Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung

The existing epidemiologic literature was comprehensively reviewed to retrieve all epidemiologic studies (case control and cohort studies) that examined exposure to traditional over the counter nonsteroidal anti-inflammatory drugs (OTC NSAIDs) and the risk of cancers of the colon, breast, prostate and lung from 1980 forward. These malignancies account for more that half of all cancer deaths in the United States and the United Kingdom. Estimates of effects (relative risks or odds ratios) and 95% confidence intervals were abstracted from these reports for meta-analysis. Regular intake of OTC NSAIDs produced highly significant composite risk reductions of 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Furthermore, in a series of case control studies, daily use of a selective COX-2 inhibitor, either celecoxib or rofecoxib, significantly reduced the risk for each of these malignancies. The evidence is compelling that anti-inflammatory agents with selective or non-selective activity against cycloooxygenase- 2 (COX-2) have strong potential for the chemoprevention of cancers of the colon, breast, prostate and lung. Results confirming that COX-2 blockade is effective for cancer prevention have been tempered by observations that some selective COX-2 inhibitors pose a risk to the cardiovascular system. Nevertheless, meta-analysis of independent estimates from 72 studies provides no evidence that the selective COX-2 inhibitor, celecoxib, influences the relative risk of cardiovascular disease (composite relative risk = 0.98, 95% CI = 0.88–1.10). Molecular studies reveal that over-expression of COX-2 is a prominent feature of premalignant and malignant neoplasms. Evidence is accumulating that carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX-2 and the prostaglandin cascade in the “inflammogenesis of cancer”. Received 20 October 2008; accepted 18 November 2008     

Novel non-steroidal anti-inflammatory drugs: what we have learned from animal studies

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently associated with serious adverse effects related to the inhibition of cyclooxygenase (COX) in tissues where prostanoids exert physiological effects, such as gastric mucosal defence, renal homeostasis and platelet aggregation. The discovery of a second COX isoform (COX-2) specifically induced in pathological tissues led to the development of selective COX-2 inhibitors, believed to have an improved safety profile compared to traditional NSAIDs. Animal studies, however, have revealed a protective role for the COX-2 enzyme in the stomach, kidney, heart, vasculature and reproductive system, and therefore, the safety of COX-2 selective inhibitors needs to be reassessed. On the other hand, new therapeutic indications have emerged as a result of the role played by COX-2 overexpression in cancer or Alzheimer's disease. A second approach aimed at obtaining safer NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional NSAIDs chemically linked to NO-releasing moieties retain the therapeutic efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional therapeutic applications in cardiovascular diseases, Alzheimer's disease and cancer have been suggested. Animal data, however, need to be confirmed in large clinical trials. Finally, the increase in endogenous NO via a selective increase in inducible NO synthase in the gastric mucosa is the mechanism underlying the good gastric tolerability and the gastroprotective effects of the non-selective NSAID amtolmetin guacyl, documented to date in the rat.     

Celecoxib for the treatment of atherosclerosis

Introduction: It is widely accepted that inflammation plays a pivotal role in the progression of atherosclerosis. Anti-inflammatory drugs and especially selective cyclooxygenase-2 (COX-2) inhibitors have attracted a keen interest.

Areas Covered: In the present drug evaluation article, the authors elucidate the role of celecoxib, a selective COX-2 inhibitor, in the treatment of atherosclerosis. They discuss the atherogenic properties of the COX-2 enzyme. In addition, they address the studies that support an atheroprotective role of celecoxib. Moreover, they provide a review of the literature on the role of COX-2 inhibitors in increasing the rate of major adverse cardiovascular events. Finally, they discuss the emerging evidence that supports celecoxib as an adjuvant or neo-adjuvant therapy to percutaneous coronary intervention (PCI).

