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Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?

¹ Tissue Modulation Laboratory, Division of Bioengineering, Faculty of Engineering, ² Dept of Physiology, National University of Singapore, ⁵ NUS Tissue Engineering Program, Dept of Orthopedic Surgery, ⁶ Dept of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, ³ Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany, and ⁴ Molecular Hepatology, School of Medicine and Pharmacology, Faculty of Medicine, Dentistry and Heath Sciences, The University of Western Australia, Perth, Australia.

CORRESPONDENCE: M. Raghunath, Division of Bioengineering, Faculty of Engineering, and Dept of Biochemistry, Yong Loo Lin School of Medicine, Division Office Block E3A #04-15, 7 Engineering Dr. 1, Singapore 117574. E-mail: bierm{at}nus.edu.sg

Keywords: Antifibrotic, collagen, fibroblast, histone deacetylase inhibitor, pulmonary fibrosis, suberoylanilide hydroxamic acid

Received: June 5, 2008
Accepted January 25, 2009

Pulmonary fibrosis represents a fatal stage of interstitial lung diseases of known and idiopathic aetiology. No effective therapy is currently available. Based on an indication-discovery approach we present novel in vitro evidence that the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA), an FDA approved anti-cancer drug, has antifibrotic and anti-inflammatory potential.

Human lung fibroblasts (fetal, adult and idiopathic adult pulmonary fibrosis) were treated with transforming growth factor (TGF)-β1 with or without SAHA. Collagen deposition, -smooth muscle actin (-SMA) expression, matrix metalloproteinase (MMP)1 activity, tissue inhibitor of MMP (TIMP)1 production, apoptosis and cell proliferation were assessed. Pro-inflammatory cytokines relevant to pulmonary fibrosis were assayed in SAHA-treated human peripheral blood mononuclear cells (PBMC) and its subpopulations.

SAHA abrogated TGF-β1 effects on all the fibroblast lines by preventing their transdifferentiation into -SMA positive myofibroblasts and increased collagen deposition without inducing apoptosis. However, MMP1 activity and TIMP1 production was modulated without a clear fibrolytic effect. SAHA also inhibited serum-induced proliferation of the fibroblast lines and caused hyperacetylation of -tubulin and histone. Cytokine secretion was inhibited from PBMC and lymphocytes at nonapoptotic concentrations.

Taken together, these data demonstrate combined antifibrotic and anti-inflammatory properties of SAHA, suggesting its therapeutic potential for pulmonary fibrosis.

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