What do cox 2 inhibitors do

However, it is a potent, selective inhibitor of COX-3 and most likely produces analgesia by inhibiting this enzyme Non-steroidal anti-inflammatory drugs NSAIDs , such as diclofenacor ibuprofen, are also potent inhibitors of COX-3 expressed in cultured cells, but being highly polar, they are unlikely to reach brain COX-3 in effective concentrations. Moreover, selective COX-3 inhibitors, aminopyrine and antipyrine have been shown to act centrally to cause their antipyretic and analgesic effects in mice.

COX-3 is considered to play a key role in the biosynthesis of prostanoids known to be important mediators in pain and fever. However, the existence of COX-3at the nucleotide sequence level in humans has been called to question. A recent sequencing study of the human COX-1 gene found that the first intron contained an additional nucleotide, as compared to canine COX This difference may lead to a frameshift precluding translation into a functional protein This may lead eventually to the development of new drugs that target thedesired pathway, thereby providing more precise and more effective treatment.

The simplified paradigm of constitutive COX-1 and inducible COX-2 has many exceptions: COX-1 can be regulated during development, whereas COX-2 is constitutively expressed in the brain, reproductive tissues and kidney In addition to its implication in the kidney development, COX-2 plays an important role in the regulation of renal function perfusion, water handling, and renin release in both normal and paraphysiological conditions i.

Moreover, cyclic hormonal induction of COX-2 is important for ovulation and, at the end of pregnancy, high uterine levels of COX-2 are necessary for the onset of labor.

As a result, like for classical NSAIDs, the use of selective COX-2 inhibitors should be avoided in the early stages of pregnancy whereas they should be useful in delaying premature delivery 32 , When the latter is inflamed or ulcerated, COX-2 is rapidly induced at sites of injury where it produces large amounts of PGs involved in the healing process.

So, selective COX-2 inhibitors should be avoided in patients with gastric susceptibility In addition, selective inhibitors of COX-2 depress prostacyclin PGI2 , an atheroprotective agent, but not COX-1 derived thromboxane A2 TXA2 , a proaggregatory and vasoconstrictor mediator, which might predispose patients to heart attack and stroke.

Thus, the use of these compounds in cardiovascular diseases still requires vigilance Subsequently, the sale of Bextra valdecoxib was also suspended by Pfizer in This raised a question on the safety of selective COX-2 inhibitors. A meta-analysis of published and unpublished tabular data from randomized trials revealed that selective COX-2 inhibitors and traditional NSAIDs high dose regimens of ibuprofen and diclofenac have similar incidence of adverse cardiovascular events Various studies suggest that the cardiovascular toxicity associated with the use of selective COX-2 inhibitors might be dependent on the dose as well as on the duration of treatment Large epidemiological trials studying users and non-users of aspirin have shown that cyclooxygenase COX inhibitors and non-steroidal anti-inflammatory drugs NSAIDs could be of benefit against the development and growth of malignancies.

Moreover, clinical trials in patients with familial adenomatous polyposis syndrome have shown the efficacy of non-selective and selective COX-2 inhibitors in the reduction of the number and the size of colorectal polyps. However, a primary chemopreventive effect has not been demonstrated yet. NSAIDs are also supposed to have a preventive and growth inhibitory effect in extra-colonic epithelial malignancies.

Several preclinical studies show promising results with combination treatments of either chemotherapy or radiotherapy with COX inhibitors. Preclinical studies with the simultaneous use of inhibitors of the epidermal growth factor receptor and COX-2 inhibitors have shown also promising results.

Encouraging results with the first clinical trials combining chemotherapy with COX-2 inhibitors in patients with cancer in the advanced and neoadjuvant setting have recently been reported.

Hence, we can state that targeting the COX-2 pathway is a promising strategy in the prevention and treatment of solid tumors. Ongoing trials are expected to answer — at least partly — the remaining questions concerning COX-2 and cancer.

Here, we focus on the rationale for using selective COX-2 inhibitors as anti-cancer agents. Increased amounts of COX-2 are found commonly in both premalignant and malignant tissues Overexpression of COX-2 appears to be a consequence of both increased transcription and enhanced mRNA stability 44 , Regulation of cyclooxygenase 2 COX-2 in cancer.

