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Journal of Cancer Prevention

Review

Journal of Cancer Prevention 2013; 18(2): 123-134

Published online June 30, 2013

https://doi.org/10.15430/JCP.2013.18.2.123

© Korean Society of Cancer Prevention

Cyclooxygenase-1 and -2: Molecular Targets for Cervical Neoplasia

Hee Seung Kim1, Taehun Kim1, Mi-Kyung Kim1, Dong Hoon Suh2, Hyun Hoon Chung1, and Yong Sang Song1,3,4

1Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, 2Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, 3Cancer Research Institute, Seoul National University College of Medicine, 4Major in Biomodulation, World Class University, Seoul National University, Seoul, Korea

Correspondence to :
Yong Sang Song, Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: +82-2-2072-2822, Fax: +82-2-762-3599, E-mail: yssong@snu.ac.kr

Received: June 1, 2013; Revised: June 18, 2013; Accepted: June 20, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cyclooxygenase (COX) is a key enzyme responsible for inflammation, converting arachidonic acid to prostaglandin and thromboxane. COX has at least two isoforms, COX-1 and COX-2. While COX-1 is constitutively expressed in most tissues for maintaining physiologic homeostasis, COX-2 is induced by inflammatory stimuli including cytokines and growth factors. Many studies have shown that COX-2 contributes to cancer development and progression in various types of malignancy including cervical cancer. Human papillomavirus, a necessary cause of cervical cancer, induces COX-2 expression via E5, E6 and E7 oncoproteins, which leads to prostaglandin E2 increase and the loss of E-cadherin, promotes cell proliferation and production of vascular endothelial growth factor. It is strongly suggested that COX-2 is associated with cancer development and progression such as lymph node metastasis. Many studies have suggested that non-selective COX-2 inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors might show anti-cancer activity in COX-2 -dependent and -independent manners. Two phase II trials for patients with locally advanced cervical cancer showed that celecoxib increased toxicities associated with radiotherapy. Contrary to these discouraging results, two phase II clinical trials, using rofecoxib and celecoxib, demonstrated the promising chemopreventive effect for patients with cervical intraepithelial neoplasia 2 or 3. However, these agents cause a rare, but serious, cardiovascular complication in spite of gastrointestinal protection in comparison with NSAIDs. Recent pharmacogenomic studies have showed that the new strategy for overcoming the limitation in clinical application of COX-2 inhibitors shed light on the use of them as a chemopreventive method.

Keywords: Cyclooxygenase, Cyclooxygenase-2 inhibitor, Cervical cancer

Cyclooxygenase (COX) pathway is known to be one of major routes for producing bioactive prostanoids such as prostaglandin (PG) E2, D2, F2α, I2 (prostacyclin) and thromboxane (TX) A2. COX exists as at least two different enzymes in mammalian cells: COX-1 and COX-2, which are located on human chromosomes 9 and 1 respectively.1,2 COX-1 is constitutively expressed in many normal cells, and PGs produced by COX-1 are important for maintaining the integrity of gastric mucosa and allowing normal platelet aggregation and renal function. On the other hand, COX-2 is induced by oncogene, growth factors and cytokines, and COX-2-derived PGs can stimulate cell proliferation, promote angiogenesis, increase invasiveness and adhesion to the extracellular matrix and inhibit immune surveillance and apoptosis.3?5 Furthermore, COX-2-derived PGs have been shown to contribute to cancer development, progression and metastasis.6 Therefore, the inhibition of COX-2 has been anticipated to prevent the development and progression of cancer and to promote the response to cytotoxic agents as well as ionizing radiation.7

Although non-steroidal anti-inflammatory drugs (NSAIDs), which non-specifically inhibit both COX-1 and COX-2, induce adverse effects on gastrointestinal (GI) tract, selective COX-2 inhibitors such as rofecoxib and celecoxib reduce the adverse effects of NSAIDs on GI tract with relief of chronic pain.8,9 However, selective COX-2 inhibitors are known to be associated with increased cardiovascular adverse effects.10 Since many preclinical and clinical studies have shown that COX-2-derived PGs are associated with cervical neoplasia and COX-2 inhibitors have anti-cancer effect, we will show the role of COX-2 and the efficacy of COX-2 inhibitors in cervical neoplasia, and will suggest the new strategy for overcoming the limitation in clinical application of COX-2 inhibitors through this review.

Chronic inflammation mediated by COX-2 is associated with carcinogenesis and cancer progression. It is caused by various factors including bacterial infections and chemical irritants. The longer the inflammation persists, the higher is the risk of associated carcinogenesis. Moreover, neoplasia could be caused by inflammatory mediators inducing preneoplastic mutation, stimulation of angiogenesis and resistance to apoptosis, and these inflammatory mediators may activate signaling molecules involved in inflammation and carcinogenesis such as COX-2 and nuclear factor-kappa B (NF-kB).11

Carcinogenesis by COX-2 has been explored in terms of the inhibition of apoptosis, promotion of angiogenesis, invasiveness and immunosuppression in various types of malignancy.7 Especially, PG E2, an end product of COX-2, may increase the activity of mitogen-activated protein kinase (MAPK),12 affect ras-controlled signal transduction pathways,13 and suppress the activity of caspase-3, a key enzyme in apoptotic process.14 Besides, COX-2-derived PGs may increase the production of vascular endothelial growth factor (VEGF) and promote neovascularization in cancer.15,16

COX-2 overexpression may lead to the invasiveness of cancer to basement membrane, stroma, penetration to blood vessels and metastasis, which are mediated by matrix metalloproteinases (MMPs) such as MMP-1, -2 and -9.6,17 Additionally, carcinogenesis is related with immunosuppression because colony-stimulating factors secreted by cancer cells activate monocytes and macrophages resulting in the synthesis of PG E2 by COX-2. PG E2 shows the immunosuppressive effect by inhibiting the production of lymphokines and tumor necrosis factors, proliferation of T- and B-cells and cytotoxic activity of natural killer cells.18,19

