBO J 2002; 21: 5635-44.
Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1091
 Yiu GK, Toker A. NFAT induces breast cancer cell invasion by
promoting the induction of cycloxygenase-2. J Biol Chem 2006;
Flockhart RJ, Diffey BL, Farr PM, Lloyd J, Reynolds NJ. NFAT
regulates induction of COX-2 and apoptosis of keratinocytes in
response to ultraviolet radiation exposure. FASEB J 2008; 22:
Cow LW, Zhu L, Loo WT, Lui EL. Aberrant methylation of
cycloxygenase-2 in breast cancer patients. Biomed Pharmacother
2005; 59: 264-7.
Nie D. Cyclooxygenases and lipoxygenases in prostate and breast
cancers. Front Biosci 2007; 12:1574-85.
Ferguson HR, Wild CP, Anderson LA, et al. Cyclooxygenase-2
and inducible nitric oxide synthase gene polymorphisms and risk of
reflux esophagitis, Barrett's
adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2008; 17:
Lee JM, Mao JT, Krysan K, Dubinett SM. Significance of
cyclooxygenase-2 in prognosis,
chemoprevention of NSCLC. Future Oncol 2007; 3: 149-53.
Schmitz KJ, Wohlschlaeger J, Lang H, et al. Cyclo-oxygenase-2
overexpression is a feature of early and well-differentiated
hepatocellular carcinoma with a favourable prognosis. J Clin Pathol
2009; 62: 690-3.
Koki AT, Leahy KM, Masferrer JL. Potential utility of Cox-2
inhibitors in chemoprevention and chemotherapy. Expert Opin
Investing Drugs 1999; 8: 1623-38.
Gately S, Kerbel R. Therapeutic potential of selective
cyclooxygenase-2 inhibitors in the management of tumor
angiogenesis. Prog Exp Tumor Res 2003; 37: 179-92.
Masferrer JL, Leahy KM, Koki AT, et al. Anti-angiogeneic and
anti-tumor activities of Cyclooxigenase-2 inhibitors. Cancer Res
2000; 60: 1306-11.
Wu XZ. New strategy of antiangiogenic therapy for hepatocellular
carcinoma. Neoplasma. 2008; 55: 472-81.
Sakamoto J, Origuchi T, Okita M, et al. Immobilization-induced
cartilage degeneration mediated through expression of hypoxia-
inducible factor-1alpha, vascular endothelial growth factor, and
chondromodulin-I. Connect Tissue Res 2009; 50 : 37-45.
Tsujii M, DuBois RN. Alterations in cellular adhesion and
apoptosis in epithelial cells over expressing prostaglandin
endoperoxide synthase-2. Cell 1995; 83: 493-501.
Tian H, McKnight S L, Russel DW. Endothelial pass domain
protein I (EPAS1), a transcription factor selectively expressed in
endothelial cells. Genes Dev 1997; 11: 72-82.
Yuan B, Ohyama K, Bassho T, Toyoda H. Contribution of
inducible nitric oxide synthase and cyclooxygenase-2 to apoptosis
induction in smooth chorion trophoblast cells of human fetal
membrane tissues. Biochem Biophys Res Commun 2006; 341:
Mrena J, Wiksten JP, Kokkola A, Nordling S, Ristimäki A,
Haglund C. COX-2 is associated with proliferation and apoptosis
markers and serves as an independent prognostic factor in gastric
cancer. Tumour Biol 2010; 31: 1-7.
Liu CH, Chang SH. Narko K, et al. Overexpression of
cyclooxygenase-2 is sufficient to induce tumoregenesis in
transgenic mice. J Biol Chem 2001; 276: 18563-9.
Chang LW, Chang YC, Ho CC, Tsai MH, Lin P. Increase of
carcinogenic risk via enhancement of cyclooxygenase-2 expression
and hydroxyestradiol accumulation in human lung cells as a result
of interaction between BaP and 17-beta estradiol. Carcinogenesis
2007; 28: 1606-12.
Chen T, Hwang H, Rose ME, Nines RG, Stoner GD.
