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The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis.

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Title: The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis.
Authors: Conforti, F
Davies, ER
Calderwood, CJ
Thatcher, TH
Jones, MG
Smart, DE
Mahajan, S
Alzetani, A
Havelock, T
Maher, TM
Molyneaux, PL
Thorley, AJ
Tetley, TD
Warner, JA
Packham, G
Ganesan, A
Skipp, PJ
Marshall, BJ
Richeldi, L
Sime, PJ
O'Reilly, KMA
Davies, DE
Item Type: Journal Article
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects.
Issue Date: 14-Apr-2017
Date of Acceptance: 3-Apr-2017
URI: http://hdl.handle.net/10044/1/48359
DOI: https://dx.doi.org/10.18632/oncotarget.17114
ISSN: 1949-2553
Publisher: Impact Journals
Start Page: 48737
End Page: 48754
Journal / Book Title: Oncotarget
Volume: 8
Copyright Statement: © 2017 The Author(s). This article is available under a Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
pulmonary fibrosis
histone deacetylase Inhibitors
biomarkers
myofibroblasts
epigenomics
COLLAGEN CROSS-LINKING
LYSYL OXIDASE
IN-VITRO
LUNG FIBROSIS
EXPRESSION
CANCER
GROWTH
FK228
FIBROBLASTS
APOPTOSIS
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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