Niclosamide alleviates pulmonary fibrosis in vitro and in vivo by attenuation of epithelial-to-mesenchymal transition, matrix proteins & Wnt/β-catenin signaling: A drug repurposing study

Life Sci. 2019 Mar 1;220:8-20. doi: 10.1016/j.lfs.2018.12.061. Epub 2019 Jan 3.

Abstract

Drug repurposing off late has been emerging as an inspiring alternative approach to conventional, exhaustive and arduous process of drug discovery. It is a process of identifying new therapeutic values for a drug already established for the treatment of a certain condition. Our current study is aimed at repurposing the old anti-helimenthic drug Niclosamide as an anti-fibrotic drug against pulmonary fibrosis (PF). PF is most common lethal interstitial lung disease hallmarked by deposition of extracelluar matrix and scarring of lung. Heterogenous nature, untimely diagnosis and lack of appropriate treatment options make PF an inexorable lung disorder. Prevailing void in PF treatment and drug repositioning strategy of drugs kindled our interest to demonstrate the anti-fibrotic activity of Niclosamide. Our study is aimed at investigating the anti-fibrotic potential of Niclosamide in TGF-β1 induced in vitro model of PF and 21-day model of Bleomycin induced PF in vivo respectively. Our study results showed that Niclosamide holds the potential to exert anti-fibrotic effect by hampering fibroblast migration, attenuating EMT, inhibiting fibrotic signaling and by regulating WNT/β-catenin signaling as evident from protein expression studies. Our study findings can give new directions to development of Niclosamide as an anti-fibrotic agent for treatment of pulmonary fibrosis.

Keywords: EMT; Niclosamide; Pulmonary fibrosis; Wnt/β-catenin.

MeSH terms

  • Animals
  • Bleomycin
  • Cell Culture Techniques
  • Cell Survival / drug effects
  • Drug Repositioning / methods
  • Epithelial Cells / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Fibroblasts / drug effects
  • Humans
  • Lung / metabolism
  • Male
  • Mice
  • Niclosamide / pharmacology*
  • Pulmonary Fibrosis / drug therapy*
  • Transforming Growth Factor beta1 / metabolism
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / drug effects

Substances

  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • beta Catenin
  • Bleomycin
  • Niclosamide