Chemopreventive properties of
Nitrosomehylbenzylamine-induced rat esophageal tumoregenesis:
down-regulation of cyclooxygenase-2, inducible nitric oxide
synthase and c-Jun. Cancer Res 2006; 66: 2853-9.
Frasor J, Weaver AE, Pradhan M, Mehta K. Synergistic up-
regulation of prostaglandin E synthase expression in breast cancer
cells by 17beta-estradiol and proinflammatory cytokines.
Endocrinology 2008; 149: 6272-9.
Zhang X, Morham SG, Langenbach R, Young DA. Malignant
transformation and anti-neoplastic actions of non-steroidal anti-
esophagus, and esophageal
targeted therapy and
black raspberries in N-
inflammatory drugs (NSAIDs) on cyclooxygenase null embryo
fibroblasts. J Exp Med 1999; 190: 451-9.
Sheng H, Sao J, Basington MK, DuBois RN. Prostaglandin E2
increases growth and motility of colorectal carcinoma cells. J Biol
Chem 2001; 276: 18075-81.
Antonakopoulos N, Karamanolis DG. The role of NSAIDs in colon
cancer prevention. Hepatogastroenterology 2007; 54: 1694-700.
Huang M, Sharma S, Mao JT, Dubinett SM. Non small cell lung
cancer-derived soluble mediators and prostaglandin E2 enhance
peripheral blood lymphocyte IL-10 transcription and protein
production. J Immunol 1996; 157: 5512-20.
Stolina M, Sharma S, Zhu L, Dubinett SM. Lung cancer
cyclooxygenase-2 dependent inhibition of dendritic cell maturation
and function. Proc Am Assoc Cancer Res 2000; 41: 6-19.
Hwang D, Scollard D, Byrne J, Levin E. Expression of
cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J
Natl Cancer Inst 1998; 90: 455-60.
Gasparini G, Longo R, Sarmiento RA, Morabito A. Inhibitors of
cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol
2003; 4: 605-15.
Brueggemeier RW, Quinn AL, Parret ML, Joarder FS, Harris RE,
Robertson FM. Correlation of aromatase and cyclooxygenase gene
expression in human breast cancer specimens. Cancer Lett 1999;
Harris RE, Robertson FM, Abou-Issa HM, Farrar WB,
Brueggemeier RW. Genetic induction and up regulation of
cyclooxygenase (COX) and aromatase (CYP19): an extension of
the dietary fat hypothesis of breast cancer. Med Hypotheses 1999;
Brueggemeier RW, Diaz-Cruz ES. Relationship between aromatase
and cyclooxygenases in breast cancer: potential for new therapeutic
approaches. Minerva Endocrinol 2006; 31: 13-26.
Weise FW, Thompson PA, Kadlubar FF. Carcinogen substrate
specificity of human COX-1 and COX-2. Carcinogenesis 2001; 21:
Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2
promotes human cholangiocarcinoma cell growth and invasion
through EP1 receptor-mediated activation of the epidermal growth
factor receptor and Akt. J Biol Chem 2005; 280: 24053-63.
Simeone AM, Nieves-Alicea R, McMurtry VC, Colella S, Krahe R,
Tari AM. Cyclooxygenase-2 uses the protein kinase C/ interleukin-
8/urokinase-type plasminogen activator pathway to increase the
invasiveness of breast cancer cells. Int J Oncol 2007; 30: 785-92.
Tinahones F, Salas J, Mayas MD, et al. VEGF gene expression in
adult human thymus fat: a correlative study with hypoxic induced
factor and cyclooxygenase-2. PLoS One 2009: 14; 4: e8213.
Dormond O, Foletti A, Paroz C, Ruegg C. NSAIDs inhibits alpha-
V-beta-3 integrin-mediated and cdc42/Rac-dependent endothelial-
cell spreading, migration and angiogenesis. Nature Med 2001; 7:
Buchanan FG, Wang D, Bargiacchi F, DuBois RN. Prostaglandin
E2 regulates cell migration via the intracellular activation of the
epidermal growth factor receptor. J Biol Chem 2003; 278: 35451-7.
