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A drug screen with approved compounds identifies amlexanox as a novel Wnt/β-catenin activator inducing lung epithelial organoid formation.

Br. J. Pharmacol., DOI: 10.1111/bph.15581 (2021)
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Open Access Green: Postprint online verfügbar 07/2022

Background and purpose: Emphysema is an incurable disease characterized by loss of lung tissue leading to impaired gas exchange. Wnt/β-catenin signaling is reduced in emphysema and exogenous activation of the pathway in experimental models in vivo and in human ex vivo lung tissue improves lung function and structure. We sought to identify a pharmaceutical able to activate Wnt/β-catenin signaling and asses its potential to activate lung epithelial cells and repair.

Experimental approach: We screened 1216 human-approved compounds for Wnt/β-catenin signaling activation using luciferase reporter cells, and selected candidates based on their computational predicted protein targets. We further performed confirmatory luciferase reporter and metabolic activity assays. Finally, we studied the regenerative potential in murine adult epithelial cell derived lung organoids and in vivo using a murine elastase-induced emphysema model.

Key results: The primary screen identified 16 compounds that significantly induced Wnt/β-catenin-dependent luciferase activity. Selected compounds activated Wnt/β-catenin signaling without inducing cell toxicity or proliferation. Two compounds were able to promote organoid formation, which was reversed by pharmacological Wnt/β-catenin inhibition, confirming the Wnt β-catenin-dependent mechanism of action. Amlexanox was used for in vivo evaluation and preventive treatment resulted in improved lung function and structure in emphysematous mouse lungs. Moreover, gene expression of Hgf, an important alveolar repair marker, was increased, whereas disease marker Eln was decreased, indicating that amlexanox induces pro-regenerative signaling in emphysema.

Conclusion and implications: Using a drug screen based on Wnt/β-catenin activity, organoid assays, and a murine emphysema model, amlexanox was identified as a novel potential therapeutic for emphysema.

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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Organoids ; Regenerative Medicine ; Wnt/β-catenin Signaling Pathway ; Amlexanox ; Chronic Obstructive Pulmonary Disease ; Emphysema; Hepatocyte Growth-factor; Concise Guide; Ikk-epsilon; Copd; Repair; Regeneration; Apoptosis; Platform; Update; Tbk1
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Förderungen H2020 European Research Council
Deutsche Zentrum für Lungenforschung