NSAIDs and Desmoid Tumours

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Mechanism of Action of NSAIDs

Several reviews [51-53] have summarized the intriguing and accumulating evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) have potential as anti-cancer drugs. NSAIDs have been shown experimentally to stimulate apoptosis and to inhibit angiogenesis, two mechanisms that help to suppress malignant transformation and tumour growth.

The mechanism of action common to NSAIDs is the inhibition of cyclooxygenase (COX) enzymatic conversion of the polyunsaturated fatty acid arachi-donic acid (produced by the hydrolysis of phospho-lipids catalyzed by phospholipase A) to prostaglandin G2 (PGG2) [56]. PGG2 is converted to prostaglandin H2 by the peroxidase activity of the

COX enzyme, and then PGH2 may be converted by tissue-specific isomerases to one of the five biologically active prostanoids: PGE2, prostaglandin D2, prostaglandin F2a, prostacyclin or thromboxane [57].

Two distinct isoforms of COX, designed COX-1 and COX-2 have been recognized [58, 59]. COX-1 is expressed constitutively in many tissues, and it plays a central role in platelet aggregation and gastric cyto-protection [58-59]. Although COX-2 is expressed constitutively in the human kidney and brain, its expression is induced in many tissues during inflammation, wound healing and neoplasia.

NSAIDs vary in their abilities to inhibit COX-1 or COX-2 at different concentrations and in different tissues [60, 61]. Aspirin is the only NSAID known to react covalently with COX-1 and COX-2 by selective acetylation of a specific serine residue at position 529 and 516, respectively [62, 63]. Aspirin acetylation of COX-1 results in a complete blockade of arachido-nate oxidation to PGH2, aspirin has thus been report ed to be a more potent suppressor of PGH2 formation by the activity of COX-1 than that formed by COX-2 [64]. The other NSAIDs such as ibuprofen and indomethacin, produce reversible or irreversible inhibition of both COX-1 and COX-2 by competing with the arachidonic acid for the active site of the enzyme [56].

Although NSAIDs are widely used and are effective, their long-term use is limited by gastrointestinal effects such as dyspepsia and abdominal pain, gastric and duodenal perforation or bleeding, and small bowel and colonic ulcerations. The discovery of COX-1 and COX-2 has led to the suggestion that the therapeutic effect of NSAIDs is primarily the result of inhibition of COX-2, whereas the toxicity of NSAIDs may primarily result from inhibition of COX-1 [65] In fact, NSAIDs toxicity in the gastrointestinal mucosa is the result of inhibition of COX-1 activity in platelets, which increases the tendency of bleeding, and in gastric mucosa, where prostanoids play an important role in protecting the stomach from erosion and ulceration [55]. While the conventional NSAIDs inhibit COX-1 and COX-2 to the same extent, the development of a new group of anti-inflammatory drugs, the coxibs, selective inhibitors of COX-2 (e.g. celecoxib, rofecoxib, valdecoxib, etori-coxib, lumiracoxib), represent a response to the unsatisfactory therapeutic profile of NSAIDs and it was hoped that coxibs would be better tolerated than non-selective NSAIDs and would be equally efficacious and that selective inhibition of COX-2 could be an effective strategy for preventing cancer.

Several prostaglandins such as PGE2, suppress immunosurveillance through down-regulation of lymphokines, T-cell and B-cell proliferation, cytotoxic activity of natural killer cells and secretion of TNFa and interleukin 10 [66]. It has been shown that there is a close relationship between PGE2 and EGF-receptor signalling systems. PGE2 induces the activation of metalloproteinases MMP2 and MMP9, increases expression of TGFa, transactivates EGF receptor, and triggers mitogenic signalling in gastric epithelial and colon cancer cells as well as in rat gastric mucosa in vivo. This mechanism may explain how PGE2 exerts its trophic action on gastric and intestinal mucosa, resulting in hypertrophy and cancer. The inhibition of prostaglandin synthesis by NSAIDs can explain the anti-tumoral effect of these drugs.

Despite continuing uncertainty about the molecular pathways by which NSAIDs may inhibit neopla-sia, there is mounting evidence that tumour inhibition, for example in colorectal cancer, may be mediated by at least two distinct cellular processes: the ability of NSAIDs to restore apoptosis in APC-deficient cells [67, 68] and their capacity, particularly in the case of coxibs, to inhibit angiogenesis. Apoptosis, or programmed cell death is needed to maintain homeostasis in continuously replicating tissues such as intestinal mucosa [69]. The suppression of apop-tosis allows APC-deficient cells to accumulate and form adenomatous polyps. Further suppression of apoptosis occurs as these cells develop additional genetic mutations and phenotypic changes [70]. In Vitro, both non-selective NSAIDs and selective COX-2 inhibitors stimulate apoptosis in APC-deficient colonic cells that have not undergone malignant transformation [71]. Non-selective NSAIDs lose their ability to inhibit chemically induced tumours when polyps undergo malignant transformation. In contrast, selective COX-2 inhibitors stimulate apoptosis and suppress growth in many carcinomas, including cultured human cancers of the stomach, oesophagus, tongue, brain, lung and pancreas [72-77]. The precise mechanism by which NSAIDs restore apoptosis remains controversial [78], but treatment of colorectal carcinoma cells with NSAIDs or coxibs increases the concentration of arachidonic acid that, if unes-terified, modulates mitochondrial permeability and causes release of cytochrome C, thus leading to apop-tosis [79].

