Review |
COX and cancer
From the Department of Cancer Medicine, Imperial College of Science, Technology & Medicine, London, UK
Address correspondence to Professor J. Waxman, Department of Cancer Medicine, Faculty of Medicine, Imperial College of Science, Technology & Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN. email: j.waxman{at}ic.ac.uk
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Introduction |
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 Top Introduction COX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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The willow tree has been a source of remedies against fever and inflammation since ancient times. Just over a century ago, Hoffman isolated and modified an active compound from the willow tree and offered it for sale as aspirin. Subsequently, a number of similar compounds have been derived, and these have been classified as non-steroidal anti-inflammatory drugs or NSAIDs. These drugs inhibit the enzyme cyclo-oxygenase (COX), which catalyses the conversion of arachidonic acid to prostaglandins (PGs). PGs are important mediators of signal transduction pathways, and are involved in cellular adhesion, growth and differentiation. Aspirin and other NSAIDs are extensively used in cancer patients, primarily for analgesia. However, since the late 1970s, researchers have been interested in whether regular ingestion of aspirin and other NSAIDs can decrease cancer risk. The most persuasive evidence to date relates to colorectal cancer. Is there a role for these drugs in the primary prevention of cancer, or even the treatment of established disease? Here, we review the theoretical, experimental, epidemiological and clinical data relevant to this question.
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COX enzymes |
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TopIntroductionCOX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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Two isoforms of COX exist, with distinct tissue distributions and physiological functions. COX-1 is constitutively expressed in many tissues and cell types, whereas the inducible isoenzyme COX-2 is pro-inflammatory in nature, and expressed only in response to certain stimuli such as mitogens, cytokines and growth factors. NSAIDs may achieve different degrees of inhibition of COX-1 and COX-2. Specific COX-2 inhibitors such as celecoxib and rofecoxib have been developed, and these largely avoid the gastrointestinal side-effects associated with NSAID use, which are thought to be due mainly to COX-1 inhibition.
A number of studies have demonstrated over-expression of COX-2 in solid malignancies including colon,1 prostate,2 and breast3, as well as pancreas, non-small-cell lung, bladder, endometrium and skin basal and squamous cell.4 A significant relation between over-expression of COX-2 and survival of patients with various cancers has been reported in retrospective studies.5 In general, COX2 expression is higher in well-to-moderately differentiated tumours and in metastases. Evidence of changes in COX-1 expression in cancer cells is more limited.
Oncogenes, growth factors, cytokines, and tumour promoters stimulate COX-2 transcription via protein kinase C and RAS-mediated signalling.6–8 Less is known about negative modulators. Wild-type (but not mutant) p53 markedly suppresses transcription of COX-2.9 Several recent studies of human tumours highlight the importance of p53 status as a determinant of COX-2 levels. For example, COX-2 levels are higher in cancers of the oesophagus, stomach, lung and breast that express mutant (rather than wild-type) p53.10,11 It is likely that other factors, such as hypermethylation of the promoter12 and post-transcriptional mechanisms, also determine COX-2 levels in neoplastic tissues.
Genetic studies support a relationship between COX-2 and tumourigenesis. Increased expression of COX-2 is observed in polyps from the Min mouse, which is an animal model for human familial adenomatous polyps.13 Removal of the COX-2 gene by knockout mutation reduces the number and size of intestinal polyps in Apc 
716 mice.14 COX-2 over-expression in experimental models promotes tumour development. Multiparous female transgenic mice that are engineered to over-express human COX-2 in mammary glands develop focal mammary gland hyperplasia, dysplasia and metastatic tumours.15 Also, transgenic mice that over-express COX-2 in skin develop epidermal hyperplasia and dysplasia.16
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Anti-tumoural activity of COX-2 inhibition |
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TopIntroductionCOX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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The potency of COX-2 inhibitors in vivo can be attributed to the inhibition of the enzyme in the tumour as well as in stromal cells, resulting in anti-proliferative and pro-apoptopic actions within the tumour, and anti-angiogenic and pro-immune surveillance activities in endothelial and myeloid cells. The combination of COX-2 inhibitor with standard cancer chemotherapeutic and/or radiation may provide additional therapeutic paradigms in the treatment of various human cancers.
