Cyclooxygenase-1 and -2: Molecular Targets for Cervical Neoplasia (original) (raw)

Progress in COX2 Inhibitors: A Journey So Far

Current Medicinal Chemistry, 2010

The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity. A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors. This leads to the belief that these effects are mechanism based and may be class effect. However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors. Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds. This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003)(2004)(2005)(2006)(2007)(2008)(2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds. Molecular modeling aspects are also briefly discussed.

COX-2-Specific Inhibitors - the Emergence of a New Class of Analgesic and Anti-inflammatory Drugs

Clinical Rheumatology, 2000

The prostaglandin series of bioactive compounds is formed by the interaction of two distinct but related enzymes, cyclo-oxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutive form which is present mainly in the gastric mucosa, kidney and platelets. COX-2 is mainly an inducible form, although also to some extent present constitutively in the CNS, the juxtaglomerular apparatus of the kidney and in the placenta during late gestation. Both isoforms contribute to the in¯ammatory process, but COX-2 is of considerable therapeutic interest as it is induced, resulting in an enhanced formation of prostaglandins, during acute as well as chronic in¯ammation. Conventional NSAIDs inhibit both isoforms to a similar extent and in an approximately equal dose and concentration range. The two recently developed and clinically available selective COX-2 inhibitors, celecoxib and rofecoxib, are about 100±1000 times more selective on the COX-2 than on the COX-1 isoform. In Europe rofecoxib is today indicated for the symptoms and signs of osteoarthritis, whereas celecoxib is indicated for both osteoarthritis and rheumatoid arthritis. The major clinical interest of these drugs has been related to the lower incidence of gastrointestinal bleeding which, with the conventional COX-1/COX-2 agents has been a source of hospitalisation, disablement and death, especially in the elderly. Clinical trials have convincingly demonstrated that celecoxib and rofecoxib in clinical use induce very few gastrointestinal complications compared to conventional and non-selective NSAIDs. However, the well known contraindications for NSAIDs, such as late pregnancy, aspirin-induced asthma, congestive heart failure and renal dysfunction, will so far apply also to the COX-2 inhibitors. Compared to the traditional and non-selective NSAIDs, COX-2 inhibitors may provide an insight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecoxib and rofecoxib, knowledge about their clinical usefulness in various in¯ammatory disease states and pain disorders is increasing. For the many patients suffering from such conditions, the selective COX-2 inhibitors are likely to become a signi®cant addition to the therapeutic arsenal of analgesic and anti-in¯ammatory drugs.

COX-2 Inhibitors — Lessons in Drug Safety

New England Journal of Medicine, 2005

Approximately six years after the cyclooxygenase-2 (COX-2) inhibitors were approved for use in the United States, the results of three randomized, placebo-controlled trials provide new evidence about the cardiovascular risks of rofecoxib, celecoxib, and valdecoxib. 1-3 The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a study of patients with a history of colorectal adenomas, was stopped early because rofecoxib doubled the risk of major cardiovascular events (relative risk, 1.92; 95 percent confidence interval, 1.19 to 3.11). These findings confirmed the increased risk of myocardial infarction previously seen in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial 4 and some observational studies. 5 The public announcement of the APPROVe results, which coincided with Merck's withdrawal of rofecoxib from the market in September 2004, prompted scientists to review the cardiovascular-safety results of a similar trial, the Adenoma Prevention with Celecoxib (APC) Study. 2 At either 200 or 400 mg twice a day, celecoxib in the APC trial was associated with a tripling of the risk of cardiovascular events (relative risk, 2.8; 95 percent confidence interval, 1.3 to 6.3). In the third COX-2 inhibitor trial reported in this issue of the Journal, 3 the short-term use of valdecoxib and its prodrug parecoxib was associated with increased cardiovascular risk in patients undergoing coronary bypass surgery.

A review on COX and their inhibitors: Present and future

2014

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. These prostaglandins are also known as autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. The inflammatory molecule PGE2 lowers pain thresholds and the primary goal of oral inhibitors of PGE2 is to reduce pain. This review article provides an overview and an update on the progress achieved in the area of COX inhibitors and their role in health and disease conditions. It also discusses some unresolved issues related to the use of selective COX-2 inhibitors as a safe and promising therapeutic option not only for the treatment of inflamm...

Non-COX-2 targets and cancer: Expanding the molecular target repertoire of chemoprevention

Biochemical Pharmacology, 2005

Chemoprevention represents a highly promising approach for the control of cancer. That nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and other cancers has led to novel approaches to cancer prevention. The known inhibitory effect of NSAIDs on the eicosanoid pathway prompted mechanistic and drug development work focusing on cyclooxygenase (COX), culminating in clinical trials of cyclooxygenase 2 (COX-2) inhibitors for cancer prevention or treatment. However, two COX-2 inhibitors have been withdrawn due to side effects. Here we review several pathways of the eicosanoid cascade that are relevant to cancer; summarize the evidence regarding the role of COX-2 as a target for cancer prevention; and discuss several of the molecular targets that may mediate the chemopreventive effect of NSAIDs. The clinically modest results obtained to date with COX-2 specific inhibitors used in cancer prevention; the multiple COX-2-indpendent targets of both NSAIDs and COX-2 inhibitors; and the limitations of some COX-2 inhibitors indicate that exploiting these (non-COX-2) molecular targets will likely yield effective new approaches for cancer chemoprevention.

International Journal of Research in Pharmacy and Chemistry Role of CYCLOOXYGENASE-2 in Cancer

Multiple lines of evidence indicate that cyclooxygenase 2 (COX 2) is a bona fide pharmacological target for anticancer therapy. Epidemiological studies show that use of nonsteroidal anti-inflammatory drugs (NSAIDs), which are prototypic inhibitors of COX, are associated with a reduced risk of several malignancies, including colorectal cancer 1. Consistent with this, tumor formation and growth are reduced in animals that are either engineered to be COX 2 deficient or treated with a selective COX 2 inhibitor 2-8. The finding that NSAIDs inhibit COX suggested that prostaglandins, the products of COX activity, substantially contribute to carcinogenesis. For example, COX-derived prostaglandins have been implicated in angiogenesis 9. 10. The recent development of selective inhibitors of the inducible form of COX, COX 2, represents another important advance. Importantly, selective COX 2 inhibitors cause fewer serious