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

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis
The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis
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.
1949-2553
1-18
Conforti, Franco
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Davies, Elizabeth R.
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Calderwood, Claire J.
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Thatcher, Thomas H.
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Jones, Mark G.
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Smart, David E.
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Mahajan, Sumeet
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Alzetani, Aiman
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Havelock, Tom
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Maher, Toby M.
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Molyneaux, Philip L.
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Thorley, Andrew J.
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Tetley, Teresa D.
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Warner, Jane A.
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Packham, Graham
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Ganesan, A.
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Skipp, Paul J.
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Marshall, Benjamin J.
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Richeldi, Luca
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Sime, Patricia J.
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O'Reilly, Katherine M.A.
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Davies, Donna E.
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Conforti, Franco
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Davies, Elizabeth R.
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Calderwood, Claire J.
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Thatcher, Thomas H.
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Jones, Mark G.
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Smart, David E.
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Mahajan, Sumeet
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Alzetani, Aiman
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Havelock, Tom
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Maher, Toby M.
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Molyneaux, Philip L.
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Thorley, Andrew J.
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Tetley, Teresa D.
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Warner, Jane A.
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Packham, Graham
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Ganesan, A.
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Skipp, Paul J.
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Marshall, Benjamin J.
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Richeldi, Luca
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Sime, Patricia J.
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O'Reilly, Katherine M.A.
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Davies, Donna E.
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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., 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, 1-18. (doi:10.18632/oncotarget.17114).

Record type: 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.

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17114-250869-3-PB - Version of Record
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Accepted/In Press date: 3 April 2017
e-pub ahead of print date: 14 April 2017
Published date: 14 April 2017
Organisations: Cancer Sciences, Institute for Life Sciences, Allergy & Inflammation Research, Support Staff - Technical, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 408662
URI: https://eprints.soton.ac.uk/id/eprint/408662
ISSN: 1949-2553
PURE UUID: d7629908-13de-4b7a-8fd2-85f68aacf39c
ORCID for Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Paul J. Skipp: ORCID iD orcid.org/0000-0002-2995-2959
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991

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Date deposited: 25 May 2017 04:03
Last modified: 10 Dec 2019 01:59

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Contributors

Author: Franco Conforti
Author: Elizabeth R. Davies
Author: Claire J. Calderwood
Author: Thomas H. Thatcher
Author: Mark G. Jones
Author: David E. Smart
Author: Sumeet Mahajan ORCID iD
Author: Aiman Alzetani
Author: Tom Havelock
Author: Toby M. Maher
Author: Philip L. Molyneaux
Author: Andrew J. Thorley
Author: Teresa D. Tetley
Author: Jane A. Warner
Author: Graham Packham ORCID iD
Author: A. Ganesan
Author: Paul J. Skipp ORCID iD
Author: Luca Richeldi
Author: Patricia J. Sime
Author: Katherine M.A. O'Reilly
Author: Donna E. Davies ORCID iD

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