Human papillomavirus (HPV) is the most prevalent sexually infectious agent and causes cervical cancer. Especially, HPV 16 E6 and E7 oncoproteins stimulate to produce amphiregulin, which induces the transcription of COX-2 gene by activating MAPK cascade (Fig. 1A).5 HPV 16 E5 oncoprotein also induces the transcription of COX-2 gene in a ligand-dependent and -independent activation of epidermal growth factor receptor (EGFR) and MAPK cascade,20?22 and causes the increased expression of VEGF by activating MEK/ERK 1/2 and PI3K/Akt, which are associated with cervical carcinogenesis (Fig. 1B).20,23,24 Moreover, chronic infection of HPV in cervical epithelium increases PG E2 by COX-2, which leads to the loss of E-cadherin, increased cell proliferation and production of VEGF.25?27

COX-2 is highly expressed in various types of cervical neoplasm such as cervical intraepithelial neoplasia (CIN) (7.4%), adenocarcinoma (13%) and squamous cell carcinoma (28.8%) of cervix, suggesting that COX-2 expression can be associated clinically with cervical cancer development and progression.28?30 Besides, COX-2 gene has been shown to be involved in early cervical carcinogenesis and accelerate tumor progression by increasing VEGF.25

COX-2 has been also shown to be expressed in dysplastic epithelium (7.4%) but not in stromal cells of CIN (0%).31 This fact is contrary to previous studies of COX-2 overexpression in colon cancer where the increased COX-2 expression in stromal cells was related with carcinogenesis, suggesting that PGs derived from COX-2 in stromal cells would be secreted and bind to receptors on adjacent epithelial cells, then might promote carcinogenesis with the “landscaping effect”.32 Unlike colon cancer, the landscaping effect of stromal cells seems to have no role in cervical carcinogenesis because it may be influenced by HPV itself.

Interestingly, COX-2 overexpression may be also associated with old age and menopause in CIN.31 Although the reason is unclear, the lack of progesterone for menopausal women could explain this fact because progesterone has been shown to suppress COX-2 expression in some cells.33

COX-2 overexpression is associated with lymph node metastasis in cervical cancer.34,35 Although COX-2 over-expression was not an independent prognostic factor for survival,36,37 it may enhance metastatic potentials of tumors by inducing genes which promote lymphangiogenesis and increase metastatic properties of cervical cancer.38

Moreover, COX-2 overexpression is related with NF-kB activation, which is localized to the cytoplasm in resting cells and binds to the DNA recognition sites in the regulatory regions of target genes after it migrates into the nucleus on various stimuli.34,35,39 Many studies have been focused on NF-kB as a molecular target for chemoprevention, which plays a crucial role in the regulation of inflammatory and immunes responses and in carcinogenesis. Stimuli regulated by NF-kB during inflammation can be redirected as tumor growth signals. NF-kB has been found constitutively activated in many human cancer samples, supporting an important role of NF-kB in cancer development.40 Moreover, COX-2 is inducible via the activation of NF-kB by many factors such as cytokines and growth factors.41

NSAIDs and selective COX-2 inhibitors such as celecoxib have been commonly used as analgesics, anti-inflammatory drugs. After several studies reported their apoptotic effect in various types of cancer cells,42?44 the efficacy of COX-2 inhibitors has been evaluated for the prevention or treatment of cervical neoplasia. In detail, anti-cancer activity of COX-2 inhibitors is mediated in part through the inhibition of the COX-2 activity.45?47 However, anti-cancer activity exerted by COX-2 inhibitors is independent of their COX-2 inhibitory properties because the growth of hematopoietic and epithelial tumor cells without COX-2 expression has been reported to be suppressed by COX-2 inhibitors.48,49 Besides, in cervical cancer cells, celecoxib induces apoptosis independent of COX-2 inhibition through two major pathways: death receptor pathway followed by the activation of caspase-8, which then activates the downstream effector caspases such as caspase-3, -6 and -7, triggering cell death; mitochondrial pathway by the activation of caspase-9, which leads to the loss of mitochondrial membrane potential.42,50

Celecoxib-induced apoptosis is mediated by a Fas/Fas- associated protein with death domain (FADD)-dependent mechanism in Fasligand (FasL)-independent manner, and involved in the activation of NF-kB.42 Growth arrest and DNA damage inducible gene (GADD153), a transcription factor involved in apoptosis, also plays a key role in celecoxib-induced apoptosis in cervical cancer cells by regulating the expression of proapoptotic proteins such as Bak.51

NSAIDs seem to have comparable efficacy to celecoxib. In a study on the association among COX-1, COX-2 and VEGF expression in cervical cancer, VEGF expression was strongly correlated with COX-1 expression, and COX-2 expression was associated with lymph node metastasis,28 suggesting that NSAIDs may be efficient to treat cervical cancer.52,53 Furthermore, NSAIDs including aspirin, sulindac and indomethacin have been reported to decrease cell proliferation and colony formation in a time and dose- dependent manner in cervical cancer cells, and increase apoptosis and radiotherapeutic efficacy by pretreatment of cervical cancer cells through bcl-2 repression and caspase-3 induction.54

On the other hand, COX expression in cervical cancer may be associated with the effect of radiotherapy.55,56 Especially, COX-1 expression decreases significantly radiosensitivity in cervical cancer cell lines in spite of no association between COX-2 expression and radio-resistance. These data suggest that COX-1 might imply more importance than COX-2 regarding the innate radiosensitivity of cervical cancer, and that NSAIDs, non-selective COX-2 inhibitors, might increase the radiotherapeutic effectiveness if cervical tumor cells have not yet lost their ability to express COX-1.56

COX-2 inhibitors for the prevention of cervical cancer

The efficacy of COX-2 inhibitors has a definite advantage to treat CIN because cervical conization may be avoided, reducing obstetrical complications including preterm delivery, and preterm premature rupture of membrane. In a prospective, randomized, placebo-controlled, double-blind study with rofecoxib 25 mg daily for 6 months for the treatment of 16 patients with CIN 2 and CIN 3, regression rate was higher in patients treated with rofecoxib than those treated with placebo (25% vs. 12.5%) without no severe side effects although the results were statistically not significant due to early withdrawal of refecoxib from the market by increased cardiovascular adverse effect.57 Also, clinical response rate and complete pathologic response were higher for patients treated with celecoxib than in those treated with placebo (75% vs. 31%; 33% vs. 15%, respectively) in a randomized, double-blind, placebo-controlled phase II trial of celecoxib 200 mg twice a day or placebo for the treatment of 25 patients with CIN 2 or CIN 3.58