NSAIDs and selective COX-2 inhibitors significantly inhibit chemically-induced carcinogenesis in rodents, but only the latter have been shown to be effective in established tumours.17 In rats with sporadic colorectal adenomas or azomymetahne-induced adenocarcinomas, celecoxib prevented the development of invasive cancer by 93%.18 In a rat mammary model, 90% tumour regression with celecoxib was demonstrated, as well as a 25% decrease in the number of palpable tumours.19 In some pre-clinical studies, NSAIDs inhibit the growth of different tumour types transplanted in various animal models, and selective COX-2 inhibitors may suppress metastasis in experimental tumours.20–22 Also, data suggest that co-treatment of a COX-2 inhibitor augments the anti-tumour effects of other modalities such as chemotherapy and radiation.23,24 The anti-tumourigenic effects of pharmacological inhibitors of COX-2 may involve other mechanisms than COX-2 inhibition: for example, high concentrations of NSAIDs or selective inhibitors of COX-2 suppress the growth of cells in culture that do not express COX-2.25
Apoptosis
There is accumulating evidence that NSAID treatment can restore apoptosis in several experimental and clinical settings. Apoptosis can be increased in cultured HT-29 human colon cancer cells by salicylate, sulindac or sulindac sulphide, and other conventional NSAIDs.26,27 NSAIDs increase apoptosis in rats exposed to chemical carcinogens,28 and normal apoptosis can be restored in familial adenomatous polyposis patients by a 3-month treatment with sulindac.29 These effects are likely to occur by both COX-dependent and COX-independent mechanisms (e.g. involving PPARs, lipo-oxygenases, NF-kB, and Bcl-2-mediated pathways25,30,31).
Angiogenesis
Another cellular function by which NSAIDs may exert their anti-tumoural effects involves the suppression of angiogenesis and neovascularization. COX-2 induces pro-angiogenic factors such as vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, interleukin 6 and 8, and TIE2,32 and it produces prostaglandins that have both autocrine and paracrine effects on proliferation and migration of endothelial cells in vitro.33 COX-2 is over-expressed in tumour endothelial cells.33 A significant association of COX-2 with tumour vascularization, microvessel density and VEGF has been reported in human head and neck cancer, and microvessel density was related to COX-2 expression in gastric adenocarcinoma.34 In vivo models show that COX-2 derived prostaglandins stimulate angiogenesis, and that COX-2 inhibition slows neovascularization. For example, celecoxib has been shown to inhibit fibroblast growth factor (FGF)-induced corneal angiogenesis in rats. Celecoxib reduced both the number and length of sprouting capillaries in a dose-dependent fashion.35
Tsujii and co-workers, by co-culturing endothelial cells and colon carcinoma cells, demonstrated that COX-2 modulates the production of angiogenic factors by tumour cells, whereas COX-1 regulates angiogenesis of endothelial cells in normal tissues.32 Similar inferences were made from colon cancer xenograft nude mouse studies. Two mechanisms of NSAID-induced inhibition of angiogenesis were postulated: inhibition of COX-1 activity in endothelial cells, and inhibition of COX-2 activity in colon carcinoma cells by down-regulation of angiogenic factors.
Recently, the potential link between COX-2 and 
Vß3 integrin, an adhesion receptor critically involved in mediating tumour angiogenesis, has come under the spotlight. Dormond and co-workers demonstrated that inhibition of endothelial-cell COX-2 by NSAIDs suppresses Vß3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro, and suppression of FGF-induced angiogenesis in vivo.36 These results provide a functional link between COX-2, integrin Vß3 and Cdc42-/Rac-dependent endothelial-cell migration.
