Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cis-diamminedichloroplatinum (CDDP)-resistant scirrhous gastric cancer cell line, OCUM-2M/DDP, was established by chronic exposure of cells of the parent scirrhous gastric cancer cell line, OCUM-2M, to CDDP at progressively increasing concentrations. The OCUM-2M/DDP cell line had an 11.3-fold higher level of resistance relative to its parent cell line as determined by a succinate dehydrogenase inhibition test. The biological and biochemical characteristics of the resistant and parent cell line were compared. There were differences in the modal chromosome number and DNA index, suggesting that some alterations of the DNA in the CDDP-resistant cells had occurred. Neither the parent nor resistant cell line expressed mdr-1 mRNA. After exposure to CDDP for 4 h, the intracellular platinum content of OCUM-2M cells was significantly higher than that of OCUM-2M/DDP cells (51.9 +/- 1.8 vs 16.4 plus 1.0 ng/mg protein, mean +/- SD, respectively). The GSH levels in OCUM-2M cells and OCUM-2M/DDP cells were 3.5 +/- 1.0 micrograms/mg protein and 16.8 +/- 1.2 micrograms/mg protein, respectively. These levels were also significantly different. These findings suggest that the possible mechanisms of acquired resistance to CDDP in OCUM-2M/DDP cells may be a decrease in intracellular CDDP accumulation and detoxication by GSH. This OCUM-2M/DDP cell line could be used in further investigations of the mechanism of CDDP resistance in gastric cancer.
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PMID:Establishment of a cisplatin-resistant gastric carcinoma cell line OCUM-2M/DDP. 913 37

Thioredoxin (TRX) is a widely distributed Mr 13,000 protein with a redox-active dithiol/disulfide in the active site. The TRX system, consisting of TRX, TRX reductase, and NADPH, has an intracellular reducing capacity. Another reducing capacity, glutathione (GSH), can be associated with cis-diaminedichloroplatinum (cDDP) resistance. Therefore, we examined the involvement of TRX in cDDP resistance using two cell lines designated St/DDP and HT/DDP, which were established from the human gastric cancer cell line St-4 and the colon cancer cell line HT-29. St/DDP and HT/DDP were seven and five times as resistant to cDDP as their parental lines, and the expression of TRX in these variants was increased by 2.5- and 2-fold, respectively. The expression of TRX in the complete revertant cells of St/DDP was reduced as low as that in St-4 cells. TRX reductase activity was also increased in St/DDP and HT/DDP, suggesting that activation of the TRX system was associated with in vitro-acquired cDDP resistance. Because cDDP is the first-line drug against ovarian cancer, we examined the expression of TRX in 11 human ovarian cancer cell lines not treated with cDDP in vitro. Positive correlation between TRX expression and cDDP resistance was observed in these cell lines (r = 0.76, P = 0.007). This correlation was comparable to that between GSH content and cDDP resistance (r = 0.69, P = 0.019). These results suggest a possible involvement of TRX, as well as GSH, in cDDP resistance.
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PMID:Increased expression of thioredoxin/adult T-cell leukemia-derived factor in cisplatin-resistant human cancer cell lines. 981 87

Glutathione transferases (GSTs) have been shown to play an important role in multiple drug resistance in cancer chemotherapy. The inactivation of GST isoforms could lead to an enhanced activity of cytotoxic drugs. Thus, we have developed glutathione phosphono analogs [(S)-gamma-glutamyl-(2RS)-(+/-)-2-amino-(dialkoxyphosphinyl)-ac etylgl ycines], which were previously shown to be inhibitors of GSTP1-1. In the present study, the inhibition characteristics of these analogs, including isoenzyme specificities, type of inhibition, and determination of K(i) values, were determined. The inhibition of class alpha GSTs was competitive towards GSH. A mixed-type, non-competitive inhibition of class mu and pi GSTs was observed. The K(i) values varied between 880 +/- 210 and 0.45 +/- 0.1 microM. The inhibitors were most effective towards class mu GSTs. In order to investigate the potential use of these GST inhibitors in intact cellular systems, two additional approaches were examined. Firstly, the metabolic stability was tested with purified gamma-glutamyl transpeptidase and cell homogenates as well as during incubation of cell lines. No appreciable degradation was observed in any of the tested systems. Secondly, to facilitate cellular uptake, three derivatives were synthesized in which the glycine carboxylic group was esterified. Uptake and a possible intracellular cleavage to the corresponding free acids were monitored by HPLC analysis. The esters were effectively transported into HT29 (colon cancer) and EPG85-257P (gastric cancer) cells, respectively, and readily converted into the more active free acids. In conclusion, the tested inhibitors may be regarded as model compounds for the development of modulating agents in cancer chemotherapy.
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PMID:Phosphono analogs of glutathione: inhibition of glutathione transferases, metabolic stability, and uptake by cancer cells. 1069 62