COX-2 inhibitors for the treatment of cervical cancer

The efficacy of selective COX-2 inhibitors has been mainly studied for patients with locally advanced cervical cancer receiving radiotherapy. However, the results were disappointing because COX-2 inhibitors showed no clinical benefit and higher toxicity by the addition to chemoradiation. In a phase I?II trial of celecoxib 400 mg twice per day for 2 weeks before and during chemoradiation using cisplatin, 31 patients with locally advanced cervical cancer were enrolled. Higher incidence of grade 3 or 4 acute toxicity (35.5%) was seen with no difference in 81% of response rate, compared with previous studies about the chemoradiation alone. Besides, there was an increase in late complication such as fistula (9.7%). Thus, celecoxib in combination with chemoradiation was associated with acceptable acute toxicity, but higher late complication.59

Furthermore, the Radiation Therapy Oncology Group (RTOG) 0128 trial was performed as a phase II study to evaluate the efficacy and toxicity of celecoxib and chemoradiation for patients with locally advanced cervical cancer. In this study, 83 patients were treated with chemoradiation using cisplatin and 5-fluorouracil with the addition of celecoxib at the dose of 400 mg twice daily for 1 year. However, grade 3 or 4 toxicities were developed in 47% and late toxicities such as GI and genitourinary side effects were observed in 13% of all patients, which were higher than expected rates of complication. These data suggest that the toxicities associated with celecoxib may limit the use of this drug.60

On the other hand, a randomized clinical trial showed that the treatment of oxyphenbutazone, a non-selective COX-2 inhibitor, at the dose of 300 mg daily improved 5- and 10-year survival rates, compared to placebo in patients undergoing radiotherapy only for cervical cancer (5-year survival rate, 70 vs. 55%; 10-year survival rate, 62 vs. 44%). Taken together, there are two possible explanations for these discrepant results. First, the improvement of survival rates might be due to slowing of tumor spread and improvement of cell repair after radiotherapy by the inhibition of PGs. Second, the inhibition of both COX-1 and -2 might be important to treat cervical cancer.52

Thus, many clinical trials are required to evaluate the role of COX-2 inhibitors in the management of cervical cancer. Table 1 depicts clinical studies about the efficacy of COX-2 inhibitors in cervical neoplasia. The clinical trials of selective COX-2 inhibitors, especially celecoxib, are being on the progress for the treatment of cervical neoplasia combined with chemotherapy or radiotherapy or alone.

After selective COX-2 inhibitors were introduced as alternative analgesics to NSAIDs due to fewer GI side effects, the approval of rofecoxib (Vioxx?) and celecoxib (Celebrex?) by the Food and Drug Administration in the United States came in 1999 with their market release. Moreover, selective COX-2 inhibitors had been investigated for chemoprevention because some studies have demonstrated that inhibiting COX-2 could prevent the formation of premalignant colorectal adenomas.61?65 However, rofecoxib was withdrawn from the market on September 2004 because of the serious adverse event found in Adenomatous Polyp Prevention on Vioxx? (APPROVe) trial, demonstrating that the group assigned to rofecoxib had a fourfold increased risk of serious thromboembolic events including acute myocardial infarction and cerebrovascular accident compared with the placebo group.66 Furthermore, rofecoxib has been shown to increase cardiovascular adverse effects by meta-analysis when compared to placebo or NSAIDs (Table 2).

Benefit and risk by COX-2 inhibitors are summarized in Fig. 2. In spite of markedly less GI damage than NSAIDs, selective COX-2 inhibitors are doomed to increase cardiovascular adverse effects because selective COX-2 inhibition may reduce the production of prostacyclin, which normally inhibits platelet aggregation and vasodilation, while still allowing COX-1 mediated synthesis of TX A2 to induce platelet aggregation and vasoconstriction.67 After withdrawal of rofecoxib, the safety of celecoxib has also been investigated for cardiovascular adverse effects. Celecoxib has been shown to be safer than rofecoxib in most studies. The first reason is that the degree of COX-2 selectivity of celecoxib is a fifth of that of rofecoxib. Actually, the degree of COX-2 selectivity is known to correlate with cardiovascular and renal risks.68,69 The second reason is that a reactive metabolite of rofecoxib, a maleic anhydride derivative which contributes to atherothrombosis, cannot be derived from other COX-2 inhibitors including celecoxib, valdecoxib and lumaricoxib.70 Furthermore, the Celecoxib Long-term Arthritis Safety Study (CLASS) demonstrated no significant difference in cardiovascular event between celecoxib 800 mg/day and NSAIDs, suggesting the safety of celecoxib.71

Nonetheless, the Adenoma Prevention with Celecoxib (APC) and Prevention of Spontaneous Adenomatous Polyps (PreSAP) trials comparing celecoxib with placebo for the reduction in recurrent colorectal polyps were stopped early because of significantly higher numbers of cardiovascular adverse effects in celecoxib-treated group.72,73 Thus, the safety of celecoxib is still on debate, and further trials designed to assess the incidence of cardiovascular adverse effects by celecoxib are needed.

Natural products for the chemoprevention of cervical neoplasia

Many natural products are being investigated to inhibit COX-2 overexpression and NF-kB activation as molecular targets for chemoprevention of cervical neoplasia. First, curcumin is a yellow pigment of turmeric, a natural product with diverse biological activities. It has been shown to possess anti-inflammatory, anti-oxidant and anti-tumor properties. Much of its beneficial effect is found to be due to its inhibition of NF-kB and subsequent inhibition of proinflammatory pathways.74 Besides, curcumin synergistically augments the growth inhibitory effect of celecoxib by down-regulating COX-2 mRNA expression and inhibition of the catalytic activity of 5-lipoxygenase producing leukotrienes associated with carcinogenic process.75 Phase I trials on curcumin showed that it is safe to human up to 12,000 mg/day when taken orally and caused histological improvement of precancerous lesions including CIN.76?78 Moreover, curcumin has been shown to confer the radiosensitizing effect in cervical cancer cells.79