Xenobiotic metabolism
COX-2 catalyses the conversion of pro-carcinogens to carcinogens, especially in organs with low cytochrome P450 concentrations (such as bladder and lung). For example, it can induce the isomerization of prostaglandin endoperoxide to the mutagen malondialdehyde.37
Tumour cell invasiveness
Central to invasiveness is the ability to digest biological membranes by different matrix-metalloproteinases, and to reduce the intracellular anchorage provided by cadherin-catenin and other interactions. In vitro cellular studies have demonstrated a possible role for COX-2 in such events. Human colon cancer cells permanently transfected with a COX-2 expression vector had increased prostaglandin production, enhanced invasive properties and increased mRNA expression of metalloproteinases, compared with normal cells.38 COX-2 is also associated with increased expression of CD44, the cell surface receptor of hyaluronate, which promotes tumour cell invasion.39 In a mouse model, rofecoxib decreased the size of primary colorectal tumours and the extent of liver metastases, alone or in combination with cytotoxic agents. This was associated with lower tumour concentrations of ß-catenin and various pro-angiogenic factors.40
Aromatase modulation
PGE2 stimulates aromatase transcription, leading to increased concentrations of oestrogens.41 It has been postulated that over-expression of COX-2 in breast cancer may lead to increased PGE2 synthesis, and this in turn to progression of oestrogen-dependent disease. Consistent with this is the positive correlation between the expression of cytochrome P450 enzyme aromatase and level of COX in specimens of human breast cancer.42
Synergy with other modalities
Both chemotherapy and radiotherapy induce COX-2. Synergistic effects of NSAIDs with conventional anticancer drugs were reported as early as the 1980s, when the combination of indomethacin with methotrexate was shown to increase the killing of cultured NC cells.43 Vinblastine and taxane, which interfere with microtubule formation, stimulate the transcription of COX-2.44 Sulindac, in combination with paclitaxel and cisplatin, produces synergistic activity against several lung cancer cell lines.45 Trifan and colleagues, using two mouse tumour models, showed that celecoxib potentiates the activity of irinotecan, and also reduces the severity of diarrhoea in a dose-dependent way, by reduction of colon PGE2 levels.46
There is evidence that selective COX-2 inhibitors potentiate the efficacy of fractionated radiotherapy on tumour cells that express COX-2, both in vitro and in vivo. The effects are dose-dependent, and may be attributable to induction of apoptosis.23 There is also evidence of radiotherapy potentiating the anti-angiogenic activity of rofecoxib.47
Preclinical studies in a rat breast cancer model have demonstrated synergy between exemestane (an aromatase inhibitor) and celecoxib.48 COX-2 inhibitors may also combine to give synergistic anti-tumour activity with inhibitors of epidermal growth factor (EGF) receptors. For example, studies by Tortora and co-workers showed in vitro and in vivo enhanced anti-tumour effects of a combination of the COX-2 inhibitor SC-236 and the EGF-receptor tyrosine kinase inhibitor ZD 1839.49
High concentrations of COX-2 protein are expressed in HER2/neu over-expressing breast cancers.50 In an in vitro study on HCA7 cells expressing HER-2/neu, combined therapy with a selective COX-2 inhibitor and anti-HER2/neu monoclonal antibody inhibited growth of colorectal carcinoma more effectively than either agent alone.51
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COX-2 inhibition in human cancer |
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TopIntroductionCOX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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Epidemiological studies
At least 25 observational epidemiological studies have compared people who regularly use aspirin or other NSAIDs to those who do not, with respect to colorectal cancer or colorectal adenomatous polyps. All but one of the published studies found over 30% lower incidence or mortality rates from colorectal cancer, or lower incidence of adenomatous polyps. One of the largest cohort investigations to date was the American Cancer Society Study, which enrolled over 600 000 adults, and found mortality in regular users of aspirin 40% lower for cancers of the colon and rectum.52,53 Interestingly, the single study that did not find reduced risk of colorectal cancer or adenomatous polyps among aspirin users, also did not find reduced risk of myocardial infarction among the elderly subjects (median age 70 years at enrolment) who reported taking one aspirin daily.54 Several studies report a dose-response gradient of decreasing risk of colorectal cancer or adenomatous polyps among individuals who report more prolonged or frequent NSAID use. Two large prospective studies55,56 and one case-control study57 found the largest reductions in colorectal cancer in people who had used aspirin for at least 10 years. Another large prospective study based on prescription records in the UK between 1994 and 1997 found reduced risk of colorectal cancer in patients prescribed at least 300 mg aspirin daily, compared to non-users, but not among current users of <300 mg aspirin daily.58 The UK study lacked information on long-term use of aspirin.
