Human Gastric Adenocarcinoma Cells Research Articles

A novel 2, 6-connected inorganic-organic 3-D open framework based on {As2Mo18} with photocatalytic property and anticancer activity

A new inorganic-organic open framework based on Wells-Dawson arsenomolybdate, {Ag(diz)2}3[{Ag(diz)2}3(As2Mo18O62)]∙H2O (1) (diz=1,2-diazole) has been hydrothermally synthesized and characterized by elemental analysis, IR, TG, UV, XRD, and single-crystal X-ray diffraction. In compound 1, each {As2Mo18} cluster uses six terminal oxygen atoms on 'equator' position to attract peripheral six {Ag(diz)2} linkers, which are further connected by six Dawson clusters located on two different planes via unique equator-to-equator interlaced ways to form a unprecedented 3D network with {812∙123}{8}3 topology. Compound 1 represents the highest covalent connectivity of 3-D Dawson arsenomolybdate, which exhibits merit photocatalytic properties for degradation of refractory dyes Azon Phloxine (AP) under UV light. In addition, compound 1 has a potent inhibition effect on proliferation of Human gastric adenocarcinoma cells (SGC-7901).

Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways.

Tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are promising candidates for cancer treatment due to their ability to induce apoptosis through death receptor stimulation. However, their usage may be limited due to the resistance of cancer cells to TNF-α- and TRAIL-induced apoptosis. Currently, there is interest in screening for natural products that can sensitize cancer cells to TNF-α- and TRAIL-induced apoptosis for their use in combination with TNF-α or TRAIL. It was previously reported that the bark extract of Thevetia peruviana showed a reversal effect on TRAIL-resistance in human gastric adenocarcinoma cell lines. In the present study, the effects of the ethanolic extract of T. peruviana flowers on TNF-α- and TRAIL-induced apoptosis of human cervical cancer HeLa cells were investigated in vitro by determining cell viability and apoptosis using a WST-1 cell proliferation assay and immunoblot analysis, respectively. The ethanolic extract of T. peruviana flowers promoted TNF-α and TRAIL-mediated cell death through the activation of the caspase cascade, poly(ADP-ribose) polymerase and BH3-interacting domain death agonist cleavage. Combined treatment using the extract plus TNF-α resulted in downregulation of anti-apoptotic protein, including myeloid cell leukemia sequence-1, B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis protein and survivin, while the combined treatment with TRAIL downregulated Bcl-XL. Thus, the ethanolic extract of T. peruviana flowers has potential in sensitizing the TNF-α- and TRAIL-induced apoptosis of HeLa cells via the intrinsic and extrinsic pathways.

Antitumor activity of a Trans-thiosemicarbazone schiff base palladium (II) complex on human gastric adenocarcinoma cells.

The development of transition-metal-based antitumor drug candidates increases the metallopharmaceuticals study dramatically. Two trans-thiosemicarbazone-based, Schiff base palladium (Pd) (II) complexes, DMABTSPd (TSPd) and DMABPTSPd (PTSPd), were prepared and characterized as described in our previous study. Here, we investigated whether the two complexes have antitumor effect on human gastric adenocarcinoma cell lines, BGC-823 and SGC-7901, compared with normal human gastric mucosal epithelial cell line, Ges-1. The results show that the Pd complex with the bare amino group (DMABTSPd(TSPd)) can inhibit cell viabilities and induce apoptosis in human gastric carcinoma cells, rather than the Pd complex without the bare amino group (DMABPTSPd (PTSPd)). This occurs via a mitochondrial-related pathway by down-regulating the level of Bcl-2 expression and up-regulating the level of Bid expression. Meanwhile, DMABTSPd (TSPd) suppressed tumor growth via a mitochondrial-related pathway in a nude mouse tumor xenograft model derived from BGC-823 cells. These findings demonstrate that DMABTSPd (TSPd) is worthy of further structural optimization and representing a promising Pd complex for the development of a new antitumor therapeutic agent.

