Reach further, in an Open Access Journal Endocrinology, Diabetes & Metabolism Case Reports

ISSN 1470-3947 (print)
ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology

Published by BioScientifica
Endocrine Abstracts (2013) 31 P149 
| DOI:10.1530/endoabs.31.P149
|

Epigenetic modifiers reduce proliferation of human neuroendocrine tumour cell lines

Kate E Lines1, Katherine U Gaynor1, Mark Stevenson1, Paul J Newey1, Sian E Piret1, Panagis Filippakopoulos2, Susanne Muller2, Simona Grozinsky-Glasberg3, Ashley B Grossman1, Stefan Knapp2, Christopher Schofield2, Chas Bountra2 & Rajesh V Thakker1

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Neuroendocrine tumours (NETs), occurring at multiple sites including the pancreas, gastrointestinal tract, lung, thymus and pituitary, usually present at an advanced metastatic stage, and are increasing in incidence and prevalence as awareness and diagnostic techniques have improved. Treatments for NETs including surgery, drugs (e.g. somatostatin analogues), chemotherapy, radiotherapy and radionuclide therapy, are often not effective and as such additional therapeutic agents are required. We have assessed the efficacy of eight different compounds known to perturb functions of epigenetic related proteins, on the proliferation, over five days, of three NET cell lines (Bon-1 derived from a pancreatic NET, and H727 and H720 derived from lung NETs). We chose to study epigenetic modifiers as >40% of sporadic NETs are due to mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes the histone methyltransferase MLL1 interacting protein, menin. Moreover, pancreatic NETs also have frequent mutations of chromatin remodelling genes, and pituitary NETs have alterations in histone modification. Two of the compounds, JQ1 and PFI-1, which are inhibitors of bromodomains found on bromo and extra terminal (BET) proteins, that selectively recognise ε-N-acetylated lysine residues, including those present on histone tails, and modulate the transcription of growth stimulating genes, were found to significantly reduce the proliferation of the three NET cell lines. JQ1 reduced proliferation by up to 95% (P<0.0001) and PFI-1 reduced proliferation by up to 40% (P≤0.0002). The potency of these two compounds was subsequently assessed by a dose-titration study. To significantly reduce proliferation (i.e. to 50–60% of wild type) in the Bon-1, H727 and H720 NET cell lines, JQ1 and PFI-1 were required at low concentrations of 20–50 nM, and 100 nM–1 μM respectively. Thus, our data demonstrate that direct inhibitors of histone interacting enzymes are promising potential therapeutic targets for neuroendocrine tumours.

Declaration of funding: This work was supported by the Medical Research Council (grant number G1000467, 2010–2015).

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