Dataset Information

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.

ABSTRACT:

Background

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. Pirfenidone is the first antifibrotic agent to be approved for IPF-treatment as it is able to slow down disease progression. However, there is no curative treatment other than lung transplantation. Because epigenetic alterations are associated with IPF, histone deacetylase (HDAC)-inhibitors have recently been proven to attenuate fibrotic remodeling in vitro and in vivo. This study compared the effects of pirfenidone with the pan-HDAC-inhibitor panobinostat/LBH589, a FDA-approved drug for the treatment of multiple myeloma, head-to-head on survival, fibrotic activity and proliferation of primary IPF-fibroblasts in vitro.

Methods

Primary fibroblasts from six IPF-patients were incubated for 24h with vehicle (0.25% DMSO), panobinostat (LBH589, 85 nM) or pirfenidone (2.7 mM), followed by assessment of proliferation and expression analyses for profibrotic and anti-apoptosis genes, as well as for ER stress and apoptosis-markers. In addition, the expression status of all HDAC enzymes was examined.

Results

Treatment of IPF-fibroblasts with panobinostat or pirfenidone resulted in a downregulated expression of various extracellular matrix (ECM)-associated genes, as compared to vehicle-treated cells. In agreement, both drugs decreased protein level of phosphorylated (p)-STAT3, a transcription factor mediating profibrotic responses, in treated IPF-fibroblasts. Further, an increase in histone acetylation was observed in response to both treatments, but was much more pronounced and excessive in panobinostat-treated IPF-fibroblasts. Panobinostat, but not pirfenidone, led to a significant suppression of proliferation in IPF-fibroblasts, as indicated by WST1- and BrdU assay and markedly diminished levels of cyclin-D1 and p-histone H3. Furthermore, panobinostat-treatment enhanced ?-tubulin-acetylation, decreased the expression of survival-related genes Bcl-XL and BIRC5/survivin, and was associated with induction of ER stress and apoptosis in IPF-fibroblasts. In contrast, pirfenidone-treatment maintained Bcl-XL expression, and was neither associated with ER stress-induction nor any apoptotic signaling. Pirfenidone also led to increased expression of HDAC6 and sirtuin-2, and enhanced ?-tubulin-deacetylation. But in line with its ability to increase histone acetylation, pirfenidone reduced the expression of HDAC enzymes HDAC1, -2 and -9.

Conclusions

We conclude that, beside other antifibrotic mechanisms, pirfenidone reduces profibrotic signaling also through STAT3 inactivation and weak epigenetic alterations in IPF-fibroblasts, and permits survival of (altered) fibroblasts. The pan-HDAC-inhibitor panobinostat reduces profibrotic phenotypes while inducing cell cycle arrest and apoptosis in IPF-fibroblasts, thus indicating more efficiency than pirfenidone in inactivating IPF-fibroblasts. We therefore believe that HDAC-inhibitors such as panobinostat can present a novel therapeutic strategy for IPF.

SUBMITTER: Korfei M

PROVIDER: S-EPMC6258535 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

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.

Korfei Martina M Stelmaszek Daniel D MacKenzie BreAnne B Skwarna Sylwia S Chillappagari Shashipavan S Bach Anna C AC Ruppert Clemens C Saito Shigeki S Mahavadi Poornima P Klepetko Walter W Fink Ludger L Seeger Werner W Lasky Joseph A JA Pullamsetti Soni S SS Krämer Oliver H OH Guenther Andreas A

PloS one 20181127 11

<h4>Background</h4>Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. Pirfenidone is the first antifibrotic agent to be approved for IPF-treatment as it is able to slow down disease progression. However, there is no curative treatment other than lung transplantation. Because epigenetic alterations are associated with IPF, histone deacetylase (HDAC)-inhibitors have recently been proven to attenuate fibrotic remodeling in vitro and in vivo. This study compared ...[more]