Second, indole-3-carbinol (I3C) is derived from cruciferous vegetables such as broccoli and cabbage. I3C and its metabolite, 3,3′-diindoylmethane (DIM) target multiple aspects of cancer cell-cycle regulation and survival including NF-kB signaling, caspases activation and cyclin-dependent kinase activity.80 I3C and its metabolite have been shown to prevent cervical cancer and have the efficacy in the treatment of cervical dysplasia in the mouse model.81 A small randomized controlled clinical trial in patients with CIN 2 or 3 indicated the efficacy of I3C for the regression of CIN.82 In addition, some studies on HPV persistence or cervical neoplasia showed a possible protective effect of fruits, vegetables, vitamins C and E, α- and β-carotenes, lycopene, luterin/zeaxanthin and cryotoxanthin.83


New methods using COX-2 inhibitors

Since the safety of selective COX-2 inhibitors is controversial, patients treated with selective COX-2 inhibitors should be monitored regularly in terms of blood pressure, edema and cardiac status because regular interruptions of treatment can contribute a great deal to the safe use of selective COX-2 inhibitors.68 In addition, new methods are being investigated for overcoming the limitation of selective COX-2 inhibitors as follows.

The first is the combination of COX-2 inhibitors with other drugs. The prescription of a combined therapy of NSAIDs and proton pump inhibitors (PPIs) has been shown to have comparable ulcerous bleeding to COX-2 inhibitors (6.4% vs. 4.9%).84 However, it should be considered that PPIs may be associated with adverse effects independent of concomitant NSAID use, including pneumonia, bacterial diarrhea and hip fracture.85?87 Moreover, it can be considered that selective COX-2 inhibitors are combined with low-dose aspirin for cardioprotection. However, the CLASS trial demonstrated that a fourfold increase in the incidence of GI bleeding occurred in a subgroup of patients taking celecoxib in combination with aspirin, suggesting that the combination should not be used in patients with high-risk GI bleeding.71 Furthermore, curcumin can be combined with selective COX-2 inhibitors because it induces cardioprotective effect by scavenging oxygen-free radical.88 However, large and well-controlled clinical trials are required to determine the role of selective COX-2 inhibitors and curcumin to prevent and treat cancer.

The second method is the structural modification of NSAIDs. Nitric oxide (NO)-donating NSAIDs have been claimed to exert a broader range of anti-inflammatory action while reducing markedly GI and cardiovascular toxicity.89?91 However, these claims are poorly substantiated by clinical studies to date.

The third method is the modification of schedule for the use of selective COX-2 inhibitors. In some meta-analyses, celecoxib showed dose-dependent cardiovascular effect although rofecoxib was associated with cardiovascular adverse effect at all doses (at doses of 25 mg or less, or greater than 25 mg once daily), suggesting that celecoxib doses of up to 200 mg once daily was not related with increased cardiovascular adverse effect in spite of the need of clinical trials for evaluating dose-dependent toxicity of celecoxib.92,93 Since the combination of chemoradiation with celecoxib increased late toxicities compare to chemoradiation alone in patients with locally advanced cervical cancer,59,60 various schedules for the administration of celecoxib are being investigated in clinical trials for gynecologic cancers. For example, in a phase II study of weekly paclitaxel and celecoxib for the treatment of recurrent or persistent platinum-resistant epithelial ovarian or primary peritoneal cancer, patients receive paclitaxel on days 1, 8, and 15 and celecoxib twice daily on days 2?6, 9?13 and 16?27 with the repeat of courses every 28 days in the absence of disease progression or unacceptable toxicity.94

After withdrawal of rofecoxib from market, other selective COX-2 inhibitors including celecoxib have been focused on many clinical trials to prevent and treat various types of malignancy including cervical cancer. Since the safety of other selective COX-2 inhibitors remains controversial, it is important to select patients with low cardiovascular risk from selective COX-2 inhibitors, and to follow up them regularly for the prevention and early detection of GI, renal and cardiovascular adverse effects. For example, selective COX-2 inhibitors seem to be useful for the treatment of CIN which mainly develops in young women with HPV infection because most of them have relatively lower cardiovascular risk than old women.95 Besides, selective COX-2 inhibitors have the advantage that these agents can lessen the risk of preterm delivery by cervical conization for the treatment of CIN with lesser GI toxicity compared to non-selective COX-2 inhibitors.96

On the other hand, the role of COX-1 should be reevaluated for the prevention and treatment of cervical neoplasia because some preclinical and clinical studies have shown that the inhibition of COX-1 might increase the radiotherapeutic efficacy in cervical cancer.52,55,56 Furthermore, new strategies using natural products or COX-2 inhibitors should be proven through preclinical and clinical studies for overcoming the limitation of COX-2 inhibitors.

Fig. 1. Schematic of pathway where human papillomavirus (HPV)16 E5, E6 and E7 oncoproteins regulate cyclooxygenase-2 (COX-2) expression associated with the cervical carcinogenesis. (A) HPV16 E6 and E7 oncoproteins stimulate production of amphiregulin and thereby activate EGFR → Ras → MAPK signaling. This results, in turn, in the phosphorylation of c-Jun, leading to transduction β-like protein 1-related protein (TBLR1)-dependent degradation of the nuclear receptor corepressor (NCoR)/histone deacetylase 3 (HDAC3) complex and recruitment of the coactivator cyclic AMP-responsive element binding protein-binding protein (CBP)/p300 and phosphorylated c-Jun/c-Fos heterodimer to the COX-2 promoter. This corepressor/coactivator exchange triggered by HPV onco-proteins leads to enhanced COX-2 transcription; (B) HPV 16 E5 oncoprotein also causes the increase of phosphorylated EGFR, and thereby increases the transcription of COX-2 gene and secretion of VEGF, which enhances cervical carcinogenesis.
Fig. 2. Role of cyclooxygenase (COX) in human gastrointestinal, cardiovascular and renal functions. COX-1-derived thromboxane A2 decreases gastric acid secretion in gastrointestinal tract and renal vascular resistance in kidney, whereas it increases mucus production in gastrointestinal tract, vasoconstriction, platelet aggregation and smooth muscle proliferation in blood vessel, and vasodilation in kidney. Moreover, COX-2-derived prostaglandins E2 and I2 decrease platelet aggregation and smooth muscle proliferation in blood vessel while they increase vasodilation in gastrointestinal tract and blood vessel, and diuresis and natriuresis in kidney. On the other hand, selective COX-2 inhibitors increase thromboembolic risk, and decrease gastrointestinal side effects and renal function.
Table. 1.