Elmenols C-H, new angucycline derivatives isolated from a culture of Streptomyces sp. IFM 11490.

Chemical investigations of the ethyl acetate extract of Streptomyces sp. IFM 11490 have led to the isolation of six new angucycline metabolites, named elmenols C-H (1-6), along with the previously reported elmonin (7) and elmenols A (8) and B (9). The known LS1924A (10), 6-deoxy-8-methylrabelomycin (11), tetrangulol methyl ether (12) and angucyclinone (13) were additionally identified. The structures of the isolated compounds were elucidated by means of spectroscopic methods including UV, IR, HRESIMS, and 1D and 2D NMR. Compounds 1-6 were evaluated for their abilities to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in human gastric adenocarcinoma (AGS) cells. Compounds 5 (10 μm) and 6 (50 μm) in combination with TRAIL showed moderate activity in sensitizing TRAIL-resistant AGS cells.

Docosahexaenoic acid loaded lipid nanoparticles with bactericidal activity against Helicobacter pylori

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid present in fish oil, has been described as a promising molecule to the treatment of Helicobacter pylori gastric infection. However, due to its highly unsaturated structure, DHA can be easily oxidized loosing part of its bioactivity. This work aims the nanoencapsulation of DHA to improve its bactericidal efficacy against H. pylori.DHA was loaded into nanostructured lipid carriers (NLC) produced by hot homogenization and ultrasonication using a blend of lipids (Precirol ATO5®, Miglyol-812®) and a surfactant (Tween 60®). Homogeneous NLC with 302±14nm diameter, −28±3mV surface charge (dynamic and electrophoretic light scattering) and containing 66±7% DHA (UV/VIS spectroscopy) were successfully produced.Bacterial growth curves, performed over 24h in the presence of different DHA concentrations (free or loaded into NLC), demonstrated that nanoencapsulation enhanced DHA bactericidal effect, since DHA-loaded NLC were able to inhibit H. pylori growth in a much lower concentrations (25μM) than free DHA (>100μM).Bioimaging studies, using scanning and transmission electron microscopy and also imaging flow cytometry, demonstrated that DHA-loaded NLC interact with H. pylori membrane, increasing their periplasmic space and disrupting membrane and allowing the leakage of cytoplasmic content. Furthermore, the developed nanoparticles are not cytotoxic to human gastric adenocarcinoma cells at bactericidal concentrations. DHA-loaded NLC should, therefore, be envisaged as an alternative to the current treatments for H. pylori infection.

Characterization, drug release profile and cytotoxicity of Dentatin-Hydroxypropyl-β-Cyclodextrin complex

This current work has been conducted mainly to increase solubility and drug release properties for high hydrophobic Dentatin (DEN) by incorporation it into Hydroxypropyl-β-Cyclodextrin (HPβCD) cavity. To confirm that inclusion be succeeded, the produced complex were installed onto different machines. The latter includes: Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM). The hydrodynamic diameter and zeta potential of DEN-HPβCD complex were 2.025 ± 0.39 nm and −33.6 mV, respectively. Ultra-violet spectroscopy was employed to further confirmation of complexation process as well as to determine drug release profile. The result showed an initial burst release (19.9% within first two minutes) and then a continuous release for an extended period of 41 h (100%). The solubility of DEN was enhanced by >300 fold following complexation when a compared to DEN alone. Moreover, MTT finding showed that this complexation did not reduce cytotoxicity of DEN after applying on prostate cancer (LNCaP), human adenocarcinoma breast cancer (MDA-MB-231) and human gastric adenocarcinoma cell line (HDT). However, further investigations are required to validate efficacy of our produced inclusion using molecular analysis and in vivo studies.

Variations in the multimerization region of the Helicobacter pylori cytotoxin CagA affect virulence.