Expert opinion: Several studies have demonstrated a beneficial effect of celecoxib on the progression of atherosclerosis. Nevertheless, this evidence is mainly derived from preliminary data, while a substantial number of clinical studies have raised concerns regarding the cardiovascular safety of COX-2 inhibitors. Interestingly, recent clinical studies have supported the advantages of short-term celecoxib administration in patients undergoing PCI. However, many more large scale clinical trials are required to assess the long-term safety and efficacy of celecoxib administration in patients with cardiovascular disease.     

Selective cyclooxygenase-2 inhibitors: pharmacology,clinical effects and therapeutic potential

Since the discovery of a second isozyme of cyclooxygenase, COX-2, the field of prostaglandin and inflammation research has rapidly developed. It is becoming more evident that inhibition of COX-2 results in the analgesic and anti-inflammatory actions of non-steroidal anti-inflammatory drugs (NSAIDs), and that inhibition of COX-1 results in the adverse side-effects seen with these compounds. The mechanisms causing intestinal ulceration and renal toxicity are being elucidated, and large scale clinical trials with a preferential COX-2 inhibitor, meloxicam, and the first clinical results with highly selective COX-2 inhibitors, such as MK966 and celecoxib, support a superior benefit to risk ratio. In addition, important new areas where COX-2 expression is elevated, such as colonic cancer, have been identified and a role for COX-2 has also been proposed in Alzheimer’s disease. Inhibition of COX-2 for these indications by selective COX-2 inhibitors may provide effective new therapies in the future.     

Selective cyclooxygenase-2 inhibitors: pharmacology, clinical effects and therapeutic potential

Since the discovery of a second isozyme of cyclooxygenase, COX-2, the field of prostaglandin and inflammation research has rapidly developed. It is becoming more evident that inhibition of COX-2 results in the analgesic and anti-inflammatory actions of non-steroidal anti-inflammatory drugs (NSAIDs), and that inhibition of COX-1 results in the adverse side-effects seen with these compounds. The mechanisms causing intestinal ulceration and renal toxicity are being elucidated, and large scale clinical trials with a preferential COX-2 inhibitor, meloxicam, and the first clinical results with highly selective COX-2 inhibitors, such as MK966 and celecoxib, support a superior benefit to risk ratio. In addition, important new areas where COX-2 expression is elevated, such as colonic cancer, have been identified and a role for COX-2 has also been proposed in Alzheimer's disease. Inhibition of COX-2 for these indications by selective COX-2 inhibitors may provide effective new therapies in the future.     

Clinical pharmacology of novel selective COX-2 inhibitors

Novel coxibs (i.e. etoricoxib, valdecoxib, parecoxib and lumiracoxib) with enhanced biochemical cyclooxygenase (COX)-2 selectivity over that of rofecoxib and celecoxib have been recently developed. They have the potential advantage to spare COX-1 activity, thus reducing gastrointestinal toxicity, even when administered at high doses to improve efficacy. They are characterized by different pharmacodynamic and pharmacokinetics features. The higher biochemical selectivity of valdecoxib than celecoxib, evidenced in vitro, may be clinically relevant leading to an improved gastrointestinal safety. Interestingly, parecoxib, a pro-drug of valdecoxib, is the only injectable coxib. Etoricoxib shows only a slightly improved COX-2 selectivity than rofecoxib, a highly selective COX-2 inhibitor that has been reported to halve the incidence of serious gastrointestinal toxicity compared to nonselective nonsteroidal antiinflammatory drugs (NSAIDs). Lumiracoxib, the most selective COX-2 inhibitor in vitro, is the only acidic coxib. The hypothesis that this chemical property may lead to an increased and persistent drug accumulation in inflammatory sites and consequently to an improved clinical efficacy, however, remains to be verified. Several randomized clinical studies suggest that the novel coxibs have comparable efficacy to nonselective NSAIDs in the treatment of osteoarthritis, rheumatoid arthritis and acute pain, but they share similar renal side-effects. The apparent dose-dependence of renal toxicity may limit the use of higher doses of the novel coxibs for improved efficacy. Large-size randomized clinical trials are ongoing to define the gastrointestinal and cardiovascular safety of the novel coxibs.     