Helicobacter pylori infection has been associated with stimulation of gastric mucosal reactive oxygen species (ROS) production, and it was postulated that ROS production is due to neutrophil infiltration and activation. The aim of this study was to investigate the direct effect of H. pylori on ROS formation in gastric epithelial cells in vitro. The human gastric cancer cell line HM02 was incubated with H. pylori for 24 hr, and the effects on cell number and the intracellular radical scavenger reduced glutathione (GSH) were assessed. H. pylori caused a concentration-dependent reduction of cellular GSH concentrations over a broad bacteria-to-cell ratio (1.4-42) in the absence of cell necrosis. The radical scavengers MnTBAP (a cell permeable superoxide dismutase) and ebselen provided protection against H. pylori-induced decrease in cellular GSH concentrations. We conclude that H. pylori directly decreases cellular GSH concentrations in gastric epithelial cells. We suggest that this effect is caused by the release of ROS by H. pylori.
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PMID:Helicobacter pylori reduces intracellular glutathione in gastric epithelial cells. 1105 18

Adenophora triphylla (AT), an oriental medicinal plant, was extracted using water and several organic solvents and each fraction was assayed for its tumoricidal effects on human Jurkat T cells with 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT). The influence on induction of apoptosis and G1 arrest was also examined. The ethyl acetate fraction showed the most pronounced inhibitory effects on proliferation of Jurkat T cells. Apoptosis was induced in line with up-regulation of FasL, tyrosine phosphorylation and c-fos mRNA levels. Arrest in G1 of the cell cycle was observed in A2780 cells with a wild type p53 gene but not HT-29 cells with a mutant p53 gene. Modifying effects of AT on cell turnover and glutathione(GSH) levels in vivo were also investigated in the stomach of rats given 150 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by gavage and then fed a diet supplemented with 5% or 1% pulverized AT and 0.5% or 0.2% ethylacetate-extracted AT for 42 hours. The 5% AT and both of the ethylacetate fractions caused significant reduction in proliferating cell nuclear antigen (PCNA)-labeling in the glandular stomach epithelium as compared with the value for the MNNG alone group. In addition, the treatments significantly increased the gastric GSH levels. These results suggest that AT could be a chemopreventive agent against gastric cancer.
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PMID:Suppressive effects of Adenophora triphylla extracts on in vitro tumor cell growth and in vivo gastric epithelial proliferation. 1106 47

Helicobacter pylori (H. pylori) infection might activate nuclear factor-kappaB (NF-kappaB), an oxidant-sensitive transcription regulator of inducible expression of inflammatory genes such as cyclooxygenase-2 (COX-2). We studied the role of NF-kappaB on expression of COX-2 in H. pylori-stimulated gastric cancer cell lines by using antioxidants, glutathione (GSH), and N-acetylcysteine (NAC) as well as an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). Gastric adenocarcinoma cell lines derived from Caucasian (AGS) cells and Korean (SNU-484) cells were used to study the role of NF-kappaB on COX-2 expression by H. pylori. They were treated with GSH, NAC, or PDTC in the presence of H. pylori. mRNA expression and protein level for COX-2 were determined by Northern blot and RT-PCR analysis as well as Western blot analysis. NF-kappaB activation was examined by electrophoretic mobility shift assay. As a result, H. pylori induced a time-dependent expression of mRNA and protein for COX-2 via activation of NF-kappaB, which was inhibited by GSH, NAC, and PDTC in the cells. In conclusion, oxidant-sensitive transcription factor NF-kappaB may play a novel role in expression of COX-2 by H. pylori stimulation in gastric cancer cells.
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PMID:Oxidant-sensitive transcription factor and cyclooxygenase-2 by Helicobacter pylori stimulation in human gastric cancer cells. 1208 98

Polyozellus multiplex, a Korean wild mushroom, was extracted using methanol, and the extract was further fractionated with water and ethylacetate. Assay of each fraction with MTT revealed significant tumoristatic effects of the water fraction of Polyozellus multiplex against human gastric and other cancer cells but not normal human lymphocytes. Modifying effects of the water fraction on glandular stomach mucosa were investigated in male Wistar rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The dietary 0.5% or 1% water fraction of Polyozellus multiplex significantly increased glutathione S-transferase (GST) and superoxide dismutase (SOD) activities, and showed a tendency for increase in glutathione (GSH) levels, compared to the MNNG alone group. It also caused a significant reduction in proliferating cell nuclear antigen (PCNA)-labeling index of the glandular stomach epithelium, along with increase in p53 tumor suppressor gene expression. These results suggest that Polyozellus multiplex is a candidate for chemoprevention against gastric cancer.
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PMID:Polyozellus multiplex, a Korean wild mushroom, as a potent chemopreventive agent against stomach cancer. 1456 27