Helicobacter pylori colonizes the human stomach by infecting gastric epithelial cells. It is the primary cause of peptic ulcer disease and gastric cancer (GC). Cytotoxin-associated gene A (CagA) is a virulence factor produced by H. pylori. Strains positive for the CagA protein are associated with more severe gastric diseases. The 3' region of the cagA gene exhibits heterogeneity with respect to tyrosine phosphorylation motifs (EPIYA) and CagA multimerization motifs (CM). CagA proteins are categorized as either Western or Eastern based on EPIYA sequences. CM motifs are also identified as Western and Eastern based on CM sequences identified in Western and East Asian countries. It has been suggested that CagA proteins possessing an Eastern CM type are associated with less severe gastric disorders. In the present study, the effects of two CagA peptides with different CM motifs on cell function were compared: CagA with a Western and Eastern CM motif (CagA-WE), and CagA with two Western CM motifs (CagA-WW). CagA sequences were fused with green fluorescent protein (GFP) to form GFP-CagA fusion proteins. GFP-CagA and GFP control constructs were transfected into human gastric adenocarcinoma cells (AGS). GFP-CagA expression was verified by immunoblotting and immunofluorescence. The results demonstrated that, following 18 h, the CagA-WE-transfected cells were less adherent compared with the CagA-WW transfected cells. CagA has also been reported to cause cell elongation in AGS cells. In the current study, cell elongation was more frequent in the CagA-WW-transfected cells compared with the CagA-WE transfected cells (8.34 vs. 3.97% cells, respectively). The CagA peptides did not affect proliferation or apoptosis rates. These results suggest that different CM motif types may affect CagA virulence.

Cytotoxic activities of naturally occurring oleanane-, ursane-, and lupane-type triterpenes on HepG2 and AGS cells.

Background:It is well known that the naturally occurring modified triterpenes in plants have a wide diversity of chemical structures and biological functions. The lupane-, oleanane-, and ursane-type triterpenes are the three major members of natural triterpenes with a wide range of biological properties. A systematic approach is necessary to review their structures and biological activities according to the backbones and the different substituents.Objective:Thirty lupane-(L1-7), oleanane-(O1-14), and ursane-type (U1-9) triterpenes with structural diversity were examined to evaluate their cytotoxic activities against two cancer cell lines, human hepatocellular carcinoma (HepG2) and AGS cells.Materials and Methods:They were isolated from Hedera helix, Juglans sinensis, and Pulsatilla koreana using a series of column chromatography methods and were treated to evaluate their cytotoxic activities against HepG2 and AGS human gastric adenocarcinoma cell. Further, two triterpenes showing the most potent activities were subjected to the apoptotic screening assay using flow cytometry.Results:The polar groups, such as an oxo group at C-1, a free hydroxyl at C-2, C-3, or C-23, and a carboxylic moiety at C-28, as well as the type of backbone, explicitly increased the cytotoxic activity on two cancer cells. O5 and U5 showed significantly the potent cytotoxic activity in comparison to other glycosidic triterpenes. In annexin-V/propidium iodide (PI) staining assay, the percentage of late apoptosis (annexin-V+/PI+) 12 and 24 h after treatment with O5 and U5 at 25 μM increased from 14.5% to 93.1% and from 46.4% to 49.1%, respectively, in AGS cells. The cytotoxicity induced by O5 showed a significant difference compared to U5 for 12 and 24 h.Conclusion:In the study, we can suggest the potent moieties which influence their cytotoxic activities against two cancer cells. The polar groups at C-1, C-2, C-3, C-23, and C-28 and the linkage of sugar moieties influenced the different cytotoxic activities.SUMMARY Thirty naturally occurring oleanane-, ursane-, and lupane-type triterpenes were isolated from Hedera helix, Juglans sinensis, and Pulsatilla koreanaAn oxo, a free hydroxyl, a carboxylic moiety, and the types of aglycone influenced the cell cytotoxicityCorosolic acid and α-hederin showed the most potent cytotoxicity via apoptosis.

