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

Conforti, Franco, Davies, Elizabeth R., Calderwood, Claire J., Thatcher, Thomas H., Jones, Mark G., Smart, David E., Mahajan, Sumeet, Alzetani, Aiman, Havelock, Tom, Maher, Toby M., Molyneaux, Philip L., Thorley, Andrew J., Tetley, Teresa D., Warner, Jane A.­, Packham, Graham, Ganesan, A. ORCID: https://orcid.org/0000-0003-4862-7999, Skipp, Paul J., Marshall, Benjamin J., Richeldi, Luca, Sime, Patricia J., O’reilly, Katherine M.a. and Davies, Donna E. (2017) The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis. Oncotarget, 8. pp. 48737-48754. ISSN 1949-2553

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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.

Item Type:	Article
Uncontrolled Keywords:	pulmonary fibrosis,histone deacetylase inhibitors,biomarkers,myofibroblasts,epigenomics
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Related URLs:	http://www.oncotarget.com/abstract/17114
Depositing User:	Pure Connector
Date Deposited:	24 May 2017 05:04
Last Modified:	02 Dec 2024 01:26
URI:	https://ueaeprints.uea.ac.uk/id/eprint/63593
DOI:	10.18632/oncotarget.17114

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