Clinical trials of cyclooxygenase-2 (COX-2) inhibitors for the treatment of cervical neoplasia.

Authors or protocol IDSample sizeInterventionsTargeted diseaseResponse rate
Weppelmann and Monkemeier5276 vs. 84 (control)OxyphenbutazoneCervical cancer5-year survival rate : 70% vs. 55%10-year survival rate : 62% vs. 44%
Hefler et al.578 vs. 8 (control)RofecoxibCIN* 2?325% vs.12.5%
Farley et al.5812 vs. 13 (control)CelecoxibCIN* 2?375% vs. 31%
Herrera et al.5931CelecoxibCervical cancer81%
Gaffney et al.6084CelecoxibCervical cancerToxicity: 48%
NCT00081263 (GOG-0207)100CelecoxibCIN* 2?3-
NCT0015282845CelecoxibCervical cancer-
NCT00072540 (SWOG-S0212)100CelecoxibCIN* 2?3-

*Cervical intraepithelial neoplasia;

Active clinical trials (available at http://clinicaltrials.gov).


Table. 2.

Cardiovascular adverse effect of selective cyclooxygenase-2 (COX-2) inhibitors by meta-analysis.

Adverse effectsMeta-analysisComparison
Relative risk* with 95% CI
ControlIntervention
Serious cardiovascular eventsKearney et al.97PlaceboSelective COX-2 inhibitors1.42 (1.13?1.78)
NaproxenSelective COX-2 inhibitors1.57 (1.21?2.03)
Non-naproxenSelective COX-2 inhibitors0.88 (0.69?1.12)
Mukherjee et al.98NaproxenRofecoxib1.89 (1.03?3.45)
J?ni et al.99Control§Rofecoxib1.55 (1.05?2.29)
Garner et al.100Non-naproxen
- DiclofenacRofecoxib0.70 (0.25?1.93)
- NabumetoneRofecoxib2.90 (0.12?71.01)
- ArthrotecRofecoxib1.39 (0.63?3.08)
Cardiovascular mortality?Kearney et al.97PlaceboSelective COX-2 inhibitors1.49 (0.97?2.29)
NaproxenSelective COX-2 inhibitors1.47 (0.90?2.40)
J?ni et al.99Control§Rofecoxib0.79 (0.29?2.19)
Myocardial infarctionKearney et al.97NaproxenSelective COX-2 inhibitors2.04 (1.41?2.96)
Non-naproxenSelective COX-2 inhibitors1.20 (0.85?1.68)
J?ni et al.99PlaceboRofecoxib1.04 (0.34?3.12)
NaproxenRofecoxib2.93 (1.36?6.33)
Non-naproxenRofecoxib1.55 (0.55?4.36)
Garner et al.100PlaceboRofecoxib1.48 (0.06?36.06)
NaproxenRofecoxib4.98 (0.58?42.57)
Non-naproxen
- DiclofenacRofecoxib0.52 (0.05?5.72)
Stroke**Kearney et al.97PlaceboSelective COX-2 inhibitors1.02 (0.71?1.47)
NaproxenSelective COX-2 inhibitors1.10 (0.73?1.65)
Non-naproxenSelective COX-2 inhibitors0.62 (0.41?0.95)
J?ni et al.99Control§Rofecoxib1.02 (0.54?1.93)
Garner et al.100NaproxenRofecoxib0.08 (0.00?1.36)

*A ratio of the probability of the event occurring in the interventiongroup versus the control group;

non-fatal myocardial infarction, non-fatal stroke or cardiovascular death;

including rofecoxib, celecoxib, etoricoxib, lumiracoxib and valdecoxib;

§placebo and NSAIDs;

?Death due to cardiovascular events;

fatal or non-fatal myocardial infarction;

