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

Abstract

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)-b1 with or without SAHA. Collagen deposition, a-smooth muscle actin (a-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-b1 effects on all the fibroblast lines by preventing their transdifferentiation into a-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 a-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.

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

“…In addition, MS-275 and SAHA suppressed lipo poly saccharide (LPS)-induced NFκB p65 nuclear accumulation, IL-6, IL-18 and nitric oxide (NO) secretion as well as downregulated proangiogenic VEGF and MMP-2 and MMP-9 production in E11 cells at submicromolar levels (47). TSA or SAHA decreased fibroblast proliferation and extracellular matrix production in murine models of fibrosis (53), and blocked transforming growth factor β-(TGFβ) induced differentiation of fibroblasts into myofibroblasts and impaired epithelial-mesenchymal transformation both in vitro and in vivo. HDACi also can inhibit production of matrix metalloproteinases (MMPs) that contribute to tissue destruction (for example, via collagen and aggrecan breakdown) in inflammatory disease (54).…”

Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice

“…However, a TSA structural analogue, suberoylanilide hydroxamic acid (SAHA) (Vorinostat; Merck, Whitestation, NJ, USA), is currently being investigated in a number of clinical trials, and is the first US Food and Drug Administration approved HDACi to treat cutaneous T-cell lymphoma [8]. Previously, studies have indicated that TSA and SAHA have anti-inflammatory [9] and anti-fibrotic properties [10][11][12] in fibroblasts, such as inhibition of cell proliferation, collagen production and myofibroblastic differentiation. However, few studies have explored the mechanisms and effects of SAHA on apoptosis and their mechanisms in IPF fibroblasts.…”

Suppression of proinflammatory cytokine production by suberoylanilide hydroxamic acid an inhibitor of histone deacetylases

“…By inhibition of HDACs activity these compounds induce cellcycle arrest and apoptosis (9,10). In addition, there were increasing evidence suggesting that HDAC inhibitors, influenced proinflammatory cytokine synthesis (10,14).…”

“…Although histone acetylation is generally associated with transcriptional activation, HDI can either increase or decrease expression of specific genes. HDI are of prime interest in cancer research because they induce apoptosis and cell cycle arrest in malignant cells and are anti-angiogenic (9,10). Suberoylanilide Hydroxamic Acid (SAHA) is the HDI targeted to the class I and class II HDAC enzymes (7).…”