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

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.


INTRODUCTION
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][4][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

COX-2, INFLAMMATION AND CARCINOGENESIS
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 factorkappa 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 (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.

COX-2 EXPRESSION IN CERVICAL CARCINOGENESIS
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][29][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 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. 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 dosedependent 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   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.

ADVERSE EFFECTS OF COX-2 INHIBITORS
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 Moreover, selective COX-2 inhibitors had been investi- 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   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.