By contrast, wild-type p53 suppresses transcription of COX COX-2 is also regulated by post-transcriptional mechanisms. In addition, prostaglandin E2 PGE2 induces COX-2 by activating the tyrosine kinase activity of the EGF receptor, but it is not known whether this positive feedback mechanism is relevant in human tumors. Although many factors enhance COX-2 transcription, much less is known about negative modulators. Wild-type, but not mutant, p53 markedly suppresses the transcription of COX These findings suggest that the balance between activation of oncogenes and inactivation of tumor suppressor genes affects expression of COX-2 There is growing evidence that post-transcriptional mechanisms also determine COX-2 levels in neoplastic tissues.

Oncogenes, cytokines, growth factors and tumor promoters induce COX-2 by enhancing mRNA stability in addition to the stimulating transcription. In human colon cancers, overexpression of COX-2 is a consequence of both increased transcription and decreased mRNA turnover.

COX-2 affects many processes that have been implicated in different stages of carcinogenesis. These include xenobiotic metabolism, cell proliferation, angiogenesis, apoptosis, immune function and tumor invasiveness 15 , 42 Figure 7.

Different mechanisms through which the COXderived prostaglandins are involved in the carcinogenesis derived from The peroxidase part of COX can convert the procarcinogens to carcinogens and thus initiate tumor formation. Substantial amounts of xenobiotics natural non-human organic compounds can be co-oxidized into mutagens by the peroxidase activity of COX This reaction could be relevant at organ sites that are exposed to tobacco carcinogens such as lung, oral cavity and bladder.

Similarly, estrogens, oxidized to diethylstilbestrol demonstrate transforming and genotoxic activity. Moreover, the metabolism of the arachidonic acid itself produces mutagens. Some by-products of the oxidation of arachidonic acid, like malondialdehyde are chemically highly reactive and form adducts with DNA Previous studies have demonstrated that PGs stimulate proliferation of different cell lines derived from gastrointestinal tract such as colonic, intestinal, gastric and esophageal cell lines.

Therefore, it is not surprising that NSAIDs and selective COX-2 inhibitors as inhibitors of PG synthesis exert the inhibitory effect on the proliferation of malignant cell lines derived from gastrointestinal tract in-vitro studies and on tumor growth in-vivo. Studying downstream mechanisms can also support the role of COX-2 in carcinogenesis 15 , Their association with COX-2 inhibitors could therefore be interesting in treating cancer Apoptosis, the morphologically defined form of programmed cell death, plays a crucial role in the carcinogenesis.

The disegulation of this process can lead to abnormal survival of cells and the increased risk of mutagenesis and oncogenesis COXderived PGs regulate programmed cell-death and reduce the apoptotic rate via inhibition of the mitochondrial apoptotic pathway characterized through reduced cytochrome c release, attenuated caspase-9 and -3 activation and upregulation of bcl-2 15 , Additionally, increased prostanoid generation due to the COX-2 overexpression specifically inhibits Fas-mediated apoptosis Another evidence supporting the role of PGs in the regulation of apoptotic rate of tumor cells is the studies demonstrating that COX-2 overexpression in these cells increases their resistance to apoptosis Conversely, COX-inhibitors trigger both the mitochondrial and death receptor-mediated apoptotic pathways with resultant cytochrome c release.

Tumor cell invasion is an extremely important factor for the formation of solid tumors and necessary for their spread to distant organs. Matrix degradation and cell motility are essential in this process.

Matrix metalloproteinases MMPs are a family of matrix degradation enzymes. Their expression is associated with tumor cell invasion of the basement membrane and stroma, bloodvessel penetration and metastasis It has been demonstrated that COX-2 induces MMP expression in human colon cancer cells and therefore promotes metastasis COXderived PGs play an important role in the increased invasiveness of cancer cells.

One of the important mechanisms through which coxibs suppress the tumor invasiveness is the inhibition of matrix metalloproteinases MMP-2 and MM-9 which are known to facilitate cell invasion and migration with degrading the extracellular matrix Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is an essential process in the carcinogenesis and metastasis.

Neovascularization is regulated by the balance between pro-angiogenic factors and angiogenesis inhibitors in the local tissue environment. The link between the COXderived PGs and angiogenesis is suggested through studies showing a correlation between COX-2 gene expression and angiogenesis in premalignant tissues and cancer. Based on these observations, it is hypothesized that tumor-derived growth factors promote angiogenesis by inducing the production of COXderived PGE2 15 , PGs have ability to regulate the immune system.