Hsu AL, Ching TT, Wang D-S, Song X, Rangnekar VM, Chen C-
S. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by
blocking Akt activation in human prostate cancer cells
independently of Bcl-2. J Biol Chem 2000; 275: 11397-403.
Zhang L, Tu J, Yu ZL, Wu YD, Xu CM, Zhang ST. Effects of the
inhibition of cyclooxygenase-2 on human esophageal cancer cells:
inhibition of cell proliferation and induction of apoptosis. Pathol
Oncol Res 2010; 16: 39-45.
Iwase M, Takaoka S, Uchida M, et al. Accelerative effect of a
selective cycloxygenase-2 inhibitor on Fas-mediated apoptosis in
human neutrophils. Int Immunopharmacol 2006; 6: 334-41.
Alam M, Wang JH, Coffey JC, et al. Characterization of the effects
of Cyclooxygenase-2 inhibition in the regulation of apoptosis in
human small and non-small cell lung cancer cell lines. Ann Surg
Oncol 2007; 30: 2678-84.
Li M, Wu X, Xu XC. Induction of apoptosis in colon cancer cells
by cyclooxigenase-2 inhibitor NS398 through a Cytochrome-c-
dependent pathway. Clin Cancer Res 2001; 7: 1010-16.
Nzeako UC, Guicciardi ME, Yoon J-H, Bronk SF, Gores GF. Cox-
2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells.
Hepatology 2002; 35: 552-9.
1092 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al.
 Krysan K, Merchant FH, Zhu L, et al. Cox-2-dependent
stabilization of survivin in non-small cell lung cancer. The FASEB
J 2003; 18: 206-8.
Khan Z, Tiwari RP, Mulherkar R, et al. Detection of survivin and
p53 in human oral cancer: correlation with clinicopathological
findings. Head and Neck 2009; 31: 1039-48.
Khan Z, Bhadouria P, Radha Gupta, Bisen PS. Tumor control by
manipulation of the human anti-apoptotic survivin gene. Curr
Cancer Ther Rev 2006; 2: 73-9.
Khan Z, Khan N, Varma AK, et al. Oxaliplatin-mediated Inhibition
of Survivin Increases Sensitivity of Head and Neck Squamous Cell
Carcinoma Cell Lines to Paclitaxel. Curr Cancer Drug Targets
2010; 10: 660-9.
Khan Z, Khan N, Tiwari RP, Patro IK, Prasad GBKS, Bisen PS.
Down-regulation of survivin
radioresistance of head and neck squamous carcinoma cells.
Radiother Oncol 2010; 96: 267-73.
Barnes N, Haywood P, Flint P, Knox WF, Bundred NJ. Survivin
expression in in situ and invasive breast cancer relates to Cox-2
expression and DCIS recurrence. Br J Cancer 2006; 94: 253-8.
Bodmer JL, Holler N, Reynard S, et al. TRAIL receptor-2 signals
apoptosis through FADD and caspase-8. Nat Cell Biol 2000; 2:
Tang X, Sun YJ, Half E, Kou MT, Sinicrope F. Cyclooxygenase-2
overexpression inhibits death receptor 5 expression confers
resistance to tumor necrosis factor- related apoptosis-inducing
ligand induced apoptosis in human colon cancer cell. Cancer Res
2002; 62: 4903-8.
Subbaramaiah K, Altorki N, Chung WJ, Mestre JR, Sampat A.
Dannenberg AJ. Inhibition of cyclooxygenase-2 gene expression by
p53. J Biol Chem 1999; 274: 10911-5.
Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B,
Kwong E, et al. Suppression of intestinal polyposis in Apc 716
mice by inhibition of cyclooxygenase-2 (Cox-2). Cell 1996; 87:
Kawamori T, Rao CV, Seibert K, Reddy BS. Chemopreventive
activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against
colon carcinogenesis. Cancer Res 1998; 58: 409-12.
Harris RE, Alshafie GA, Abou-Issa H, Seibert K. Chemoprevention
of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor.
Cancer Res 2000; 60: 2101-3.