New pyridoxal based chemosensor for selective detection of Zn2+: Application in live cell imaging and phosphatase activity response

Abstract Although a variety of fluorescence based chemosensors have been utilized for selective detection of Zn2+, pyridoxal containing simple Schiff bases still remained less explored. Here, we combine pyridoxal hydrochloride and 1,2-diaminocyclohexane to generate a new sensor molecule, H4PydChda [5-Hydroxymethyl-4-({2-[5-hydroxymethyl-2-methylpyridin-3-hydroxy-4-ylethylene)-amino]-cyclohexylimino}-methyl-2-methylpyridin-3-ol]. Chemosensor H4PydChda exhibits selective turn-on type response in presence of Zn2+ in ethanol-water mixture at physiological pH. Appreciable fluorescence enhancement occurs upon addition of Zn2+ to H4PydChda as a result of inhibited C N isomerisation and excited state intramolecular proton transfer (ESIPT) leading to efficient chelation enhanced fluorescence (CHEF). The relevant properties, including reversibility, life time measurements and detection limit have been determined for the sensor system. The experimental and theoretical supports in terms of 1H and 13C NMR spectroscopy and DFT/TDDFT study are provided to establish the binding mode of H4PydChda to Zn2+. H4PydChda was employed as a sensor for detection of Zn2+ in Human gastric adenocarcinoma (AGS) cells. Moreover, the resulting probe-Zn2+complex shows convincing phosphatase activity (kcat = 21.59 s−1), opening a promising avenue for further research.

Comparing the effects of endogenous and synthetic cannabinoid receptor agonists on survival of gastric cancer cells

AimsAnti-neoplastic activity induced by cannabinoids has been extensively documented for a number of cancer cell types; however, this topic has been explored in gastric cancer cells only in a limited number of approaches. Thus, the need of integrative and comparative studies still persists. Materials and methodsIn this study we tested and compared the effects of three different cannabinoid receptor agonists-anandamide (AEA), (R)-(+)-methanandamide (Meth-AEA) and CP 55,940 (CP)- on gastric cancer cell morphology, viability and death events in order to provide new insights to the use of these agents for therapeutic purposes. Key findingsThe three agents tested exhibited similar concentration-dependent effects in the induction of changes in cell morphology and cell loss, as well as in the decrease of cell viability and DNA laddering in the human gastric adenocarcinoma cell line (AGS). Differences among the cannabinoids tested were mostly observed in the density of cells found in early and late apoptosis and necrosis, favoring AEA and CP as the more effective inducers of apoptotic mechanisms, and Meth-AEA as a more effective inducer of necrosis through transient and rapid apoptosis. SignificanceThrough a comparative approach, our results support and confirm the therapeutic potential that cannabinoid receptor agonists exert in gastric cancer cells and open possibilities to use cannabinoids as part of a new gastric cancer therapy.

Antiproliferative activity and chemical composition of the venom from the Amazonian toad Rhinella marina (Anura: Bufonidae)

Little is known on the composition of Peruvian Amazon toad venoms. The large toad Rhinella marina is common in the cleared tropical forests of the Iquitos region and is regarded as poisonous. The venom from two different populations of R. marina was collected in the Departamento de Loreto, Perú. The samples were assessed for antiproliferative effect and composition. Some 29 compounds were identified or tentatively identified from the venom by spectroscopic and spectrometric means. The main free bufadienolide was marinobufagin 7 while marinobufotoxin 15 and bufalitoxin 9 were the main bufadienolide argininyl diacid derivatives. The alkaloids dehydrobufotenin 28 and bufotenidin 29 were present in both venoms. The main difference in the venoms was the relative ratio of argininyl diacids from bufadienolides to free bufadienolides. The argininyl diacids included derivatives from bufalin, marinobufagin, telocinobufagin, hellebrigenin, resibufogenin and bufotalinin. Four compounds, including undecadienoyl aginine 6 and three argininyl diacids from bufadienolides were tentatively identified for the first time in the samples. The venom showed a strong antiproliferative effect towards MRC-5 normal human lung fibroblasts (0.063–0.247 μg/mL), AGS human gastric adenocarcinoma cells (0.076–0.272 μg/mL), SK-MES-1 human lung cancer cells (0.154–0.296 μg/mL), J82 human bladder carcinoma cells (0.169–0.212 μg/mL), and HL-60 human promyelocytic leukemia (0.071–0.283 μg/mL). The antiproliferative effect is mediated by ROS production and cell cycle arrest in human breast cancer cells (MCF7 and MDA-MB-231). This is the first report on the composition of R. marina venom from the Peruvian Amazon pointing out the need to include different venom samples to get a better picture from the activity and composition of South American toad defense substances.