This is of great clinical importance since immunosuppression correlates with the progression of the neoplastic diseases. Macrophages are activated and produce PG E2 which in turn inhibits the production of regulatory cytokines, the B and T-cell proliferation, and decreases the cytotoxic activity of natural killer NK cells.

Interestingly, the induction of IL and its immunosuppressive effects are related to PG E2 production. Thus, the overproduction of COXderived PGs could result in the inhibition of cell-mediated antitumor response MDR-1 or P-glycoprotein , is an efflux pump for chemotherapeutic drugs and thereby contributes to multidrug resistance. Overexpression of COX-2 has been found to increase the production and function of MDR-1 in cells in culture, an effect that was prevented by treatment with a selective COX-2 inhibitor.

Although much work is required to establish the clinical significance of this interaction, it is appealing to speculate that selective COX-2 inhibitors will enhance the anti-tumor activity of cancer chemotherapy by reducing the multidrug resistance Estrogen deprivation is an effective therapy for the prevention and treatment of hormone-dependent breast cancer.

The final step in estrogen biosynthesis is catalyzed by aromatase. PGE2 increases the aromatase activity in cells in culture and, thus, should stimulate cell proliferation indirectly by increasing the estrogen biosynthesis. This implies that inhibiting the production of estrogen in breast tissue using a selective COX-2 inhibitor might be useful for either preventing or treating breast cancer It can be concluded that: 1 COXderived PGs play a key role in the tumorogenesis; 2 The tumor-promoting effect of PGs may be attributed to their ability to stimulate the cell proliferation and migration, to inhibit the apoptosis and to increase angiogenesis and invasiveness; 3 in accordance to the proposed major role of COX-2 in cancerogenesis, selective COX-2 inhibitors have been shown in numerous studies to exhibit strong chemopreventive effect on the development of cancers.

This inflammatory response may damage neurons and exacerbate the pathological processes underlying the disease. Since COX-2 expression in the brain and PGE2 content in the cerebrospinal fluid have been reported to be elevated in AD together with the finding that COX-2 protein levels in the brain correlate with the severity of amyloidosis and clinical dementia, it has been suggested that COX-2 inhibition by NSAIDs might be involved in the apparent protection in this setting. However, the results of a recent randomized, double-blind clinical trial of rofecoxib vs.

Immediate-release Voltaren. Delayed-release Voltaren XR. With misoprostol Arthrotec. Immediate-release Lodine. Extended-release Lodine XL. Immediate-release Orudis. Extended-release Orvail. Over-the-counter Orudis KT. Immediate-release Naprosyn. Delayed-release EC Naprosyn. Immediate-release Anaprox, Anaprox DS. Extended-release Naprelan.

Over-the-counter Aleve. Montvale, N. Cost to the patient will be higher, depending on prescription filling fee. Direct comparisons of the COX-2 inhibitors are lacking. Long-term studies of the chronic administration of these drugs on rates of perforation ulcers and bleeds are currently underway. Already a member or subscriber? Log in. Interested in AAFP membership? Learn more. Noble received her doctor of pharmacy degree from the University of Mississippi School of Pharmacy.

King received her doctor of pharmacy degree from the University of Mississippi School of Pharmacy. Olutade received her medical degree from the University of Ibadan College of Medicine, Nigeria, and completed a family practice residency at Morehouse School of Medicine, Atlanta. Address correspondence to Sara L. Noble, Pharm. State St. Reprints are not available from the authors. The authors thank William H. Replogle, Ph. Kristopher Harrell, Pharm.

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Fam Med. Griffin MR. Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. Singh G, Rosen Ramey D. COX-2 inhibitors are also prescribed for many forms of back pain. This article answers common questions about the side effects of COX-2 inhibitors and naproxen, another type of NSAID that has been called into question.

The article also examines recent research and explains the recommendations given by the U. See Potential Risks and Complications of Celecoxib. The studies tested new uses of the drugs and have shown an increased risk for cardiovascular problems among certain groups of patients. Arcoxia etoricoxib is available in many countries, but not in the United States. Some doctors recommend that you take no NSAID medication except low-dose 81 milligram aspirin after the 30 th week of your pregnancy, because NSAIDs may affect the developing heart of the fetus.

Most NSAID drugs are considered safe to take while breastfeeding, but you and your doctor should review the drug safety information for any of these medicines before you take them. Always talk to your doctor before taking any medication, especially while pregnant or breastfeeding.