**fatal or non-fatal thrombotic or hemorrhagic stroke.


  1. Yokoyama, C, and Tanabe, T (1989). Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem Biophys Res Commun. 165, 888-94.
    CrossRef
  2. Tay, A, Squire, JA, Goldberg, H, and Skorecki, K (1994). Assignment of the human prostaglandin-endoperoxide synthase 2 (PTGS2) gene to 1q25 by fluorescence in situ hybridization. Genomics. 23, 718-9.
    Pubmed CrossRef
  3. Sheng, H, Shao, J, Washington, MK, and DuBois, RN (2001). Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem. 276, 18075-81.
    Pubmed CrossRef
  4. Dohadwala, M, Luo, J, Zhu, L, Lin, Y, Dougherty, GJ, and Sharma, S (2001). Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem. 276, 20809-12.
    Pubmed CrossRef
  5. Subbaramaiah, K, and Dannenberg, AJ (2007). Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: evidence of a corepressor/coactivator exchange. Cancer Res. 67, 3976-85.
    Pubmed CrossRef
  6. Tsujii, M, Kawano, S, and DuBois, RN (1997). Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A. 94, 3336-40.
    Pubmed CrossRef
  7. Dempke, W, Rie, C, Grothey, A, and Schmoll, HJ (2001). Cyclooxygenase-2: a novel target for cancer chemotherapy?. J Cancer Res Clin Oncol. 127, 411-7.
    Pubmed CrossRef
  8. Schmassmann, A, Peskar, BM, Stettler, C, Netzer, P, Stroff, T, and Flogerzi, B (1998). Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol. 123, 795-804.
    Pubmed CrossRef
  9. Vane, JR, Bakhle, YS, and Botting, RM (1998). Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 38, 97-120.
    Pubmed CrossRef
  10. Strand, V (2007). Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?. Lancet. 370, 2138-51.
    CrossRef
  11. Shacter, E, and Weitzman, SA (2002). Chronic inflammation and cancer. Oncology (Williston Park). 16, 217-26.
    Pubmed
  12. Sheng, H, Shao, J, Morrow, JD, Beauchamp, RD, and DuBois, RN (1998). Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 58, 362-6.
    Pubmed
  13. Gilhooly, EM, and Rose, DP (1999). The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines. Int J Oncol. 15, 267-70.
    Pubmed
  14. Villa, P, Kaufmann, SH, and Earnshaw, WC (1997). Caspases and caspase inhibitors. Trends Biochem Sci. 22, 388-93.
    CrossRef
  15. Marm?, D (1996). Tumor angiogenesis: the pivotal role of vascular endothelial growth factor. World J Urol. 14, 166-74.
    Pubmed CrossRef
  16. Chiarugi, V, Magnelli, L, and Gallo, O (1998). Cox-2, iNOS and p53 as play-makers of tumor angiogenesis (review). Int J Mol Med. 2, 715-9.
    Pubmed
  17. Attiga, FA, Fernandez, PM, Weeraratna, AT, Manyak, MJ, Patierno, SR, and Patierno, SR (2000). Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res. 60, 4629-37.
    Pubmed
  18. Balch, CM, Dougherty, PA, Cloud, GA, and Tilden, AB (1984). Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. Surgery. 95, 71-7.
    Pubmed
  19. Kambayashi, T, Alexander, HR, Fong, M, and Strassmann, G (1995). Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10. J Immunol. 154, 3383-90.
    Pubmed
  20. Kim, SH, Juhnn, YS, Kang, S, Park, SW, Sung, MW, and Bang, YJ (2006). Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ERK1,2 and PI3K/Akt. Cell Mol Life Sci. 63, 930-8.
    Pubmed CrossRef
  21. Fehrmann, F, and Laimins, LA (2003). Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation. Oncogene. 22, 5201-7.
    Pubmed CrossRef
  22. Straight, SW, Hinkle, PM, Jewers, RJ, and McCance, DJ (1993). The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes. J Virol. 67, 4521-32.
    Pubmed
  23. Kodama, J, Seki, N, Tokumo, K, Hongo, A, Miyagi, Y, and Yoshinouchi, M (1999). Vascular endothelial growth factor is implicated in early invasion in cervical cancer. Eur J Cancer. 35, 485-9.
    CrossRef
  24. Cheng, WF, Chen, CA, Lee, CN, Wei, LH, Hsieh, FJ, and Hsieh, CY (2000). Vascular endothelial growth factor and prognosis of cervical carcinoma. Obstet Gynecol. 96, 721-6.
    CrossRef
  25. Dai, Y, Zhang, X, Peng, Y, and Wang, Z (2005). The expression of cyclooxygenase-2, VEGF and PGs in CIN and cervical carcinoma. Gynecol Oncol. 97, 96-103.
    Pubmed CrossRef
  26. Young, JL, Jazaeri, AA, Darus, CJ, and Modesitt, SC (2008). Cyclooxygenase-2 in cervical neoplasia: a review. Gynecol Oncol. 109, 140-5.
    Pubmed CrossRef
  27. Kim, YM, Park, JY, Lee, KM, Kong, TW, Yoo, SC, and Kim, WY (2008). Does pretreatment HPV viral load correlate with prognosis in patients with early stage cervical carcinoma?. J Gynecol Oncol. 19, 113-6.
    Pubmed CrossRef
  28. Kim, MH, Seo, SS, Song, YS, Kang, DH, Park, IA, and Kang, SB (2003). Expression of cyclooxygenase-1 and -2 associated with expression of VEGF in primary cervical cancer and at metastatic lymph nodes. Gynecol Oncol. 90, 83-90.
    CrossRef
  29. Kang, S, Kim, MH, Park, IA, Kim, JW, Park, NH, and Kang, D (2006). Elevation of cyclooxygenase-2 is related to lymph node metastasis in adenocarcinoma of uterine cervix. Cancer Lett. 237, 305-11.
    Pubmed CrossRef
  30. Kulkarni, S, Rader, JS, Zhang, F, Liapis, H, Koki, AT, and Masferrer, JL (2001). Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin Cancer Res. 7, 429-34.
    Pubmed
  31. Kim, K, Jeon, YT, Park, IA, Kim, JW, Park, NH, and Kang, SB (2009). Cyclooxygenase-2 expression in cervical intraepithelial neoplasia. Ann N Y Acad Sci. 1171, 111-5.
    Pubmed CrossRef
  32. Prescott, SM (2000). Is cyclooxygenase-2 the alpha and the omega in cancer?. J Clin Invest. 105, 1511-3.
    Pubmed CrossRef
  33. Hardy, DB, Janowski, BA, Corey, DR, and Mendelson, CR (2006). Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression. Mol Endocrinol. 20, 2724-33.
    Pubmed CrossRef
  34. Yamamoto, K, Arakawa, T, Taketani, Y, Takahashi, Y, Hayashi, Y, and Ueda, N (1997). TNF alpha-dependent induction of cyclooxygenase-2 mediated by NF kappa B and NF-IL6. Adv Exp Med Biol. 407, 185-9.
    Pubmed CrossRef