PMID: 30481203

Similar Datasets

Project description:Rationale: Two antifibrotic medications, nintedanib and pirfenidone, have been approved for the treatment of idiopathic pulmonary fibrosis (IPF) in the United States. Few data have been published on the use of these medications in clinical practice.Objectives: To investigate patterns of use of antifibrotic medications in the United States.Methods: The Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry, has enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Data from patients enrolled from June 5, 2014, to March 4, 2018, were used to determine antifibrotic medication use ("treatment") in the enrollment window and in a follow-up window approximately 6 months later. Associations between patient characteristics and treatment status were tested using logistic regression.Results: Overall, 551 of 782 eligible patients (70.5%) were treated in the enrollment window. Younger age, lower forced vital capacity percentage predicted, oxygen use with activity, worse self-rated health (based on the Short Form 12 or St. George's Respiratory Questionnaire score), referral to the enrolling center by a pulmonologist, use of a lung biopsy in diagnosis, and carrying a diagnosis of IPF to the enrolling center were associated with being treated. Among 534 patients treated at enrollment who had follow-up data, 94.0% remained treated in follow-up. Better self-rated health (based on the Short Form 12 mental component score or EuroQoL score) and not using oxygen with activity at enrollment were associated with continuing treatment in follow-up. Among 172 patients who were untreated at enrollment and had follow-up data, 29.7% started treatment in follow-up. Lower diffusing capacity of the lung for carbon monoxide percentage predicted, a family history of interstitial lung disease, a history of sleep apnea, and a definite diagnosis of IPF at enrollment were associated with starting treatment in follow-up.Conclusions: The majority of patients in the IPF-PRO Registry were receiving an approved medication for IPF at enrollment. Treatment at enrollment was associated with greater disease severity, more compromised quality of life, and the use of oxygen with activity.Clinical trial registered with ClinicalTrials.gov (NCT01915511).

Project description:Purpose: Pirfenidone and nintedanib are two novel antifibrotic agents licensed for the treatment IPF. Prior to being approved for use in England for patients with FVC >50% and <80%, these were made available for all IPF patients under the Mild Patient Program (MPP) and Patient In Need Scheme (PIN). Prescribing of these medications is restricted to specialist centers. We sought to characterize the population of patients prescribed antifibrotics and determine the drug tolerability of these medications in the Northern hub of the Southwest of England regional ILD network. Methods: A retrospective analysis of all patients treated with antifibrotics between August 2012 and July 2017 was undertaken. Baseline characteristics including patient demographics and pulmonary physiology, in addition to drug tolerability and reasons for treatment cessation were collated. Data were compared using unpaired student's t-test, Chi-squared, Mann-Whitney rank sum or ANOVA as appropriate. Logistic regression analysis evaluated clinical characteristics associated with discontinuation of pirfenidone therapy. P < 0.05 was considered statistically significant. Findings: A total of 164 patients, all with consensus diagnoses of IPF, were identified. Of these, 70.1% (115/164) received pirfenidone as their initial therapy. Baseline age, gender and pulmonary physiology did not differ significantly between groups. Drug discontinuation occurred most commonly due to adverse drug reactions events (ADRs) for both pirfenidone [40.0% (46/115)] and nintedanib [16.3% (8/49)]. Anorexia, rash and gastrointestinal disturbance were reported most commonly as the reason for cessation of pirfenidone; anorexia, nausea and weight loss for nintedanib. Duration of therapy prior to discontinuation because of ADRs did not differ significantly between medication groups but patients with a baseline FVC < 65% predicted, had a significantly shorter duration of pirfenidone prior to discontinuation due to ADRs, compared to those with a FVC 65-80% predicted. Multivariate logistic regression did not identify any independent baseline characteristics that predicted discontinuation of pirfenidone therapy prior to 52 weeks. Implications: Idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib had comparable treatment emergent adverse event (TEAE) profiles in clinical practice to those reported in clinical trials. The TEAE profile of pirfenidone was higher than clinical trial data would suggest, although comparable to real-world datasets. Further work is required to explore the possible reasons underpinning this finding, including whether this is related to population co-morbidities or center threshold. No new safety concerns were identified.

Dataset Information

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.

Background

Methods

Results

Conclusions

Publications

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.

Similar Datasets

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