SFEBES2014 Poster Presentations Neoplasia, cancer and late effects (25 abstracts)
Bromodomain inhibitors reduce proliferation and increase apoptosis of human neuroendocrine tumour cells
Kate E Lines 1 , Mark Stevenson 1 , Katherine U Gaynor 1 , Paul J Newey 1 , Sian E Piret 1 , Hannah Lingard 2 , Panagis Filippakopoulos 2 , Susanne Muller 2 , Simona Grozinsky-Glasberg 3 , Ashley Grossman 1 , Stefan Knapp 2 , Chris Schofield 2 , Chas Bountra 2 & Rajesh V Thakker 1
1Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK; 2Structural Genomics Consortium, University of Oxford, Oxford, UK; 3Neuroendocrine Tumour Unit, Endocrinology & Metabolism Service, Department of Medicine,Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Pancreatic neuroendocrine tumours (NETs) are reported to show frequent mutations in chromatin remodelling genes, while pituitary NETS have alterations in histone modification. Histone modifications, and specifically acetylated residues on histone tails are recognised by members of the bromo and extra terminal (BET) protein family, via their bromodomains, causing alterations in the transcription of growth stimulating genes. BET bromodomain inhibitors have been demonstrated to successfully reduce tumour growth in mouse models, including those for nuclear protein in testis (NUT)-midline carcinoma, non-small cell lung cancer, leukaemia and glioblastoma. We therefore assessed the efficacy of two pan-BET inhibitors, JQ1 and PFI-1, on proliferation, apoptosis and senescence of three human NET cell lines (BON-1 cells derived from a pancreatic NET, and H727 and H720 cells derived from lung NETs) and one mouse cell line (AtT20 cells derived from the pituitary). Proliferation was assessed by the Cell Titre Blue fluorescent assay, apoptosis by caspase 3/7 cleavage, and cellular senescence by β-galactosidase (X-gal) staining. Our results show that JQ1 and PFI-1 had significant effects on proliferation, apoptosis and senescence. Thus, in all four cell lines JQ1 reduced proliferation by up to 95% (P<0.0001), with an average IC60 of 36 nM, while PFI-1 reduced proliferation by up to 40% (P≤0.0002), with an average IC60 of 800 nM. JQ1 also significantly increased apoptosis by up to 3.5-fold (P<0.0005) in all four cell lines, and PFI-1 increased apoptosis in BON-1 and H720 cells by up to twofold (P<0.05). JQ1 significantly increased cellular senescence, of BON-1 and H727 cells, by up to sixfold (P<0.0001) and PFI-1 significantly increased senescence of BON-1 cells by twofold (P>0.0005). Thus, our data demonstrate that BET protein inhibitors may represent potential compounds for the treatment of neuroendocrine tumours.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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