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High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation
Michael Rehman, … , Paolo Carloni, Serena Zacchigna
Michael Rehman, … , Paolo Carloni, Serena Zacchigna
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e123987. https://doi.org/10.1172/jci.insight.123987.
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Research Article Cell biology Pulmonology

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

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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.

Authors

Michael Rehman, Simone Vodret, Luca Braga, Corrado Guarnaccia, Fulvio Celsi, Giulia Rossetti, Valentina Martinelli, Tiziana Battini, Carlin Long, Kristina Vukusic, Tea Kocijan, Chiara Collesi, Nadja Ring, Natasa Skoko, Mauro Giacca, Giannino Del Sal, Marco Confalonieri, Marcello Raspa, Alessandro Marcello, Michael P. Myers, Sergio Crovella, Paolo Carloni, Serena Zacchigna

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Figure 8

Haloperidol inhibits αSMA expression by cancer-associated myofibroblasts in vivo.

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Haloperidol inhibits αSMA expression by cancer-associated myofibroblasts...
(A) Schematic of orthotopic lung tumors associated with cancer-associated fibroblasts (cancer cells are indicated in brown). (B) Hematoxylin and eosin staining of representative sections of lungs of mice injected with LG cancer cells into the tail vein, upon treatment with either PBS (control) or haloperidol. (C) αSMA staining (red) of sections of tumor-bearing lungs in mice treated with either PBS (control) or haloperidol. Nuclei are stained blue with Hoechst. (D) Quantification of the tumor area in lungs of mice treated with either PBS or haloperidol (n = 5/gp). (E) Quantification of the number of tumor foci in lungs of mice treated with either PBS or haloperidol (n = 5/gp). (F) Quantification of αSMA+ area in tumor-bearing lungs of mice upon treatment with either PBS or haloperidol (n = 5/gp). (G) Representative images of Ki-67 (white) and αSMA (red) staining in sections of lung in COLL-EGFP mice (fibroblasts in green) treated with PBS (control) or haloperidol. Arrows indicate Ki-67+COLL-EGFP+αSMA+ cells. (H) Quantification of the Ki-67+αSMA+ myofibroblasts in lung cancer sections of COLL-EGFP mice treated with either PBS or haloperidol (n = 5/gp). Scale bars: 1 mm (B) and 50 μm (C and G). Values in D–F and H are mean ± SEM.*P < 0.05, ***P < 0.001 by unpaired t test.

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