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Endocrine Abstracts (2018) 59 P117 | DOI: 10.1530/endoabs.59.P117

SFEBES2018 Poster Presentations Neoplasia, cancer & late effects (13 abstracts)

Epigenetic inhibitor treatment reduces proliferation via induction of apoptosis in a human typical bronchial carcinoid cell line

Andreas Selberherr 1, , Kate E Lines 1 , Simona Gronzinsky-Glasberg 3 , Chas Bountra 4 & Rajesh V Thakker 1

1OCDEM, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 2Department of Surgery, Medical University of Vienna, Vienna, UK; 3Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4Structural Genomics Consortium, University of Oxford, Oxford, UK.

Neuroendocrine tumours (NETs), occurring at multiple sites including the pancreas, lung and pituitary, are increasing in incidence and usually present at an advanced metastatic stage, and current medical treatments have limited efficacy. Epigenetic modifiers are promising new drugs, as mutations in the multiple endocrine neoplasia type 1 (MEN1) gene, encoding the histone methyltransferase MLL1 interacting protein, menin, are known to cause both familial and sporadic NETs. Moreover, pancreatic and pituitary NETs frequently have mutations of chromatin remodelling genes, and alterations in histone modification. In addition, the epigenetic modifier JQ1, a bromo and extra terminal (BET) protein inhibitor that modulates the transcription of growth stimulating genes, is a potent in vitro and in vivo inhibitor of NET proliferation. An additional 41 compounds interacting with different epigenetic related proteins are now available and could provide improved therapeutic options. We therefore tested their efficacy on proliferation of the pancreatic NET cell line BON-1 and the bronchial typical carcinoid cell line H727. Proliferation was evaluated over five days and compared to JQ1 as positive control, and DMSO treatment as a negative control. GSK-J4, an inhibitor of the KDM6 subfamily of Jumonji demethylases was found to exceed the inhibitory effect of JQ1 in the H727 cell line, significantly reducing proliferation by up to 71% (P<0.0001), compared to 56% for JQ1; GSK-J4 did not alter proliferation of BON-1 cells. Further investigation using a dose escalation study, demonstrated that a concentration of 5mM– of GSK-J4 could specifically, and optimally reduce H727 cell proliferation, compared to equivalent treatment with its inactive isomer GSK-J5. In addition, 5-day GSK-J4 treatment significantly increased apoptosis of H727 cells (by 57%, P<0.05) compared to GSK-J5 control treatment. Thus, our data shows the first epigenetic modifier that effectively reduces proliferation by induction of apoptosis in a typical bronchial carcinoid cell line.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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