Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart.

Duncan Horlock,Daniel G Donner,Bianca C Bernardo,Julie R Mcmullen,Catherine E Winbanks,Helen Kiriazis,Paul Gregorevic,Xiao-Ming Gao,David M Kaye

doi:10.3390/ph14030263

Abstract

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung disease. We investigated the anti-fibrotic effects of tilorone in human cardiac fibroblasts in vitro by performing a radioisotopic assay for [3H]-proline incorporation as a proxy for collagen synthesis. Exploratory studies in human cardiac fibroblasts treated with tilorone (10 µM) showed a significant reduction in transforming growth factor-β induced collagen synthesis compared to untreated fibroblasts. To determine if this finding could be recapitulated in vivo, mice with established pathological remodelling due to four weeks of transverse aortic constriction (TAC) were administered tilorone (50 mg/kg, i.p) or saline every third day for eight weeks. Treatment with tilorone was associated with attenuation of fibrosis (assessed by Masson’s trichrome stain), a favourable cardiac gene expression profile and no further deterioration of cardiac systolic function determined by echocardiography compared to saline treated TAC mice. These data demonstrate that tilorone has anti-fibrotic actions in human cardiac fibroblasts and the adult mouse heart, and represents a potential novel therapy to treat fibrosis associated with heart failure.

Highlights

IntroductionHeart failure (HF), the end result of a number of cardiovascular disease states, is a life-threatening disorder affecting at least 26 million people worldwide, markedly affecting patients’ quality of life [1]
BMP7 protein had beneficial effects in the prevention of fibrosis in mouse models of Heart failure (HF) [15,16], we investigated the anti-fibrotic effects of tilorone in human cardiac fibroblasts in vitro and in vivo using a mouse model of pathological cardiac remodelling due to pressure overload
In a follow up preliminary study, human cardiac fibroblasts expressed increased levels of collagenous proteins after stimulation with Transforming Growth Factor β (TGFβ) by ~2-fold when compared to untreated fibroblasts (Figure 1)

Summary

Introduction

Heart failure (HF), the end result of a number of cardiovascular disease states, is a life-threatening disorder affecting at least 26 million people worldwide, markedly affecting patients’ quality of life [1]. Caring for patients with HF comes at a significant economic cost, posing a burden on healthcare systems, and placing significant emotional, physical, and financial costs for caregivers. Cardiovascular medicine, and surgery, the outlook for patients with HF remains poor, with almost 50% of patients with HF dying within 5 years of first diagnosis [2,3].

Methods

Results

Discussion

Conclusion