In situ PKA activity assay by selective detection of its catalytic subunit using antibody arrays

Protein kinase A (PKA) plays a pivotal role in various biological processes and the pathogenesis of several diseases. However, systematic investigation of PKA functions in cells and tissues is limited due to the lack of a suitable high-throughput in situ PKA activity assay. Here, we present an array-based in situ PKA activity assay that employs selective detection of the catalytic form of PKA (cPKA; active and autophosphorylated) using antibody arrays. Antibody arrays were fabricated by applying anti-cPKA antibody onto welltype amine arrays. The limit of detection was 0.02 μg/ mL. We successfully applied this assay to determine changes in intracellular and extracellular PKA activities in human gastric adenocarcinoma (AGS) cells and human umbilical vein endothelial cells (HUVECs) treated with forskolin. Forskolin induced activation of intracellular PKA in a dose-dependent manner, and this PKA activation was inhibited by the potent PKA inhibitor H-89. Extracellular PKA activity was also elevated by forskolin in a dose-dependent manner in AGS cells, but this elevation was hardly detectable in HUVECs. Thus, our antibody array-based in situ PKA activity assay is suitable for investigating the regulation and functions of intracellular and extracellular PKA in cells and tissues and has a potential for use in cancer diagnosis.

Genetically engineered Newcastle disease virus expressing human interferon-λ1 induces apoptosis in gastric adenocarcinoma cells and modulates the Th1/Th2 immune response.

Interferon-λ1 (IFN-λ1), a recently discovered cytokine of the typeIII IFN family, was found to be a therapeutic alternative to typeI IFN in terms of tumors. Using reverse genetics technique, we generated a recombinant Newcastle disease virus (NDV) LaSota strains named as human IFN‑λ1 recombinant adenovirus (rL-hIFN-λ1) containing human IFN-λ1 gene and further evaluated the expressing of IFN-λ1 in human gastric adenocarcinoma cell line SGC-7901 after infected with rL-hIFN-λ1 by using western blot analysis, RT-PCR and immunofluorescence analyses. IFN-λl specific receptor IFNLR1 was detected on several gastric tumor cell lines including SGC-7901 and AGS and on PBMCs.The expression of the IFN-λ1 proteins reached a high level detected in the supernatant harvested 24h after the infection of tumor cells. The proliferation changes of SGC infected with rL-hIFN-λ1 was significantly inhibited compared with NDV-infected group. Apoptosis was significantly induced by rL-hIFN-λ1 in gastric cancer cells compared with NDV virus tested by TUNEL assay, western blot analysis and AnnexinV flow cytometry. Due to the high dose of IFN-λ1 expressed by the rL-hIFN-λ1-infected tumor cells, the immune study showed that rL-hIFN-λ1 increased IFN-γ production [the Thelper cell subtype1 (Th1) response] and inhibited interleukin(IL)-13 production [the Thelper cell subtype2 (Th2) response] to change the Th1/Th2 response of tumor microenvironment which inhibited tumor growth. This study aims at building recombinant NDV rL-hIFN-λ1 as an efficient antitumor agent.