  35. Surh, YJ, Chun, KS, Cha, HH, Han, SS, Keum, YS, and Park, KK (2001). Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 480?481, 243-68.
    CrossRef
  36. Kyzas, PA, Stefanou, D, and Agnantis, NJ (2005). COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma. Mod Pathol. 18, 153-60.
    Pubmed CrossRef
  37. Su, JL, Shih, JY, Yen, ML, Jeng, YM, Chang, CC, and Hsieh, CY (2004). Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res. 64, 554-64.
    CrossRef
  38. Yao, M, Lam, EC, Kelly, CR, Zhou, W, and Wolfe, MM (2004). Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer. Br J Cancer. 90, 712-9.
    Pubmed CrossRef
  39. Lim, JW, Kim, H, and Kim, KH (2001). Nuclear factor-kappaB regulates cyclooxygenase-2 expression and cell proliferation in human gastric cancer cells. Lab Invest. 81, 349-60.
    Pubmed CrossRef
  40. Barnes, OJ, and Karin, M (1997). Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 336, 1066-71.
    Pubmed CrossRef
  41. Ohshima, H, Tazawa, H, Sylla, BS, and Sawa, T (2005). Prevention of human cancer by modulation of chronic inflammatory processes. Mutat Res. 591, 110-22.
    Pubmed CrossRef
  42. Kim, SH, Song, SH, Kim, SG, Chun, KS, Lim, SY, and Na, HK (2004). Celecoxib induces apoptosis in cervical cancer cells independent of cyclooxygenase using NF-kappaB as a possible target. J Cancer Res Clin Oncol. 130, 551-60.
    Pubmed CrossRef
  43. Gr?sch, S, Tegeder, I, Niederberger, E, Br?utigam, L, and Geisslinger, G (2001). COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. Faseb J. 15, 2742-4.
    Pubmed
  44. Hsu, AL, Ching, TT, Wang, DS, Song, X, Rangnekar, VM, and Chen, CS (2000). The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem. 275, 11397-403.
    Pubmed CrossRef
  45. Smalley, WE, and DuBois, RN (1997). Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv Pharmacol. 39, 1-20.
    CrossRef
  46. Elder, DJ, and Paraskeva, C (1998). COX-2 inhibitors for colorectal cancer. Nat Med. 4, 392-3.
    CrossRef
  47. Williams, CS, Mann, M, and DuBois, RN (1999). The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 18, 7908-16.
    Pubmed CrossRef
  48. Waskewich, C, Blumenthal, RD, Li, H, Stein, R, Goldenberg, DM, and Burton, J (2002). Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines. Cancer Res. 62, 2029-33.
    Pubmed
  49. Totzke, G, Schulze-Osthoff, K, and J?nicke, RU (2003). Cyclooxygenase-2 (COX-2) inhibitors sensitize tumor cells specifically to death receptor-induced apoptosis independently of COX-2 inhibition. Oncogene. 22, 8021-30.
    Pubmed CrossRef
  50. Hengartner, MO (2000). The biochemistry of apoptosis. Nature. 407, 770-6.
    Pubmed CrossRef
  51. Kim, SH, Hwang, CI, Juhnn, YS, Lee, JH, Park, WY, and Song, YS (2007). GADD153 mediates celecoxib-induced apoptosis in cervical cancer cells. Carcinogenesis. 28, 223-31.
    Pubmed CrossRef
  52. Weppelmann, B, and Monkemeier, D (1984). The influence of prostaglandin antagonists on radiation therapy of carcinoma of the cervix. Gynecol Oncol. 17, 196-9.
    CrossRef
  53. Tsuji, S, Tsujii, M, Kawano, S, and Hori, M (2001). Cyclooxygenase-2 upregulation as a perigenetic change in carcinogenesis. J Exp Clin Cancer Res. 20, 117-29.
    Pubmed
  54. Kim, KY, Seol, JY, Jeon, GA, and Nam, MJ (2003). The combined treatment of aspirin and radiation induces apoptosis by the regulation of bcl-2 and caspase-3 in human cervical cancer cell. Cancer Lett. 189, 157-66.
    CrossRef
  55. Jeon, YT, Seo, SS, Kim, JW, Park, NH, Kang, SB, and Lee, HP (2006). Cyclooxygenase expressions and response to radiation therapy in uterine cervix cancer. J Gynecol Oncol. 17, 105-11.
  56. Jeon, YT, Song, YC, Kim, SH, Wu, HG, Kim, IH, and Park, IA (2007). Influences of cyclooxygenase-1 and -2 expression on the radiosensitivities of human cervical cancer cell lines. Cancer Lett. 256, 33-8.
    Pubmed CrossRef
  57. Hefler, LA, Grimm, C, Speiser, P, Sliutz, G, and Reinthaller, A (2006). The cyclooxygenase-2 inhibitor rofecoxib (Vioxx) in the treatment of cervical dysplasia grade II?III A phase II trial. Eur J Obstet Gynecol Reprod Biol. 125, 251-4.
    Pubmed CrossRef
  58. Farley, JH, Truong, V, Goo, E, Uyehara, C, Belnap, C, and Larsen, WI (2006). A randomized double-blind placebo-controlled phase II trial of the cyclooxygenase-2 inhibitor Celecoxib in the treatment of cervical dysplasia. Gynecol Oncol. 103, 425-30.
    Pubmed CrossRef
  59. Herrera, FG, Chan, P, Doll, C, Milosevic, M, Oza, A, and Syed, A (2007). A prospective phase I?II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment. Int J Radiat Oncol Biol Phys. 67, 97-103.
    Pubmed CrossRef
  60. Gaffney, DK, Winter, K, Dicker, AP, Miller, B, Eifel, PJ, and Ryu, J (2007). A Phase II study of acute toxicity for Celebrex (celecoxib) and chemoradiation in patients with locally advanced cervical cancer: primary endpoint analysis of RTOG 0128. Int J Radiat Oncol Biol Phys. 67, 104-9.
    Pubmed CrossRef
  61. Marnett, LJ, and Kalgutkar, AS (1999). Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol Sci. 20, 465-9.
    CrossRef
  62. Steinbach, G, Lynch, PM, Phillips, RK, Wallace, MH, Hawk, E, and Gordon, GB (2000). The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 342, 1946-52.
    Pubmed CrossRef
  63. Giardiello, FM, Yang, VW, Hylind, LM, Krush, AJ, Petersen, GM, and Trimbath, JD (2002). Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 346, 1054-9.
    Pubmed CrossRef
  64. Baron, JA (2003). Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog Exp Tumor Res. 37, 1-24.
  65. Hawk, ET, Viner, J, Richmond, E, and Umar, A (2003). Non-steroidal anti-inflammatory drugs (NSAIDs) for colorectal cancer prevention. Cancer Chemother Biol Response Modif. 21, 759-89.
    Pubmed CrossRef
  66. Bresalier, RS, Sandler, RS, Quan, H, Bolognese, JA, Oxenius, B, and Horgan, K (2005). Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 352, 1092-102.