Other experimental models suggest that NSAIDs induce apoptosis by either COX dependent or COX independent mechanisms. In the latter case, the G0/G1 cell-cycle block caused by celecoxib in colon cancer cell lines and In Vivo models is related to a decreased expression of cyclins A and B1, and to the expression of cell-cycle inhibitory proteins p21WAF1 and p27KIP1 [80] as well as the coxib NS-398 enhanced apoptosis in cells which do not express COX-2 enzyme [78]. NSAIDs have also been reported to induce apoptosis through 15-lipoxygenase-1, independent of COX-2 [81]. However, many of these effects have been demonstrated only with high concentrations of NSAIDs In Vitro and are of uncertain clinical relevance.

Several studies have shown a relation between angiogenesis and COX-2 expression [82], so a second cellular process by which NSAIDs and in particular COX-2 inhibitors may inhibit tumour growth is through inhibition of angiogenesis and neovascularization [83]. COX-2 induces proangiogenic factors such as VEGF, inducible nitric oxide synthase, inter-leukins 6 and 8, and TIE2 [83, 84], and it produces prostaglandins that have both autocrine and paracrine effects on proliferation and migration of endothelial cells In Vitro [82, 85]. COX-2 is overex-pressed in "activated" tumour endothelial cells, whereas COX1 is expressed in normal endothelial cells [82]. COX-2 derived prostaglandins stimulate angiogenesis In Vivo, and COX-2 inhibition of endothelial cells slows down tumour growth. In par ticular, COX-2 modulates the production of angiogenic factors by tumour cells, whereas COX-1 regulates angiogenesis of endothelial cells in normal tissue [83]. Therefore the hypothesized mechanism by which NSAIDs block angiogenesis is the inhibition of COX-1 and COX-2 activity in endothelial cells. Other studies supported these data also in In Vivo models, focusing on the role of celecoxib in inhibiting of blood vessel formation, tumour growth and development of metastasis [86]. In contrast, toxic concentrations of aspirin or indomethacin are required to block vascular endothelial tube formation [83, 87]. These experiments suggest that COX-2 may be essential for tumour vascularization and growth.

Finally, Brueggemeier et al. [88] showed co-expression of the aromatase enzyme and COX-2 in human breast cancer, with a significant association with gene expression of both: Thus, COX-2 may be the cause of progression of oestrogen-dependent breast cancer by autocrine and paracrine mechanisms, by direct stimulation of tumour cell proliferation, or by indirect upregulation of aromatase activity [88].

Treatment with NSAIDs

The fact that both E-catenin and mutated APC are implicated in colon cancer and DT development [89, 100] and that prostaglandins and cyclooxygenase have a role in colonic neoplasia and FAP progression [68, 91-93], has prompted the use of NSAIDs in the treatment of DTs. However, there are enough differences between desmoids and colonic neoplasms so that data, including blockade of angiogenesis, modulation of aromatase, and pro-apoptotic activity cannot be easily generalized from one tumour to another. We showed that there was a high expression of COX-1 and COX-2 in DT cells and tissues derived from different patients undergoing surgery (Picariel-lo et al., 2006, personal communication). In particular, the amount of COX-2 protein was higher than that of COX-1, suggesting the role of COX-2 in the pathogenesis of this neoplasia. In addition, the expression of COXs was different in the different cultures, suggesting an extreme variability between individual tumours. Indomethacin or sulindac, an indomethacin analogue with prolonged effect, has been frequently used alone or in combination with anti-oestrogens. The mechanisms of action of the anti-COX drugs are complex: sulindac sulphide, the pharmacologically active metabolite of sulindac, induces a significant growth reduction in desmoid cells In Vitro [94], but the drug does not induce apoptosis at clinically significant concentrations in these cells. However, this NSAID molecule induces apoptosis in an endothelial cell line. The latter effect seems very important considering the role of the microvasculature in tumour growth and could explain the efficacy of sulindac sulphide in the treatment of DTs. Other recent studies have also shown that in DT cell cultures, the inhibition of COX-2 expression with a new coxib, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furon one), blocks the cellular growth, but does not promote apoptosis, suggesting that regulation of apoptosis does not play a major role in this neoplasm [95] and calling for other mechanisms to explain the effect of this drug.

Several small series of patients have been treated with a daily dosage of 200-400 mg of sulindac. The duration of treatment varied from a few months to several years. Overall, an objective response rate of about 50% was observed: in the majority of the patients a partial regression was shown and only in a few patients was a complete regression obtained [87, 96-97]. This treatment seems less efficacious in patients undergoing partial resection of their DT prior to medical therapy [19]. Most responses were observed after a few weeks of treatment.

More often, sulindac has been employed in combination with anti-oestrogen even if the effect is similar to that observed in patients treated with sulindac alone. Recently, 11 patients were treated with a combination of celecoxib, an anti-COX2, and tamoxifen, showing a complete regression in 1 patient, a partial regression in 3, a stable disease in 5 and no tumour recurrence in 2 patients in whom the drugs were used as adjuvant therapy after surgical excision [22]. As anti-cancer therapy, coxibs present important theoretical advantages: they are orally active, have moderate side effects, and have few medical contraindications. Their good toxicological profile allows long-term medical treatment. In conclusion, even if the small number of cases studied and appropriately referred to in the literature and the absence of prospective randomized trials makes estimation of the effect of NSAIDs difficult, they can be effective in controlling DT growth and should be used as a firstline treatment.

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