A few epidemiological studies have examined the relationship between use of aspirin and other NSAIDs and digestive tract cancers other than that of the large intestine. In the American Cancer Society study, aspirin use was inversely associated with fatal cancers of the oesophagus and stomach as well as colon and rectum, but not generally with cancers outside the gastrointestinal tract.53 A reduced risk of oesophageal and gastric cancers with aspirin use has been observed in other studies,59,60 although a Finnish cohort study found no significant association in either case.61
The epidemiological evidence for a protective role of NSAIDs in breast cancer is not as convincing. Four out of six case-control studies have found a significant inverse association between risk of breast cancer and NSAID use, with the relative risk ranging from 0.6 to 1.1; the other two reported no association.62 Three cohort studies have reported no association, but others, including the recently published prospective US Women's Health Initiative Observational Study, have reported a significant reduction in the risk of breast cancer.63
The relationship of NSAID use with prostate cancer risk is similarly equivocal. A population-based case-controlled study from New Zealand reported a trend towards reduced risk of advanced of advanced prostate cancer associated with regular use of NSAIDs, but the association failed to reach statistical significance.64 An examination of aspirin use and the risk of prostate cancer among participants in the US Health Professionals Follow-up Study concluded that regular aspirin use was not likely to prevent prostate cancer as a whole, although a possible benefit of frequent aspirin use on risk of developing metastatic prostate cancer could not be excluded.65 Another study has demonstrated that regular daily use of ibuprofen or aspirin was associated with a 66% reduction in prostate cancer risk,66 and a study from Minnesota reported that NSAID users enjoyed a 55% reduction in the risk of prostate cancer, although the apparent protection was confined to men over the age of 60.67
An association between NSAID use and risk of lung cancer has been suggested in a number of epidemiological studies, although a large proportion of these investigations were not specifically designed to investigate this relationship (as is the case with a many other cancers in this context). In a recent hospital-based case-control study focusing on the role of aspirin in lung cancer, and including 868 cases with primary lung cancer and 935 controls, lung cancer risk was significantly lower for aspirin users compared with non-users, although there was no clear evidence of a dose-response relationship.68
Randomized trials
The US Physicians' Health Study showed no reduction in either invasive or in situ colorectal cancer incidence, nor a reduction in colorectal cancer mortality among 22 071 male physicians randomized to 325 mg aspirin or placebo every other day for 5 years and followed for 12 years.69 The relatively short duration of randomized treatment and low dose of aspirin limit the interpretability of these results. A randomized clinical trial with the non-selective COX inhibitor sulindac demonstrated a reduction in the number and size of adenomatous polyps in familial adenomatous polyposis patients.70 In another study, celecoxib 400 mg twice daily for 6 months reduced the number of colorectal polyps by 28%.71 On the basis largely of this result, celecoxib obtained accelerated approval from the US Food and Drug Administration as preventative therapy.
COX-2 inhibitors in primary cancer treatment
While there has been much interest surrounding the use of COX-2 inhibition in the primary prevention of cancer, an issue that has not attracted as much attention until recently is the notion of using COX inhibitors as anti-tumour drugs in established cancers. One of the first studies to suggest an effect of NSAIDs on survival from advanced cancer was a Swedish investigation that compared the effect of administering indomethacin, prednisolone or placebo to patients with insidious or overt malnutrition due to metastatic malignancy.72 As well as reducing suffering from pain, indomethacin (as well as prednisolone) prolonged mean survival, compared with placebo-treated patients.
