A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

Höpfner, Michael; Sutter, Andreas; Huether, Alexander; Ahnert‐Hilger, Gudrun; Scherübl, Hans

doi:10.1186/1471-2407-4-23

Cited by 29 publications

(13 citation statements)

References 50 publications

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“…These observations suggest that infection and inflammation of the GI tract cause significant alteration in enterochromaffin cell function and 5-HT production and the immunological profile of the inflammatory response may be an important determinant of the changes that occur in the 5-HT response in the gut. Our findings on Th1/Th2 regulation of enterochromaffin cell biology corroborate with recent studies on lower numbers of enterochromaffin cells and a lower amount of 5-HT in Th1-biased bacterial infection with C rodentium 31 and on the inhibitory effect of IFN-γ on the proliferation of BON tumour cells (model of human enterochromaffin cells) 32. Related to this it has recently been shown that the rate of epithelial cell turnover in the large intestine was higher in resistant BALB/c mice in T muris infection compared with that in susceptible AKR mice and that the rate of epithelial cell movement is under immune control by IL13 33.…”

Section: Discussionsupporting

confidence: 91%

Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in Th1 and Th2 dominant environments

Motomura

Ghia

Wang

et al. 2007

Gut

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The study demonstrated that enterochromaffin cell and 5-HT responses to the same infectious agent are influenced by Th1 or Th2 cytokine predominance and suggests that the immunological profile of the inflammatory response is important in the regulation of enterochromaffin cell biology in the gut. In addition to new data on enterochromaffin cell function in enteric infection and inflammation, this study provides important information on the immuno-endocrine axis in the gut, which may ultimately lead to improved strategies against gut disorders.

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Section: Discussionsupporting

confidence: 91%

Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in Th1 and Th2 dominant environments

Motomura

Ghia

Wang

et al. 2007

Gut

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“…Moreover, in vitro studies using BON tumour cells (model of human EC cells) have shown that interferon c exerts antiproliferative effects on these cells and inhibits 5-HT production from these cells. 42 Our present results provide clear evidence of CD4 + T cell-mediated immunological control of EC cell hyperplasia and 5-HT production in intestinal infection and CD4 + T cells in 5-HT production inflammation. The transfer of purified CD4 + T cells from infected mice into naive SCID mice significantly increased the number of EC cells and the amount of 5-HT.…”

Section: Discussionsupporting

confidence: 64%

CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection

Wang

Steeds

Motomura

et al. 2007

Gut

110

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Background: Enterochromaffin (EC) cells are dispersed throughout the gastrointestinal (GI) mucosa and are the main source of 5-hydroxytryptamine (5-HT) in the gut. 5-HT has been implicated in the pathophysiology of several GI disorders, but the mechanisms regulating 5-HT production in the gut are unknown. Aim: To investigate the role of CD4 + T cells in the production of 5-HT using a model of enteric parasitic infection. Methods and results: Severe combined immunodeficient (SCID) mice and their wild-type controls were infected with the nematode Trichuris muris and killed on various days after infection to study colonic EC cells and 5-HT production. The number of EC cells and the amount of 5-HT produced were significantly higher in infected wild-type mice than in non-infected mice. The number of EC cells and the amount of 5-HT after infection were significantly lower in SCID mice after infection than in wild-type mice. The number of EC cells and the amount of 5-HT was significantly increased after reconstitution of SCID mice with CD4 + T cells from infected mice and this was accompanied by an upregulation of colonic CD3 T cells and T helper 2 (Th2) cytokines. Laser capture microdissection-based molecular and immunofluorescence techniques revealed the presence of interleukin 13 receptor a1-chain on EC cells. Conclusion: These results show an important immunoendocrine axis in the gut, where secretory products from CD4 + T cells interact with EC cells to enhance the production of 5-HT in the gut via Th2-based mechanisms. These results show new insights into the mechanisms of gut function, which may ultimately lead to improved therapeutic strategies in functional and inflammatory disorders of the GI tract.

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“…Western blotting was performed as described previously [30] . In brief, whole-cell extracts were prepared by lysing cells.…”

Section: Western Blot Analysismentioning

confidence: 99%

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

Baradari

Höpfner²,

Huether³

et al. 2007

WJG

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AIM:To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib. METHODS:Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry. RESULTS:MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21 Waf/CIP1 . Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multikinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects. CONCLUSION:The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.

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A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

Cited by 29 publications

References 50 publications

Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in Th1 and Th2 dominant environments

Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in Th1 and Th2 dominant environments

CD4+ T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection

Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells

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