Alshafie GA, Abou-Issa HM,
Chemotherapeutic evaluation of celecoxib, a cyclooxygenase-2
inhibitor, in a rat mammary tumor model. Oncology Reports 2000;
Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ.
Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast
cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem
2002; 277: 18649-57.
 Benoit V, Relic B, de Leval X, Chariot A, Merville M-P, Bours V.
Regulation of HER-2 oncogene expression by cyclooxygenase-2
and prostaglandin E2. Oncogene 2004; 23: 1631-35.
 Naruse K, Yamada Y, Nakamura K, Aoki S, Taki T, Zennami K, et
al. Potential of molecular targeted therapy of HER-2 and Cox-2 for
invasive transitional cell carcinoma of the urinary bladder. Oncol
Rep 2010; 23: 1577-83.
 Harris RE, Beebe-Donk J, Alshafie GA. Reduction in the risk of
human breast cancer by selective cyclooxygenase-2 (Cox-2)
inhibitors. BMC Cancer 2006; 6: 27-32.
 Sooriakumaran P, Langley SE, Laing RW, Coley HM. COX-2
inhibition: a possible role in the management of prostate cancer? J
Chemother 2007; 19: 21-32.
 Dhawan D, Craig BA, Cheng L, Snyder PW, Mohammed SI,
Stewart JC, et al. Effects of short-term celecoxib treatment in
patients with invasive transitional cell carcinoma of the urinary
bladder. Mol Cancer Ther 2010; 9: 1371-7.
 Rijcken FE, Hollema H, van der Zee AG, van der Sluis T,
Boersma-van Ek W, Kleibeuker JH. Sulindac treatment in
hereditary non-polyposis colorectal cancer. Eur J Cancer 2007;
 Hawk E, Viner JL. The Adenoma Prevention with Celecoxib and
Prevention of Colorectal Sporadic Adenomatous Polyps Trials:
Stepping Stones to Progress. Cancer Epidemiol Biomarkers Prev
2007; 16: 185-7.
by oxaliplatin diminishes
 Seibert K, Harris RE.
 Singh B, Lucci A. Role of cyclooxygenase-2 in breast cancer. J
Surg Res 2002; 108:173-9.
Wang D, Dubois RN. Cyclooxygenase-2: a potential target in
breast cancer. Semin Onco1 2004; 31: 64-73.
Gabriel N, Hortobagyi. Trastuzumab in the Treatment of Breast
Cancer. N Engl J Med 2005; 353: 1734-6.
Ershler WB. Capecitabine Monotherapy: Safe and Effective
Treatment for Metastatic Breast Cancer. The Oncologist 2006; 11:
 Chow LWC, Toi M. Prospective pilot study of the preoperative use
of celecoxib (Celebrex (TM)) and FEC for the treatment of locally
advanced breast cancer. Breast Cancer Res Treat 2002; 76: 154-67.
 Dang CT, Dannenberg AJ, Subbaramaiah K, Dickler MN, Moasser
MM, Seidman AD, et al. Clifford A. Hudis. Phase II Study of
Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients
Who Have Progressed after Prior Trastuzumab-Based Treatments.
Clin Cancer Res; 2004; 10: 4062-7.
 Fabi A, Metro G, Papaldo P, Mottolese M, Melucci E, Carlini P, et
al. Impact of celecoxib on capecitabine tolerability and activity in
pretreated metastatic breast cancer: results of a phase II study with
biomarker evaluation.Cancer Chemother Pharmacol 2008; 62: 717-
 Zhao Y, Agarwal VR, Mendelson CR, Simpson ER. Estrogen
biosynthesis proximal to a breast tumor is stimulated by PGE2 via
cyclic AMP, leading to activation of promoter II of the CYP19
(aromatase) gene. Endocrinology 1996; 137: 5739-42.
 Miller WR, Dixon JM, Cameron DA, Anderson TJ. Biological and
clinical effects of aromatase inhibitors in neoadjuvant therapy. J
Steroid Biochem Mol Biol 2001; 79: 103-7.
 Chow LW, Wong JL, Toi M. Celecoxib anti-aromatase
neoadjuvant (CAAN) trial for locally advanced breast cancer:
preliminary report. J Steroid Biochem Mol Biol 2003; 86: 443-7.
