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

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 ?-smooth muscle actin (?SMA) 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-? 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 ?SMA. 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.

SUBMITTER: Rehman M

PROVIDER: S-EPMC6538355 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Rehman Michael M Vodret Simone S Braga Luca L Guarnaccia Corrado C Celsi Fulvio F Rossetti Giulia G Martinelli Valentina V Battini Tiziana T Long Carlin C Vukusic Kristina K Kocijan Tea T Collesi Chiara C Ring Nadja N Skoko Natasa N Giacca Mauro M Del Sal Giannino G Confalonieri Marco M Raspa Marcello M Marcello Alessandro A Myers Michael P MP Crovella Sergio S Carloni Paolo P Zacchigna Serena S

JCI insight 20190418 8

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 haloper ...[more]

PMID: 30996132

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Dataset Information

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

Publications

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

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