A mechanistic study of cigarette smoke and cyclooxygenase-2 on proliferation of gastric cancer cells

Cigarette smoke has been shown to cause gastric cancer. Overexpression of cyclooxygenase-2 (COX-2) is a common characteristic in gastric malignancy. The present study aimed to explore the correlation between cigarette smoke and COX-2 in the promotion of tumorigenesis in human gastric cancer cells (AGS). We further studied the action of COX-2 on other proto-oncogenes on gastric tumor growth. Results showed that chloroform extract (CE) and ethanol extract (EE) from cigarette smoke dose-dependently stimulated gastric cancer cell proliferation, which was accompanied with an activation of ornithine decarboxylase (ODC) activity, COX-2, and c-myc expressions. Both antisense of c-myc and alpha-difluoromethylornithine (DFMO, specific ODC inhibitor) inhibited cell proliferation without affecting COX-2 expression in response to cigarette smoke extracts (CSE). However, selective COX-2 inhibitor (SC-236) not only blocked the proliferative activity but also the ODC activity and c-myc protein expression by CSE in gastric cancer cells. Further, supplementation of exogenous prostaglandin (PG) E(2) reversed all the inhibitory actions of SC-236. Our results underline the importance of COX-2 in the cancer-promoting effect of CSE and its modulation on its downstream growth-related genes, such as c-myc and ODC in cancer cell proliferation. These results reveal that CSE-induced gastric carcinogenesis is via the COX-2/c-myc/ODC and PGE(2)-dependent pathway. Hence, selective COX-2 inhibitor could be an effective therapeutic agent for gastric cancer in smokers.     

Cyclo-oxygenase-2 inhibitors and the kidney: a case for caution.

Cyclo-oxygenase (COX) is one of the key enzymes in the biosynthesis of prostaglandins. Two isoforms of this enzyme COX-1 and COX-2 are known to exist. Among other functions, prostaglandins play an important role in the protection of the gastric mucosa and maintenance of renal function in pathophysiological conditions which would otherwise threaten it. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis, resulting in gastric mucosal injury and renal dysfunction in susceptible individuals. The recent introduction of selective COX-2 inhibitors, celecoxib and rofecoxib, appear to induce less gastrointestinal morbidity. Although conclusive data are still lacking, there is evidence to suggest that COX-2 antagonists may be capable of causing some of the same renal syndromes seen in association with the older, less selective NSAIDs.     

Comment and reply on: Atorvastatin: safety and tolerability

In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.     

Celecoxib and cardiovascular risks

In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.     

Coxibs and cardiovascular side-effects: from light to shadow

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".     

Roles of cyclooxygenase-2 and prostaglandin E receptors in gastric mucosal defense in <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-infected mice

Background/Aim: Helicobacter pylori (H. pylori) induces cyclooxygenase-2 (COX-2) expression. The aim of this study was to assess the roles of COX-2 and PGE₂ receptors (EPs) in gastric defense in H. pylori-infected mice. Methods: Gastric lesions were induced by oral administration of 0.15 N HCl in 60 % ethanol (HCl/EtOH) to mice infected with H. pylori, and macroscopically evaluated 30 min later. Mice were administered NS-398 (COX-2 selective inhibitor) concomitantly with selective EP agonists 4 hours before HCl/EtOH challenge. Results: H. pylori infection prevented the gastric damage induced by HCl/EtOH, and this protective effect was abolished by NS-398. Selective agonists of EP1, EP2, and EP4, but not the EP3 agonist, reversed the inhibitory effect of NS-398 on prevention of damage by H. pylori infection. The EP4 agonist and EP2/EP4 agonists inhibited the increase in TNF-α mRNA expression and neutrophilic infiltration caused by NS-398, respectively. Conclusion: COX-2-derived PGE₂ may play an important role in resistance to HCl/EtOH damage in H. pylori-infected mice by activating EP1, EP2, and EP4. Received 1 August 2006; accepted 21 August 2006     

