s-1743 and Adenocarcinoma

Patients with dysplasia in Barrett's esophagus (BE) have a considerable risk of developing esophageal adenocarcinoma (EAC). The mucosal expression of the pro-inflammatory angiotensin II receptor type 1 (AT1R) is elevated in these patients, suggesting a role in carcinogenesis. The purpose of this study was to determine whether interference with the renin-angiotensin system (RAS) would influence downstream markers of carcinogenesis.. Endoscopic mucosal biopsies from BE patients with low-grade dysplasia (LGD) were sampled before and after a three-week period of RAS-interfering treatment. Thirty patients were randomly allocated to enalapril (ACE inhibitor, 5 mg od), candesartan (AT1R antagonist, 8 mg od), or no drug. The expression of 12 proteins known to be associated with RAS and carcinogenesis was assessed using western blot.. We found altered expression of several proteins after enalapril treatment (decreased: NFκB, p = .043; NLRP3, p = .050; AMACR, p = .017; and caspase 3, p = .025; increased: p53, p = .050). Candesartan treatment was associated with increased iNOS expression (p = .033). No significant changes were seen in the no-drug group.. Interference with angiotensin II formation was associated with altered expression of inflammation- and carcinogenesis-related proteins. The present results speak in favor of involvement of angiotensin II in BE dysplasia, but the role of AT1R should be investigated further.

Topics: Adenocarcinoma; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Barrett Esophagus; Benzimidazoles; Biomarkers, Tumor; Biphenyl Compounds; Enalapril; Endoscopy; Esomeprazole; Esophageal Neoplasms; Female; Humans; Hyperplasia; Male; Middle Aged; Neoplasm Proteins; Nitric Oxide Synthase Type II; Precancerous Conditions; Prospective Studies; Proton Pump Inhibitors; Renin-Angiotensin System; Risk Factors; Sweden; Tertiary Care Centers; Tetrazoles

Neoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer. However, response to radiochemotherapy varies widely. Proton pump inhibitors (PPIs) have been demonstrated to impact on chemotherapy in a variety of other cancers. We analyzed the impact of PPI treatment on esophageal cancer cell lines, and investigated mechanisms that mediate the effect of PPI treatment in this tumour.. We investigated the effect of esomeprazole treatment on cancer cell survival, adhesion, migration and chemotherapy in human adeno-(OE19) and squamous-cell-carcinoma (KYSE410) cell lines. Furthermore, we investigated the effect of PPI treatment on intra-/extracellular pH and on expression of resistance-relevant miRNAs.. Esomeprazole significantly inhibited tumour cell survival (in a dose-dependent manner), adhesion and migration in both tumour subtypes. Furthermore, esomeprazole augmented the cytotoxic effect of cisplatin and 5-FU in both tumour subtypes. Surprisingly, PPI treatment led to a significant increase of intracellular pH and a decrease of the extracellular pH. Finally, we found esomeprazole affected expression of resistance-relevant miRNAs. Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types.. Our study demonstrates for the first time that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapy in esophageal cancer cell lines. Furthermore, we observed that in this tumour entity, PPIs do not lead to intracellular acidification, but affect the expression of resistance-relevant miRNAs.

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Esomeprazole; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Hydrogen-Ion Concentration; MicroRNAs; Neoplasm Invasiveness; Proton Pump Inhibitors

Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents.. We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice.. PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin.. Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenocarcinoma; Animals; Antineoplastic Agents; Benzimidazoles; Blotting, Western; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Electrophoresis, Polyacrylamide Gel; Esomeprazole; Fluorouracil; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Inhibitory Concentration 50; Lymphoma; Melanoma; Mice; Mice, SCID; Microscopy, Confocal; Omeprazole; Pantoprazole; Proton Pump Inhibitors; Sulfoxides; Transplantation, Heterologous; Vinblastine