    Pubmed CrossRef
  67. Clark, DW, Layton, D, and Shakir, SA (2004). Do some inhibitors of COX-2 increase the risk of thromboembolic events?: Linking pharmacology with pharmacoepidemiology. Drug Saf. 27, 427-56.
    Pubmed CrossRef
  68. Jaksch, W, Dejaco, C, and Schirmer, M (2008). 4 years after withdrawal of rofecoxib: where do we stand today?. Rheumatol Int. 28, 1187-95.
    Pubmed
  69. Grosser, T (2006). The pharmacology of selective inhibition of COX-2. Thromb Haemost. 96, 393-400.
    Pubmed CrossRef
  70. Mason, RP, Walter, MF, McNulty, HP, Lockwood, SF, Byun, J, and Day, CA (2006). Rofecoxib increases susceptibility of human LDL and membrane lipids to oxidative damage: a mechanism of cardiotoxicity. J Cardiovasc Pharmacol. 47 , S7-14.
    Pubmed CrossRef
  71. Juni, P, Rutjes, AW, and Dieppe, PA (2002). Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs?. BMJ. 324, 1287-8.
    Pubmed CrossRef
  72. Solomon, LA, Munkarah, AR, Schimp, VL, Arabi, MH, Morris, RT, and Nassar, H (2006). Maspin expression and localization impact on angiogenesis and prognosis in ovarian cancer. Gynecol Oncol. 101, 385-9.
    Pubmed CrossRef
  73. Armstrong, DJ (2007). Celecoxib and CVS risk-lessons from the APC and PreSAP studies. Rheumatology (Oxford). 46, 561-2.
    Pubmed CrossRef
  74. Thangapazham, RL, Sharma, A, and Maheshwari, RK (2006). Maheshwari, Multiple molecular targets in cancer chemoprevention by curcumin. Aaps J. 8, E443-9.
    Pubmed CrossRef
  75. Shishodia, S, Chaturvedi, MM, and Aggarwal, BB (2007). Role of curcumin in cancer therapy. Curr Probl Cancer. 31, 243-305.
    Pubmed
  76. Cheng, AL, Hsu, CH, Lin, JK, Hsu, MM, Ho, YF, and Shen, TS (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21, 2895-900.
    Pubmed CrossRef
  77. Lao, CD, Ruffin, MT, Normolle, D, Heath, DD, Murray, SI, and Bailey, JM (2006). Dose escalation of a curcuminoid formulation, BMC Complement. Altern Med. 6, 10.
    Pubmed
  78. Sharma, RA, McLelland, HR, Hill, KA, Ireson, CR, Euden, SA, and Manson, MM (2001). Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 7, 1894-900.
    Pubmed CrossRef
  79. Javvadi, P, Segan, AT, Tuttle, SW, and Koumenis, C (2008). The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway. Mol Pharmacol. 73, 1491-501.
    Pubmed CrossRef
  80. Weng, JR, Tsai, CH, Kulp, SK, and Chen, CS (2008). Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 262, 153-63.
    Pubmed
  81. Jin, L, Qi, M, Chen, DZ, Anderson, A, Yang, GY, Arbeit, JM, and Auborn, KJ (1999). Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 59, 3991-7.
    Pubmed CrossRef
  82. Bell, MC, Crowley-Nowick, P, Bradlow, HL, Sepkovic, DW, Schmidt-Grimminger, D, and Howell, P (2000). Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 78, 123-9.
    Pubmed CrossRef
  83. Garc?a-Closas, R, Castellsagu?, X, Bosch, X, and Gonz?lez, CA (2005). The role of diet and nutrition in cervical carcinogenesis: a review of recent evidence. Int J Cancer. 117, 629-37.
    Pubmed CrossRef
  84. Chan, FK, Hung, LC, Suen, BY, Wu, JC, Lee, KC, and Leung, VK (2002). Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 347, 2104-10.
    Pubmed CrossRef
  85. Laheij, RJ, Sturkenboom, MC, Hassing, RJ, Dieleman, J, Stricker, BH, and Jansen, JB (2004). Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 292, 1955-60.
    Pubmed CrossRef
  86. Vakevainen, S, Tillonen, J, Salaspuro, M, Jousimies-Somer, H, Nuutinen, H, and Farkkila, M (2000). Hypochlorhydria induced by a proton pump inhibitor leads to intragastric microbial production of acetaldehyde from ethanol. Aliment Pharmacol Ther. 14, 1511-8.
    Pubmed CrossRef
  87. Sturkenboom, MC, Burke, TA, Tangelder, MJ, Dieleman, JP, Walton, S, and Goldstein, JL (2003). Adherence to proton pump inhibitors or H2-receptor antagonists during the use of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 18, 1137-47.
    Pubmed CrossRef
  88. Miriyala, S, Panchatcharam, M, and Rengarajulu, P (2007). Cardioprotective effects of curcumin. Adv Exp Med Biol. 595, 359-77.
    Pubmed CrossRef
  89. Bannwarth, B (2005). Do selective cyclo-oxygenase-2 inhibitors have a future?. Drug Saf. 28, 183-9.
    Pubmed CrossRef
  90. Fiorucci, S, Santucci, L, Wallace, JL, Sardina, M, Romano, M, and del Soldato, P (2003). Interaction of a selective cyclo-oxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa. Proc Natl Acad Sci U S A. 100, 10937-41.
    Pubmed CrossRef
  91. Wallace, JL, and Del Soldato, P (2003). The therapeutic potential of NO-NSAIDs. Fundam Clin Pharmacol. 17, 11-20.
    Pubmed CrossRef
  92. Hernandez-Diaz, S, Varas-Lorenzo, C, and Garcia Rodriguez, LA (2006). Non-steroidal antiinflammatory drugs and the risk of acute myocardial infarction. Basic Clin Pharmacol Toxicol. 98, 266-74.
    Pubmed CrossRef
  93. McGettigan, P, and Henry, D (2006). Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 296, 1633-44.
  94. Peto, J, Gilham, C, Deacon, J, Taylor, C, Evans, C, and Binns, W (2004). Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort. Br J Cancer. 91, 942-53.
    Pubmed
  95. Sadler, L, and Saftlas, A (2007). Cervical surgery and preterm birth. J Perinat Med. 35, 5-9.
    Pubmed CrossRef
  96. Kearney, PM, Baigent, C, Godwin, J, Halls, H, Emberson, JR, and Patrono, C (2006). Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 332, 1302-8.
    Pubmed CrossRef
  97. Mukherjee, D, Nissen, SE, and Topol, EJ (2001). Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 286, 954-9.
    Pubmed CrossRef
  98. J?ni, P, Nartey, L, Reichenbach, S, Sterchi, R, Dieppe, PA, and Egger, M (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 364, 2021-9.
    CrossRef
  99. Garner, SE, Fidan, DD, Frankish, R, and Maxwell, L (2005). Rofecoxib for osteoarthritis. Cochrane Database Syst Rev. , CD005115.

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