Panobinostat, an approved treatment for multiple myeloma, exerts anti-fibrotic activity, inducing cell death and reducing the proliferation of lab-grown fibroblasts from idiopathic pulmonary fibrosis (IPF) patients, a preclinical study reports.
The data also suggest that, despite an ability to inhibit cellular pathways involved in fibrosis, approved IPF therapy Esbriet (pirfenidone, marketed by Genentech) is not as effective as panobinostat in blocking the growth of IPF fibroblasts.
The study, “Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis,” was published in the journal PLOS ONE.
Studies have shown that IPF progression is linked to alterations in proteins important for DNA structure and function, called histones. Specifically, some studies have shown that inhibitors of a type of histone-modifying enzyme called a histone deacetylase (HDAC; responsible for removing chemical groups called acetylations) are able to reduce fibrotic changes in lab cultures of cells (in vitro) and animal models (in vivo).
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One of these HDAC inhibitors is panobinostat (LBH589), a therapy marketed by Novartis under the brand name Farydak, which is approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma.
Based on these preliminary positive data, the present study was aimed at comparing the anti-fibrotic activity of Esbriet with that of panobinostat in lung cells (namely fibroblasts) collected from IPF patients. The goal of the study was to gather preclinical data “to evaluate the potential use of panobinostat as additional, future IPF therapy,” according to the researchers.
Lung fibroblasts collected from six IPF patients were exposed in the laboratory to either panobinostat, Esbriet, or a control solution.
Results showed that treatment with either one of the therapies reduced the expression of many pro-fibrotic genes, compared with control-treated cells. In line with this, both therapies also induced a decrease in the active form of a factor important for fibrotic responses, referred to as STAT3.
However, panobinostat, but not Esbriet, significantly suppressed the proliferation of IPF fibroblasts, as indicated by a marked reduction in the levels of several replication markers. The therapy also induced a type of cell death called apoptosis in fibroblasts.
Researchers concluded that Esbriet “reduces profibrotic signaling also through STAT3 inactivation,” but the therapy allows the “survival of (altered) fibroblasts.”
In contrast, panobinostat reduces pro-fibrotic signals, while it also inhibits cell proliferation and promotes the cell death of IPF fibroblasts.
According to the team, panobinostat “clearly was more efficient than pirfenidone [Esbriet] in inactivating IPF-fibroblasts, through induction of cell cycle arrest and apoptosis, an effect pirfenidone did not exert.”
Therefore, they believe that “HDAC-inhibitors such as panobinostat can present a novel therapeutic strategy for IPF.”
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