 Maaser K, Däubler P, Barthel B, Heine B, von Lampe B, Stein H,
et al. Oesophageal squamous cell neoplasia in head and neck
cancer patients: upregulation of COX-2 during carcinogenesis. Br J
Cancer 2003; 88: 1217-22.
 Kim K, Wu HG, Park SW, Kim CJ, Park C. Expression of
Nasopharyngeal Cancer. Cancer Res Treat 2004; 36: 187-91.
 Kim YY, Lee EJ, Kim YK, Kim SM, Park JY, Myoung H, et al.
Anti-cancer effects of celecoxib in head and neck carcinoma. Mol
Cells 2010; 29: 185-94.
 Lau L, Hansford LM, Cheng LS, Hang M, Baruchel S, Kaplan DR,
et al. Cyclooxygenase inhibitors modulate the p53/HDM2 pathway
and enhance chemotherapy-induced apoptosis in neuroblastoma.
Oncogene 2007; 26: 1920-31.
 Ochiai M, Oguri T, Isobe T, Ishioka S, Yamakido M.
Cyclooxygenase-2 (COX-2) mRNA Expression Levels in Normal
Lung Tissues and Non-small Cell Lung Cancers. Jpn J Cancer Res
1999; 90: 1338-43.
 Mascaux C, Martin B, Verdebout JM, Ninane V, Sculier JP. COX-
2 expression during early lung squamous cell carcinoma
oncogenesis. Eur Respir J 2005; 26: 198-203.
 Qadri SS, Wang JH, Redmond KC, O' Donnell AF, Aherne T,
Redmond HP. The role of COX-2 inhibitors in lung cancer. Ann
Thorac Surg 2002; 74: 1648-52.
 Park SY, Kim YM, Pyo H. Gefitinib radiosensitizes non-small cell
lung cancer cells through inhibition of ataxia telangiectasia mutated
Molecular Cancer 2010, 9: 222, DOI:10.1186/1476-4598-9-222.
 Sandler AB, Dubinett SM. COX-2 inhibition and lung cancer.
Semin Oncol 2004; 31: 45-52.
 Liao Z, Komaki R, Milas L, Yuan C, Kies M, Chang JY, et al. A
Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent
Celecoxib for Patients with Unfavorable Performance Status
Inoperable/Unresectable Non–Small Cell Lung Cancer. Clin
Cancer Res 2005; 11; 3342-8.
 Chen L, He Y, Huang H, Liao H, Wei W. Selective COX-2
inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-
small cell lung cancer cell lines: in vitro toxicity and mechanism
study. Med Oncol 2008; 25, 161-71.
 Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of
cyclooxygenase (COX)-2 in human skin epidermal cancer cells:
evidence for growth suppression by inhibiting COX-2 expression.
Int J Cancer 2000; 86: 667-71.
as a Prognostic Factor in
Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1093
 Kulkarni S, Rader JS, Zhang F, Liapis H, Koki AT, Masferrer JL,
et al. Cyclooxygenase-2 Is Overexpressed in Human Cervical
Cancer. Clin Cancer Res 2001; 7: 429-34.
Wülfing C, Eltze E, von Struensee D, Wülfing P, Hertle L,
Piechota H. Cyclooxygenase-2 Expression in Bladder Cancer:
Correlation with Poor Outcome after Chemotherapy. Eur Urol
2004; 45, 46-52.
 Michalowski J. COX-2 Inhibitors: Cancer Trials Test New Uses for
Pain Drug. J Natl Cancer Inst 2002; 94: 248-49.
Solomon SD, McMurray JJV, Pfeffer MA, Wittes J, Fowler R,
Finn P, et al. Cardiovascular Risk Associated with Celecoxib in a
Clinical Trial for Colorectal Adenoma Prevention for the Adenoma
Prevention with Celecoxib (APC) Study Investigators. N Engl J
Med 2005; 352:1071-80.
Received: June 17, 2010
Revised: October 26, 2010 Accepted: November 01, 2010