Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors

Oncogenesis
K E LinesRajesh V Thakker

Abstract

Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, and inhibitors targeting epigenetic mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year survivals of <50% and as low as 5%, respectively, represent targets for such drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies histones by interacting with histone methyltransferases. We assessed 9 inhibitors of epigenetic pathways, for their effects on proliferation, by CellTiter Blue assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the bromo and extra terminal (BET) protein family which bind acetylated histone residues, were most effective in decreasing proliferation (by 40-85%, P<0.001) and increasing apoptosis (by 2-3.6 fold, P<0.001) in all 3 NET cell lines. The anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, assessed by pro...Continue Reading

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Citations

Apr 5, 2018·Journal of Molecular Endocrinology·Sucharitha Iyer, Sunita K Agarwal
Aug 16, 2017·Endocrine-related Cancer·Koen M A DreijerinkMyles Brown
Jul 27, 2017·Endocrine-related Cancer·Hermine Mohr, Natalia S Pellegata
Aug 5, 2017·Endocrine-related Cancer·Rachel S van LeeuwaardeGerlof D Valk
Nov 6, 2018·The Journal of Endocrinology·Kate E LinesRajesh V Thakker
Feb 17, 2018·Nature Reviews. Endocrinology·Morten FrostRajesh V Thakker
Jan 2, 2021·Frontiers in Endocrinology·Annamaria ColaoClaudio Napoli
Aug 12, 2020·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Kreepa G KooblallRajesh V Thakker
Nov 30, 2020·Endocrine Reviews·Maria Luisa BrandiRajesh V Thakker
Apr 1, 2021·Current Treatment Options in Oncology·Alejandro Garcia-AlvarezJaume Capdevila
May 1, 2021·International Journal of Molecular Sciences·Francesca MariniMaria Luisa Brandi

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Methods Mentioned

BETA
histone acetylation
PCR
RNA-Seq
acetylation
Assay

Software Mentioned

ImageJ
Picard Tools
edgeR
Ensembl
Cellquest pro
Elements BR
NIS
TopHat2
FloJo

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