Selective cyclooxygenase-2 inhibitor induces gastric mucosal damage in adrenalectomized rats

We investigated gastric ulcerogenic properties of the selective COX-2 inhibitor in adrenalectomized rats. SC-560 (selective COX-1 inhibitor) or celecoxib (selective COX-2 inhibitor) was given to sham-operated and adrenalectomized rats, with or without corticosterone replacement 11 days after the surgery, and gastric lesions were estimated 8 h later. Neither SC-560 nor celecoxib alone induced any gross damage in the gastric mucosa in sham-operated rats. In adrenalectomized rats, however, celecoxib did provoke gross damage that was prevented by corticosterone pellets. Mucosal PGE₂ content was increased 3-fold after adrenalectomy, and this response was prevented by both celecoxib and corticosterone pellets. The COX-2 mRNA was up-regulated in the stomach of adrenalectomized rats, but this expression was suppressed by corticosterone replacement. These results support our hypothesis that adrenalectomy increases gastric mucosal PGE₂ due to COX-2 expression, and the selective COX-2 inhibitor produces gastric lesions by inhibiting the additional PGE₂ production in adrenalectomized rats.     

选择性环氧化酶-2抑制剂对心血管影响的研究进展

目的 综述选择性环氧化酶-2抑制剂在心血管方面的安全性及其作用机制.方法 通过查阅国内外相关文献,分别比较归纳了不同选择性环氧化酶-2抑制剂引发心血管事件的风险性,并总结了罗非昔布、塞来昔布等对心血管的作用机制.结果 对选择性环氧化酶-2抑制剂引发心血管不良反应的研究进展进行了比较全面的总结.结论 不同选择性环氧化酶-2抑制剂在心血管安全性方面有明显差别,比较几种昔布类药物,塞来昔布相对安全,与小剂量阿司匹林联合服用可降低心血管风险性.     

Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs

Celecoxib is an NSAID that was developed as a selective inhibitor of COX-2 and approved by the FDA for the treatment of various forms of arthritis and the management of acute or chronic pain. In addition, it was more recently approved as an oral adjunct to prevent colon cancer development in patients with familial adenomatous polyposis and is presently being investigated for its chemotherapeutic potential in the therapy of advanced cancers. However, in laboratory studies it was discovered that celecoxib was able to suppress tumor growth in the absence of any apparent involvement of COX-2, and additional pharmacologic activities associated with this drug were found. Intriguingly, the two pharmacologic effects, inhibition of COX-2 and suppression of tumor growth, were found to reside in different structural aspects of the celecoxib molecule and, therefore, could be separated. This dualism enabled the synthesis of close structural analogs of celecoxib that exhibited increased antitumor potency in the absence of COX-2 inhibition. In theory, such compounds should be superior to celecoxib for antitumor purposes because they might reduce gastrointestinal and cardiovascular risks and the life-threatening side effects that appear during the long-term use of selective COX-2 inhibitors. In this review, the authors present the status of preclinical development of anticancer analogs of celecoxib that are COX-2 inactive, with an emphasis on 2,5-dimethyl-celecoxib (DMC) and OSU-03012.     

Cyclooxygenase (COX)-2 selective inhibitors: aspirin, a dual COX-1/COX-2 inhibitor, to COX-2 selective inhibitors

Aspirin was developed as a non-steroidal anti-inflammatory drug (NSAID) in 1899. During the century after that, aspirin has been found to show its anti-inflammatory, analgesic and anti-pyretic activities by reducing prostaglandins biosynthesis through inhibition of cyclooxygenase (COX); and then COX was found to be constituted of two isoforms, constitutive COX-1 and inducible COX-2. Currently, novel NSAIDs, acting through selective inhibition of COX-2, that have efficacy as excellent as aspirin with significantly lower incidence of gastrointestinal adverse effects are available in America and some other countries, but not in Japan. Physiological and pathophysiological roles of COX-1 and COX-2 have been explained from studies in experimental animals, but there are many differences in species and diseases between animals and humans. Thus, physiological and pathophysiological roles of COX-2 were considered from the standpoint of clinical effects of the two latest COX-2 selective inhibitors, celecoxib and rofecoxib, on inflammation, pain, fever and colorectal cancer together with their adverse effects on gastrointestinal, renal and platelet functions; and the usefulness and limits of COX-2-selective inhibitors were discussed with the trends of new NSAIDs development.     