We have examined the combined anticancer effects of docetaxel (DOC) and cisplatin (CDDP) in vitro using the gastric cancer cell lines MKN-45, MKN-74, and TMK-1. Treatment of the cell lines with 30 microg/ml of DOC for 24 h followed by incubation with 3 or 10 microg/ml of CDDP for 24 h showed a clear synergistic effect. Sequence dependency of the agents was observed in these cell lines: DOC followed by CDDP (DC) showed a stronger antitumor effect than CDDP followed by DOC (CD) in all cell lines. To clarify the mechanism of action of the DC combination, total intracellular platinum (Pt) levels were evaluated after treatment with CDDP alone or combined with DC. For the MKN-45 and -74 cell lines, cells treated with DOC (10 microg/ml for 12 h) and then CDDP showed significantly increased intracellular Pt accumulation compared to cells treated with CDDP alone. We also investigated alterations in intracellular glutathione (GSH) concentration in response to DOC and CDDP. MKN-45 and -74 cells pretreated with DOC (10 microg/ml for 12 h) showed significantly increased intracellular GSH levels compared to cells administered CDDP only. To explain these findings, messenger RNA (mRNA) levels for multidrug resistance-associated protein-1 (MRP-1), the ATP-dependent pump for Pt-GSH complexes, were quantified in CDDP-treated MKN-45 cells with and without DOC pretreatment. While CDDP administration increased MRP-1 mRNA expression in MKN-45 cells, MRP-1 was not up-regulated after CDDP administration in DOC pretreated MKN-45 cells. Our results suggested that the enhanced CDDP toxicity due to DOC pretreatment may be related to the accumulation of intracellular Pt-GSH complexes, because DOC appears to suppress the MRP-1 up-regulation induced by CDDP exposure in gastric cancer cells.
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PMID:Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism. 1529 32

Helicobacter pylori (H. pylori) often play an important role in the pathogenesis of gastritis, peptic ulcer, and probably also gastric cancer. Reactive oxygen species (ROS) produced by this bacterium may be one of the crucial factors whereby oxidative stress can play a role in the pathogenesis of ulcer disease. The aim of this study was to assess ROS activity and glutathione redox status, a principal cellular redox sensor, in H. pylori-associated indomethacin-induced gastric ulcers in rats. Gastric lesion was produced by intragastric administration of indomethacin (7 mg/kg) for three days followed by administration of H. pylori suspension (density 10(9) colony forming units). Animals receiving indomethacin only or followed by administration of H. pylori suspension were sacrificed after 11 and 18 days. ROS activity was assessed by the level of lipid peroxidation (LPO) and the glutathione redox status by the ratio between oxidized and reduced glutathione (GSSG/GSH). Indomethacin did not significantly increase the level of LPO and the GSSG/GSH ratio. When H. pylori suspension was given together with indomethacin the LPO was increased both on days 11 and 18 and GSSG/GSH on day 18. H. pylori, thus, substantially increases glutathione redox ratio and lipid peroxidation in gastric mucosa, which may play an important role in the pathological mechanisms of this bacterium. The findings support the idea that dietary antioxidants could be beneficial in combination therapy for eradication of H. pylori.
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PMID:Helicobacter pylori substantially increases oxidative stress in indomethacin-exposed rat gastric mucosa. 1586 8

Combination chemoprevention by diet-derived agents is a promising strategy for protection against gastric cancer. We therefore evaluated the combined chemopreventive effect of S-allylcysteine (SAC), an organosulfur constituent of garlic, and lycopene, a major carotenoid present in tomatoes, against N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and saturated sodium chloride (S-NaCl)-induced gastric carcinogenesis in Wistar rats. The animals were divided into eight groups of six animals each. Rats in group 1 were given MNNG by intragastric intubation on days 0 and 14 as well as S-NaCl every 3 days during weeks 0-3. Animals in groups 2-4, administered MNNG and S-NaCl as in group 1, received in addition SAC and lycopene alone and in combination, respectively, three times per week starting on the day following the first exposure to MNNG. Groups 5-7 were given the chemopreventive agents alone, whereas group 8 served as controls. The animals were sacrificed after an experimental period of 21 weeks. Measurement of lipid peroxidation and antioxidants of the glutathione redox cycle in the stomach, liver, and erythrocytes was used to monitor the chemopreventive potential of SAC and lycopene. In the tumor tissue, diminished lipid peroxidation was accompanied by an increase in reduced glutathione (GSH) and GSH-dependent enzymes, whereas in the liver and erythrocytes, enhanced lipid peroxidation was associated with antioxidant depletion. Although SAC and lycopene alone significantly suppressed the development of gastric cancer, administration of SAC and lycopene in combination was more effective in inhibiting MNNG-induced stomach tumors and modulating the redox status in the tumor and host tissues. The results of the present study validate the hypothesis that diet-derived chemopreventive agents such as SAC and lycopene in combination may interact synergistically with high efficacy and lessened toxicity against gastric cancer.
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PMID:Combination chemoprevention of experimental gastric carcinogenesis by s-allylcysteine and lycopene: modulatory effects on glutathione redox cycle antioxidants. 1637 61


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