High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

JCI Insight. 2019 Apr 18;4(8):e123987. doi: 10.1172/jci.insight.123987.

Abstract

Fibrosis is a hallmark in the pathogenesis of various diseases, with very limited therapeutic solutions. A key event in the fibrotic process is the expression of contractile proteins, including α-smooth muscle actin (αSMA) by fibroblasts, which become myofibroblasts. Here, we report the results of a high-throughput screening of a library of approved drugs that led to the discovery of haloperidol, a common antipsychotic drug, as a potent inhibitor of myofibroblast activation. We show that haloperidol exerts its antifibrotic effect on primary murine and human fibroblasts by binding to sigma receptor 1, independent from the canonical transforming growth factor-β signaling pathway. Its mechanism of action involves the modulation of intracellular calcium, with moderate induction of endoplasmic reticulum stress response, which in turn abrogates Notch1 signaling and the consequent expression of its targets, including αSMA. Importantly, haloperidol also reduced the fibrotic burden in 3 different animal models of lung, cardiac, and tumor-associated fibrosis, thus supporting the repurposing of this drug for the treatment of fibrotic conditions.

Keywords: Cell Biology; Drug screens; Fibrosis; Pulmonology; Signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Actins / metabolism
  • Animals
  • Calcium / metabolism
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Drug Repositioning
  • Endoplasmic Reticulum Stress / drug effects
  • Fibrosis / drug therapy*
  • Fibrosis / pathology
  • Haloperidol / pharmacology*
  • Haloperidol / therapeutic use
  • Humans
  • Intravital Microscopy / methods
  • Lung / cytology
  • Lung / pathology
  • Mice
  • Myocardium / cytology
  • Myocardium / pathology
  • Myofibroblasts / drug effects*
  • Myofibroblasts / pathology
  • Optical Imaging / methods
  • Primary Cell Culture
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, Notch1 / metabolism
  • Receptors, sigma / genetics
  • Receptors, sigma / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Actins
  • RNA, Small Interfering
  • Receptor, Notch1
  • Receptors, sigma
  • sigma-1 receptor
  • Haloperidol
  • Calcium

Grant support

Fellowship to M.R.