Effects of combining erlotinib and RNA-interfered downregulation of focal adhesion kinase expression on gastric cancer.

ObjectiveTo investigate the synergistic effects of combining erlotinib and RNA-interference downregulation of focal adhesion kinase (FAK) expression on the proliferation, apoptosis, invasion and migration of the human gastric adenocarcinoma cell line AGS.MethodsCells were divided into five experimental groups: Group A, nontransfected control; Group B, transfected with empty vector; Group C, transfected with FAK-shRNA; Group D, erlotinib treatment; Group E, combination erlotinib treatment and transfected with FAK-shRNA. FAK protein levels were confirmed via Western blotting. Cell proliferation (CCK-8 assay, apoptosis (flow cytometry), cell invasion (transwell assay) and migration (scratch assay) were evaluated.ResultsRNA interference significantly decreased FAK protein levels. Cell proliferation, invasion and migration were significantly lower in Groups C, D and E compared with Group A, and significantly lower in Group E than in Groups C and D.ConclusionsRNA interference effectively silences FAK expression and inhibits malignant cell proliferation and invasion in gastric cancer cells. The effect of FAK inhibition is increased by co-treatment with erlotinib.

Immunomodulatory Effects of Psyllium Extract on Helicobacter pylori Interaction With Gastric Epithelial Cells.

Natural plant product Psyllium has anti-inflammatory activity that can modulate the function of cytokines. We determined the effect of Psyllium husk extract on interleukin (IL)-8 and NF-κB secretion by gastric epithelial cells in response to Helicobacter pylori Human gastric adenocarcinoma cell line (AGS) cells were pretreated with Psyllium extract in different concentrations before H pylori infection. Cell culture supernatant was analyzed for IL-8 and NF-κB by ELISA. RNA from cells was used for real-time polymerase chain reaction for messenger RNA expression of IL-8. Psyllium extract 5 and 10 μg/mL markedly (P < .001) lowered basal IL-8 by 64.71% and 74.51%, respectively, and H pylori-stimulated IL-8 was also (P < .001) lowered by 41.67% and 66.67%, respectively. Psyllium 5 and 10 μg/mL also reduced (P < .0001) cagA-positive H pylori-induced IL-8 mRNA expression by 42.3% and 67.6%, respectively. Psyllium also reduced (P = .0001) NF-κB in response to H pylori strains confirming its role as an anti-inflammatory agent.

Curcumin Effect on the Expressional Profile of OCT4, Nanog and Nucleostemin Genes in AGS (Adenocarcinoma) Cancer Cell Line

Background: Curcumin is the natural yellow pigment in turmeric isolated from the rhizome of the plant Curcuma longa. Curcumin inhibits formation and invasive cancer cells and destroys cancer cells resistant to chemotherapeutic drugs. Objectives: The purpose of this study was the survey of effects of different concentrations of alcoholic curcumin on the octamer-binding transcription factor 4 (OCT4) Nanog and Nucleostemin genes in the AGS (human gastric adenocarcinoma) cell line. Materials and Methods: In this experimental study the AGS cell line was cultured in RPMI-1640, supplemented with penicillin/streptomycin (100 U/mL and 100 mg/mL, respectively) and 10% fetal bovine serum, at 37°C in a humidified atmosphere of 5% CO2. In 60 - 70% cell confluence, the cells were treated with curcumin concentration (20, 40, 100) μL and incubated for 24, 48 and 72 hours. Finally, total RNA were extracted and cDNA were synthesized and the expression of mentioned genes was detected. The data were analyzed by excel software. Results: Expression rate of OCT4A, OCT4B, Nanog and Nucleostemin (GLN3) at concentrations less than 20 μg/mL were reduced but OCT4B1 expression showed increased by hours respectively. Conclusions: The results showed that curcumin inhibited cell division; also, this study could be the basis for more extensive studies on the anti-cancer effect of the combined plants.