Many studies are now under way to assess the efficacy of selective COX-2 inhibitors as anti-cancer therapies, either alone or in combination with other modalities such as chemotherapy and radiotherapy. Some investigators have begun reporting preliminary findings. In a retrospective study of patients with metastatic colorectal cancer, investigators from the MD Anderson Cancer Centre (Texas, USA), found that adding celecoxib to capecitabine delayed tumour progression and improved overall survival.73 Blanke and colleagues have presented promising results in a phase II trial of celecoxib (800 mg daily), irinotecan, fluorouracil, and leucovorin as first-line treatment in 23 patients with advanced colorectal cancer. A 28% partial response rate (with stable disease in 56%) was reported in the 18 patients who were assessable. Shadeh and colleagues have investigated the combination of celecoxib (400 mg twice daily) with weekly docetaxel in patients aged >70 years with non-small-cell lung cancer. A response rate of 23% and no grade 3–4 haematological toxicity was reported. Preliminary results from a randomized study of patients with locally advanced breast cancer have demonstrated a superior response rate for a neo-adjuvant regime of celecoxib plus fluorouracil, epirubicin, and cyclophosphamide, compared with the chemotherapy drugs alone (87.5% vs. 62.5%).
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Long-term safety of COX inhibition |
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TopIntroductionCOX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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The use of antiplatelet doses of aspirin (100 mg or less) to prevent cardiovascular events did not begin until the late 1980s, and cannot be evaluated with respect to colorectal cancer. However, even antiplatelet doses of aspirin cause increases in gastrointestinal and intracerebral bleeding, especially with prolonged treatment of large numbers of healthy people. Evidence is now emerging about the safety of specific COX-2 inhibitors.74,75 These studies seem to confirm improved gastrointestinal tolerance compared with conventional NSAIDs, but there were concerns over a potential increased incidence in thrombotic cardiovascular events.74 The recent withdrawal of rofecoxib due to increased cardiovascular thrombotic risk in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial,76 followed by the withdrawal from the market of valdecoxib, has brought to a head the safety concerns with this class of agent. Moreover, while COX-2 inhibitors seem to lower the risk of gastrointestinal complications when compared with NSAIDs, there is emerging evidence that this may not be the case for renal complications.77
A joint meeting of the American Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was convened in early 2005 to review the safety of COX-2 inhibitors. The committee voted unanimously that all of the COX-2 inhibitors currently (or previously) available in the US (celecoxib, valdecoxib, rofecoxib) significantly increase the risk of cardiovascular events in users of these drugs. Considering potential benefits as well as risks and their magnitude, the committee voted unanimously in favour of keeping celecoxib on the market for its current indicated uses. Most panellists favoured restrictions on direct-to-consumer advertising of COX-2 inhibitors. All voted in favour of requiring future agents in this class (both COX-2 and non-selective NSAIDs) to perform cardiovascular safety studies prior to market introduction.
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Conclusions |
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TopIntroductionCOX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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Where are we then, in assessing the role of COX in cancer? The balance of the epidemiological evidence available to date favours a link between COX inhibition and reduced risk of colorectal cancer and colorectal adenomatous polyps. The case for a protective effect on the development of other malignancies is not as convincing, although further studies are needed. The National Cancer Institute is sponsoring a number of clinical trials with selective COX-2 inhibitors for the chemoprevention of several different malignancies [http://www.cancertrials.nci.nih]. In terms of treatment of established disease, while there are some favourable preclinical data, clinical studies are only now being conducted to assess the efficacy of selective COX-2 inhibitors in various malignancies either alone or in combination with other treatment modalities. Another important issue is the search for surrogate biomarkers able to select the patients who are most likely to benefit from coxibs, and to monitor the pharmacological effects in individual patients.
While several mechanisms have been suggested for the anti-cancer action of COX inhibitors, it remains unclear which is the most important and indeed, whether inhibition of COX-2 is the sole reason for the effects observed in this context. Also, if there is a protective role to be played by COX inhibitors in cancer, there are questions of how much drug should be taken, and for how long. Concern over the long-term safety of selective COX-2 inhibitors has recently been highlighted, and therefore the relative risks of chemoprophylaxis in this context would also need to be assessed further.
On the face of it, there may seem to be more questions than there are answers. However, the unravelling of such uncertainties could be exceptionally rewarding.
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References |
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TopIntroductionCOX enzymesAnti-tumoural activity of COX-2...COX-2 inhibition in human...Long-term safety of COX...ConclusionsReferences |
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