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Expression of cyclooxygenase-2 (COX-2) is involved in the chronic inflammation-related development of Barrett's adenocarcinoma and the use of selective COX-2 inhibitors (coxibs) might provide new chemoprevention strategy for Barrett's adenocarcinoma (BA). Despite an excellent gastrointestinal (GI) safety profile of coxibs, their use is limited because of the possible cardiovascular complications. The coupling of NSAIDs with a NO-donating moiety has led to the birth of a new class of anti-inflammatory drugs, called the COX-inhibiting nitric oxide donators (CINODs). The member of this group, NO-aspirin (NO-ASA) retains the anti-inflammatory properties of traditional aspirin (ASA), but the release of NO accounts for anti-thromboembolic effect and better GI safety profile. The role of NO-ASA in the prevention of Barrett's adenocarcinoma (BA) has not been studied so far. Therefore, the aim of the present study was: 1) to analyse the expression of COX-2 in the biopsies obtained from BE; 2) to compare the effect of NO-ASA with that of ASA on proliferation rate in Barrett''s adenocarcinoma cell line (OE-33 cells); 3) to determine the effect of both compounds on the apoptosis rate using FACS analysis and expression of 32-kDa procaspase-3 and active proapoptotic 20-kDa caspase-3 in OE-33 cell line. The expression of COX-2 was assessed in biopsies obtained from the Barrett's mucosa and normal squamous epithelial esophageal mucosa from 20 BE patients by RT-PCR and Western blot analysis, respectively. The BA cell line (OE-33) was incubated with NO-ASA or ASA (10-1000 microM). The cell proliferation and apoptosis rate was measured by BrdU and FACS-analysis, respectively. The expression of caspase-3 (active and inactive form) was analyzed by Western blot. In Barrett's mucosa a significant up-regulation of COX-2 was observed. Compared with traditional ASA, NO-ASA caused a significantly stronger induction of apoptosis (dose-dependently). Inhibition of cell proliferation in OE-33 cells observed under NO-ASA treatment was due to the apoptosis induction. The increase in apoptotic rate was accompanied by the upregulation of active 20-kDa caspase-3. At the highest concentration (1000 microM), a necrotic death of OE-33 cells was observed under NO-ASA treatment. We conclude that: NO-ASA caused induction of apoptosis in BA cell line and slight growth inhibition. These results indicate that this compound may represent a promising chemopreventive agent for Barrett's adenocarcinoma.

Aspirin (ASA) represents an important risk factor for gastric mucosal injury. Recently, vitamin C releasing aspirin (ASA-VitC) has been shown to reduce gastric toxicity of ASA in animal model of gastric injury. The aim of the present study was to compare the effect of ASA and ASA-VitC on the gastric mucosal damage before and after Helicobacter pylori (Hp) eradication in 10 young healthy Hp-positive volunteers. All subjects underwent endoscopy at day 0 (before ASA or ASA-VitC treatment) and at day 3 following treatment (1.6 g ASA/day or 1.6 g ASA + 0.96 g Vit C/day). In addition, in vitro experiments were performed in which gastric mucosal cell line (MKN-45 cells) was incubated with ASA or ASA-VitC alone or in combination with H.pylori. Expression of constitutive and inducible NO synthase (cNOS, iNOS) was analyzed by Western blot. Moreover, COX-2 expression was analyzed in gastric biopsies at mRNA and protein level by RT-PCR and Western blot, respectively. In humans, treatment with ASA-VitC induced significantly less gastric mucosal lesions than plain ASA. Furthermore, in comparison to plain ASA, ASA-VitC caused stronger inhibition of cNOS and increase in iNOS expression in the gastric mucosa. In vitro studies demonstrated a significant increase in iNOS expression in MKN-45 cells incubated with Hp. This effect was aggravated by the addition of ASA, but not ASA-VitC, to MKN-45 cells incubated with H.pylori. Both ASA and ASA-VitC stimulated the COX-2 expression in the gastric mucosa. We conclude that ASA-VitC in comparison with ASA induces less gastric mucosal damage and this protective effect may be due to its inhibitory effect on iNOS expression.

This review was designed to show the role of expression of cyclooxygenase (COX)-1 and COX-2 in the cancerogenesis of esophagus, stomach and colon. Unlike COX-1, which is expressed in the normal esophago-gastro-colonic mucosa, COX-2 was found to be expressed mainly in the pre-cancer changes in the mucosa including Barrett's esophagus, Helicobacter pylori (H. pylori)-induced gastritis and inflammatory changes in colonic mucosa. In Barrett's esophagus, prostaglandins (PGs) derived from upregulated COX-2 contribute to the progression of low-grade to high-grade dysplasia and finally to cancer. In chronic gastritis induced by chronic H. pylori infection, overexpression of COX-2 is probably induced by inflammatory cytokines, growth factors, especially gastrin and reactive oxygen species leading to mutagenesis and subsequent metaplasia, dysplasia and cancer formation. The imbalance between cell proliferation and apoptosis caused mainly by products of COX-2 leads to cancerogenesis. Similarly, in colorectal cancer the overexpression of COX-2, possibly induced by the action of growth promoting factors including progastrin and gastrin and overexpression of survivin contribute to the colorectal cancerogenesis that could be, at least in part, amended by the treatment with specific COX-2 inhibitors. We conclude that: 1) COX-2-derived PGs play a key role in the tumorigenesis in the gastrointestinal tract; 2) The tumor-promoting effect of PGs may be attributed to their ability to stimulate 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 gastrointestinal cancers.

Background: Several studies have shown a link between gastrin and gastric cancer, both in humans and animals, especially infected with Helicobacter pylori (H. pylori). However, the exact role of hypergastrinemia in gastric carcinogenesis remains still undetermined. The aim of the present study was to evaluate the interaction between gastrin, cyclooxygenase-2 (COX-2), hepatocyte growth factor (HGF) and apoptosis-related proteins (Bax, Bcl-2, caspase-3, survivin) in cultured gastric epithelial cancer cells., Material and Methods: In the present study, gastric cultured cancer cells (KATO III cells) were exposed to increasing concentrations of gastrin (1-1000 nM). Cells incubated with culture medium alone, without added gastrin, served as controls. Using RT-PCR and Western blot, we examined the mRNA and protein expression for COX-2, HGF and apoptosis-related proteins (Bax, Bcl-2, caspase-3 and survivin). In addition, the gene expression of gastrin and gastrin receptor (CCK-2) as well as the release of gastrin in culture medium in the unstimulated cells were examined by RT-PCR and RIA, respectively. The apoptosis rate in cells was measured by flow cytometric analysis., Results: The present study shows that the gastric cultured epithelial cells exhibit the expression of gastrin and CCK-2 receptors and release of gastrin into the culture medium. The epithelial gastric cancer cells incubated with gastrin showed a concentration-dependent increase of COX-2 and HGF expression. Although no significant changes in apoptosis rate were observed, the exposure of these cells was associated with a dose-dependent increase in the expression of antiapoptotic proteins Bcl-2 and survivin., Conclusions: This study demonstrates that 1) gastrin stimulates the gene and protein expression of COX-2 and HGF in human cultured gastric cancer cells and 2) gastrin shows antiapoptotic activity through the upregulation of Bcl-2 and survivin.