The Biological and Therapeutic Importance of Gastrin Gene Expression in Pancreatic Adenocarcinomas

Harris, Joseph C.; Gilliam, Andrew D.; McKenzie, Andrew J.; Evans, Sean A.; Grabowska, Anna; Clarke, Paula J.; McWilliams, Daniel F.; Watson, Sue‐Ann

doi:10.1158/0008-5472.can-04-0106

Cited by 31 publications

(23 citation statements)

References 33 publications

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“…Results for the chemotherapeutic agents were expressed as a relative percentage of total cellular metabolism compared with untreated controls (controls expressed as 100%). Additive and synergistic effects were calculated based on a previously described formula (24).…”

Section: Methodsmentioning

confidence: 99%

Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling

Levitt

Yamashita

Jian

et al. 2010

Molecular Cancer Therapeutics

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Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo.In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects. Mol Cancer Ther; 9(5); 1128-35. ©2010 AACR.

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Section: Methodsmentioning

confidence: 99%

Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling

Levitt

Yamashita

Jian

et al. 2010

Molecular Cancer Therapeutics

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“…The results were expressed as a relative percentage of viable cells compared with nontreated controls (with controls expressed as 100%). Additive and synergistic effects were calculated based on a previously described formula (25).…”

Section: Methodsmentioning

confidence: 99%

Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine

Jian

Yamashita²,

Levitt³

et al. 2009

Molecular Cancer Therapeutics

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Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-β and the phosphatidylinositol 3-kinase/AKT pathways. We preclinically evaluated enzastaurin alone and in combination with gemcitabine for transitional cell cancer (TCC). Immunohistochemistry (IHC) was done on 105 human samples from a microarray to show the expression of PKC-β. The preclinical antitumor activity of enzastaurin and gemcitabine as single agents and in combination against aggressive human -lines (-SUP and 5637) and murine subcutaneous xenografts bearing 5637 cells was determined. Western Blot was done on tumor cells in vitro to detect signaling through PKC-β, GSK-3β, and AKT. The effect on cell migration was determined in vitro. Modulation of proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (CD31) in vivo was determined by IHC. IHC done on human TCC samples from a microarray showed the expression of PKC-β in 33% of tumors. Enzastaurin induced significant apoptosis and inhibited proliferation in vitro at low micromolar concentrations. The in vitro inhibitory activity of combination enzastaurin and gemcitabine by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay seemed synergistic. Western Blotting revealed down-regulation of Akt, PKC-β, and GSK-3 β phosphorylation. Enzastaurin inhibited migration at an earlier time point independent of antiproliferative activity. Combination therapy had significantly superior antitumor activity in murine xenografts compared with untreated controls, whereas single agents did not. IHC showed reduced Ki-67 and CD31 and increased cleaved caspase-3 with combination therapy compared with controls. Enzastaurin showed preclinical antitumor activity against human TCC and enhanced the activity of gemcitabine.

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“…MGLVA1 and ST16 cells had been transfected with either pCR3.1 containing the entire gastrin cDNA in the antisense direction or an empty vector control (32). Individual clones with maximal expression from the vectors were isolated and used in this study.…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

Dickson¹,

Grabowska²,

El–Zaatari³

et al. 2006

Cancer Research

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Both gastrin and Helicobacter pylori have been shown capable of up-regulating gene expression and protein shedding of heparin-binding epidermal growth factor (HB-EGF). Furthermore, the bacteria have previously been shown to induce serum hypergastrinemia in infected individuals. The aim of this work was to assess the extent to which the ability of H. pylori to upregulate expression of HB-EGF can be attributed to its effect on gastrin. Gastric cells, transfected with either gastrin small interfering RNA or antisense plasmid or the gastrin/cholecystokinin-2 receptor (CCK-2R), were cultured for 24 hours with H. pylori +/À , a CCK-2R antagonist. Gene expression levels were measured using reverse transcription-PCR, whereas protein changes were measured using ELISA, Western blotting, and immunofluorescence. H. pylori induced significantly higher levels of HB-EGF gene expression and ectodomain shedding in the CCK-2R-transfected cells than the vector control (P < 0.01). Addition of the CCK-2R inhibitor significantly decreased gene and shedding up-regulation. Gastrin down-regulation reduced the effect of the bacteria on HB-EGF gene and protein expression levels. Endogenous gastrin and CCK-2R expression were also found to be significantly up-regulated in all cell lines as a result of exposure to H. pylori (P < 0.02). Gastric mucosal tissue from H. pylori-infected individuals had significantly higher CCK-2R expression levels than noninfected (P < 0.003), and in hypergastrinemic mice, there was an increase in HB-EGF-expressing cells in the gastric mucosa and colocalization of HB-EGF with CCK-2R-positive enterochromaffin-like cells. In conclusion, gastrin and the CCK-2R play significant roles in the induction of HB-EGF gene and protein expression and ectodomain shedding by H. pylori. (Cancer Res 2006; 66(15): 7524-31)

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The Biological and Therapeutic Importance of Gastrin Gene Expression in Pancreatic Adenocarcinomas

Cited by 31 publications

References 33 publications

Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling

Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling

Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

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