| Background and aims:Cancer is a malignant disease which seriously harms human health, composed of the world's top three causes of death together with cardiovascular and cerebrovascular diseases and accidents. Among them, gastric cancer is one of the most common gastrointestinal malignancies. Gastric cancer is the fourth most common cancer and the second leading cause of cancer related death in the world. Currently, cachexia has been generally believed that is a progressive condition, and occurs most frequently in terminal life-threatening diseases such as cancer, AIDS, chronic obstructive pulmonary disease and chronic renal failure. Cancer cachexia (CC) is mainly characterized by anorexia, anemia, increased protein degradation, loss of muscle tissue, progressive weight loss and even organ failure. Up to one-half of untreated cancer patients lose some weight; CC also accounts for about 20% of cancer deaths. CC reduces quality of life and is correlated with a shortened survival time. Its mechanism is not clear, which is generally considered to be caused by the combined effects of multiple factors, including:1) the insufficient body nutrient intake; 2) increased energy consumption of malignant tumors; 3) metabolic disorders; 4) varying levels of cytokines. Recent researches have shown that proton pump inhibitors (PPIs) selectively induced apoptosis in gastric cancer cells, whereas not affected normal gastric mucosal cells. Therefore, this study is to confirm that:1) whether the proton pump inhibitors can inhibit gastric cancer cell proliferation and whether it can promote apoptosis of gastric cancer cells; 2) whether proton pump inhibitors can improve gastric cancer related cancer cachexia; 3) how to change in cytokine levels and in hormone levels when proton pump inhibitors interfere with the process of cancer cachexia; 4) whether proton pump inhibitors can improve cancer cachexia through the influence of tumor glycolysis pathway when proton pump inhibitors interfere with the process of cancer cachexia.Methods:1) Human gastric adenocarcinoma cell line SGC-7901 was cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum in a humidified 5% CO2 atmosphere at 37℃; 2) SGC-7901 cells in logarithmic growth phase were digested with trypsin, made into single cell suspension and inoculated in the right scapular region of nude mice subcutaneously to establish animal models of cancer cachexia, which were observed in body weight, food intake, water intake, and tumor volume after intervention with PPIs; 3) The levels of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), ghrelin, leptin, corticotropin releasing hormone (CRH) and neuropeptide Y (NPY) in serum were determined by ELISA; 4) The levels of adrenocorticotropic hormone (ACTH) in plasma were determined by chemiluminescence; 5) The levels of cortisol (COR) in serum were determined by radioimmunoassay (RIA); 6) The cell cytotoxicity on gastric cancer cells intervened with different concentrations of PPIs was detected by CCK-8 assay; 7) Annexin V-FITC-PI double staining was used to detect the apoptosis rate of gastric cancer cells; 8) Western blotting and immunofluorescent staining analyses were employed to determine the protein expressions and intracellular distributions of mTOR, HIF-la and PKM2 before and after PPIs treatment in vitro.Results:1) The relative body weight in the CC group of nude mice was significantly lower than that in the NTB group. After the intervention with PPIs, the relative body weight in the PAN group and OME group was higher than that in the CC group with different degrees; 2) The food intake in the CC group of nude mice was significantly lower than that in the NTB group. After the intervention with PPIs, the food intake in the PAN group and OME group was significantly higher than that in the CC group; 3) The water intake in the CC group of nude mice was significantly lower than that in the NTB group. After the intervention with PPIs, the water intake in the PAN group and OME group was significantly higher than that in the CC group; 4) After the intervention with PPIs, the relative tumor volume in the PAN group and OME group was lower than that in the CC group with different degrees; 5) The serum levels of TNF-a in the CC group of nude mice was significantly higher than that in the NTB group. After the intervention with PPIs, the levels of TNF-αin the PAN group and OME group was significantly lower than that in the CC group; 6) The serum levels of IL-6 in the CC group of nude mice was significantly higher than that in the NTB group. After the intervention with PPIs, the levels of IL-6 in the PAN group and OME group was significantly lower than that in the CC group; 7) The serum levels of ghrelin in the CC group of nude mice was significantly higher than that in the NTB group. After the intervention with PPIs, the levels of ghrelin in the PAN group and OME group was significantly lower than that in the CC group; 8) The serum levels of leptin in the CC group of nude mice was lower than that in the NTB group. After the intervention with PPIs, the levels of ghrelin in the PAN group and OME group was significantly higher than that in the CC group; 9) The serum levels of NPY in the CC group of nude mice was significantly higher than that in the NTB group. After the intervention with PPIs, the levels of NPY in the PAN group was significantly lower than that in the CC group; 10) The serum levels of CRH in the CC group of nude mice was significantly lower than that in the NTB group. After the intervention with PPIs, the levels of CRH in the PAN group and OME group was significantly higher than that in the CC group; 11) The plasma levels of ACTH in the CC group of nude mice was higher than that in the NTB group. After the intervention with PPIs, the levels of CRH in the PAN group and OME group was significantly lower than that in the CC group; 12) The serum levels of COR in the CC group of nude mice was higher than that in the NTB group. After the intervention with PPIs, the levels of CRH in the PAN group was significantly lower than that in the CC group; 13) PPZ could inhibit the cell viability of gastric cancer cells in a dose-dependent manner, which the cell viability in 40,80,160μg/ml PPZ groups was significantly lower than that in the control group; 14) The total apoptosis rate and early apoptosis rate after PPZ treatment was in a dose-dependent manner; 15) PPZ treatment could significantly inhibit the protein expression of mTOR, HIF-1αand PKM2.Conclusions:PPIs can inhibit cell proliferation and induce apoptosis in gastric cancer cell line SGC-7901. In nude mice, it can significantly improve the state of cancer cachexia. These effects may be related to the following three mechanisms:1) affecting cytokine levels; 2) affecting hormone metabolism; 3) interfering with tumor glycolysis pathway. |
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