Constituents from Entada scandens with TRAIL-resistance Overcoming Activity

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL-resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Inductions of Caspase-, MAPK- and ROS-dependent Apoptosis and Chemotherapeutic Effects Caused by an Ethanol Extract of Scutellaria barbata D. Don in Human Gastric Adenocarcinom Cells

Objectives:The crude extracts of Scutellaria barbata D. Don (SB) have traditionally demonstrated inhibitory effects on numerous human cancers both in vitro and in vivo. Gastric cancer is one of the most common types of cancer on world. The authors investigated the effects of an ethanol extract of Scutellaria barbata D. Don (ESB) on the growth and survival of MKN-45 cells (a human gastric adenocarcinoma cell line).Methods:The MKN-45 cells were treated with different concentrations of ESB, and cell death was examined using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Analyses of sub-G1 peaks, caspase-3 and -9 activities, and mitochondrial membrane depolarizations were conducted to determine the anti-cancer effects of SB on MKN-45 cells. Also, intracellular reactive oxygen species (ROS) generation was investigated.Results:ESB inhibited the growth of MKN-45 cells, caused cell cycle arrest, and increased the sub-G1 population. In addition, ESB markedly increased mitochondrial membrane depolarization and the activities of caspase-3 and -9. ESB exerted anti-proliferative effects on MKN-45 cells by modulating the mitogen-activated protein kinase (MAPK) signaling pathway and by increasing the generation of ROS. Furthermore, combinations of anti-cancer drugs plus ESB suppressed cell growth more than treatments with an agent or ESB, and this was especially true for cisplatin, etoposide, and doxorubicin.Conclusion:ESB has a dose-dependent cytotoxic effect on MKN-45 cells and this is closely associated with the induction of apoptosis. ESB-induced apoptosis is mediated by mitochondria- , caspase- and MAPK dependent pathways. In addition, ESB enhances ROS generation and increases the chemosensitivity of MKN-45 cells. These results suggest that treatment with ESB can inhibit the proliferation and promote the apoptosis of human gastric adenocarcinoma cells by modulating the caspase-, MAPK- and ROS-dependent pathway.

Gastrin-induced miR-222 promotes gastric tumor development by suppressing p27kip1.

Background and AimsElevated circulating concentrations of the hormone gastrin contribute to the development of gastric adenocarcinoma and types-1 and 2 gastric neuroendocrine tumors (NETs). MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate proteins which in turn influence various biological processes. We hypothesised that gastrin induces the expression of specific gastric miRNAs within CCK2 receptor (CCK2R) expressing cells and that these mediate functionally important actions of gastrin.ResultsGastrin increased miR-222 expression in AGSGR cells, with maximum changes observed at 10 nM G17 for 24 h. Signalling occurred via CCK2R and the PKC and PI3K pathways. miR-222 expression was increased in the serum and gastric corpus mucosa of hypergastrinemic INS-GAS mice and hypergastrinemic patients with autoimmune atrophic gastritis and type 1 gastric NETs; it decreased in patients following treatment with the CCK2R antagonist netazepide (YF476). Gastrin-induced miR-222 overexpression resulted in reduced expression and cytoplasmic mislocalisation of p27kip1, which in turn caused actin remodelling and increased migration in AGSGR cells.Materials and MethodsmiRNA PCR arrays were used to identify changes in miRNA expression following G17 treatment of human gastric adenocarcinoma cells stably transfected with CCK2R (AGSGR). miR-222 was further investigated using primer assays and samples from hypergastrinemic mice and humans. Chemically synthesised mimics and inhibitors were used to assess cellular phenotypical changes associated with miR-222 dysregulation.ConclusionsThese data indicate a novel mechanism contributing to gastrin-associated gastric tumor development. miR-222 may also be a promising biomarker for monitoring gastrin induced premalignant changes in the stomach.

Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids

BackgroundGastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and...