Benefit-risk assessment of rofecoxib in the treatment of osteoarthritis.

NSAIDs are widely used to treat pain and inflammation in osteoarthritis. Their use in this indication is generally intermittent and fluctuates with the intensity of the disease. Nonetheless, success of the therapy is frequently limited by injury to the gastrointestinal mucosa and complications such as bleeding, ulceration and perforation. A careful and detailed evaluation of these aspects in regard to the newly introduced NSAIDs is of considerable clinical importance. This review focuses on the NSAID rofecoxib, one of the selective cyclo-oxygenase (COX)-2 inhibitors, which are claimed to be as effective as nonselective NSAIDs with better gastrointestinal tolerability. Indeed, phase II, phase III and epidemiological studies have revealed that the efficacy of rofecoxib is comparable to that of conventional NSAIDs but with lower gastrointestinal toxicity, although this advantage may not be demonstrable in every patient. In patients treated with low-dose aspirin (acetylsalicylic acid) for cardiovascular prophylaxis, celecoxib (another selective COX-2 inhibitor) seems to have no obvious advantages over conventional NSAIDs, and similar conclusions may be applied to rofecoxib. A comparison of NSAID therapy +/- concomitant low-dose aspirin was not a primary outcome in this trial with celecoxib and there is thus a need for further studies which compare the gastrointestinal risk of a selective COX-2 inhibitor plus aspirin versus a conventional NSAID. Recent debate has emerged regarding the cardiovascular safety of rofecoxib. Although there is evidence both for and against higher cardiovascular risk with rofecoxib, a retrospective cohort study recently published suggested that there is no increased risk of acute myocardial infarction in the short-term when compared with non-selective NSAIDs. The renal toxicity of rofecoxib has been thoroughly investigated. Clinical studies revealed renal effects of rofecoxib similar to those of conventional NSAIDs. Since adverse effects increase with the degree of renal impairment, monitoring of renal function should be carried out in patients at risk. Although there are still insufficient data concerning certain important adverse effects of rofecoxib, this drug is becoming an important alternative in the therapy of osteoarthritis, especially in high-risk patients. Clinicians need to weigh up the benefits and risks of rofecoxib on a case-by-base basis.     

Exploiting cyclooxygenase-(in)dependent properties of COX-2 inhibitors for malignant glioma therapy

Cyclooxygenase 2 (COX-2) is frequently found up-regulated during pathological conditions and in cancer, where it is thought to support carcinogenesis and tumor angiogenesis. The development of newer-generation non-steroidal anti-inflammatory drugs (NSAIDs) able to more selectively inhibit cyclooxygenase 2 (COX-2) raised expectations that these agents might be beneficial for cancer prevention and therapy. However, while chemopreventive effects of some selective COX-2 inhibitors have been established, it has remained unpersuasive whether these new NSAIDs, such as celecoxib, rofecoxib or etoricoxib, are able to exert cancer therapeutic effects, i.e., whether they would be beneficial for the treatment of advanced cancers that are already grown and established. This issue was further complicated by findings that celecoxib was able to exert pronounced pro-apoptotic effects in vitro and in vivo in the absence of any apparent involvement of COX-2. In fact, newly synthesized close structural analogs of the celecoxib molecule revealed that it was possible to separate COX-2 inhibitory function from the ability to trigger apoptosis; for example, the analog 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet exerts increased cytotoxic potency. This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.     

Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anticarcinogenic effects of celecoxib is still not fully understood. To investigate the extent to which the anticarcinogenic effect of celecoxib depends on COX-2 expression, we transfected human colon carcinoma cells (Caco-2) with the human COX-2 cDNA, in both sense and in antisense orientation, to generate cells which either overexpress COX-2 (human COX-2-sense, hCOX-2-s), express no COX-2 (human COX-2-antisense, hCOX-2-as) or express only very small amounts of COX-2 (control cells). Treatment of these cells with celecoxib dose-dependently (0-100microM) reduced cell survival which was accompanied by an induction of a G(0)/G(1) phase block and apoptosis. The effect of celecoxib treatment on both, cell survival and induction of apoptosis in hCOX-2-as cells was less marked than in the COX-2-expressing cells. Apoptosis was accompanied by an activation of caspase-3 and caspase-9 and cytochrome c release. In contrast, we observed no difference in sensitivity with regard to the induction of a cell cycle block between the different cell clones. The G(0)/G(1) phase block caused by celecoxib correlated with a decrease in expression levels of cyclin A and cyclin B1 and an increase in the expression of the cell cycle inhibitory proteins p21(Waf1) and p27(Kip1) irrespective of the type of cell used. These data indicate that apoptosis-inducing effects of celecoxib partly depend on COX-2 expression of the cells, whereas induction of a cell cycle block occurred COX-2 independently. Thus, the anticarinogenic effects of celecoxib can be explained by both COX-2-dependent and -independent mechanisms.     

Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray?

It has been more than 30 years since Sir John Vane first reported that the pharmacological actions of aspirin-like drugs could be explained by their ability to inhibit cyclooxygenase (COX). Since then, a second isoform of COX, named COX-2, has been discovered and highly selective inhibitors of this isoform have been marketed. Most recently, a splice variant of COX-1 mRNA, retaining intron 1, and given the names COX-3, COX-1b or COX-1v, has been described. Non-selective NSAIDs such as ibuprofen and naproxen, which inhibit both COX-1 and COX-2, have proven highly effective and safe in the short-term management of acute pain. Highly selective COX-2 inhibitors including celecoxib, rofecoxib, valdecoxib, lumiracoxib, and etoricoxib were developed with the hope of significantly reducing the serious gastrointestinal toxicities associated with chronic high-dose NSAID use. While long-term studies demonstrated that rofecoxib and lumiracoxib reduced the incidence of GI perforations, ulcerations and bleeds by approximately 60% compared to non-selective NSAIDs, recent reports also demonstrated that the chronic use of rofecoxib and celecoxib in arthritis and colorectal polyp patients, and the short-term use of parecoxib and valdecoxib in patients who had undergone coronary artery bypass surgery, resulted in a significant increase in serious cardiovascular events, including myocardial infarction and stroke compared to naproxen or placebo. COX-3 mRNA has been isolated in many tissues including canine and human cerebral cortex, human aorta, and rodent cerebral endothelium, heart, kidney and neuronal tissues. In transfected insect cells, canine COX-3 protein is expressed and was selectively inhibited by acetaminophen. However, in humans and rodents an acetaminophen sensitive COX-3 protein is not expressed because the retention of intron-1 adds 94 and 98 nucleotides to the COX-3 mRNA structure respectively. Since the genetic code is a triplicate code (3 nucleotides to form one amino acid), the retention of the intron in both species results in a frame shift in the RNA message and the production of a truncated protein with a completely different amino acid sequence than COX-1 or COX-2 lacking acetaminophen sensitivity. Advances made through a combination of basic molecular biological and pharmacological techniques, and well designed randomized controlled clinical trials have demonstrated that the apparent gastrointestinal advantage of selective COX-2 inhibitors appears to be outweighed by their potential for cardiovascular toxicity and that acetaminophen's analgesic and antipyretic effects do not involve the inhibition of the COX-1 splice variant protein, putative COX-3.