Fraunhofer-Institut für Toxikologie und Experimentelle MedizinScreening Naturstoff-basierter Wirkstoffe identifiziert Substanzen mit hoher Wirksamkeit gegen Organfibrosen
Forschende des Fraunhofer ITEM, der Medizinischen Hochschule Hannover und des Helmholtz-Zentrums für Infektionsforschung haben in einem groß angelegten Screening anti-fibrotischer Wirkstoffe Leitstrukturen identifiziert, die Organfibrosen verhindern könnten. Gegenüber den bereits zugelassenen anti-fibrotischen Wirkstoffen Nintedanib und Pirfenidon waren einige der ermittelten Substanzen im Zytotoxizitäts- und Wirksamkeitsprofil überlegen und könnten somit für die weitere klinische Translation bei der Behandlung von Organfibrosen Anwendung finden.
Abstract:
Cardiac fibroblasts constitute the major cell type of the murine and human heart. Once activated, they contribute to an excessive deposition of extracellular matrix (ECM) leading to cardiac fibrosis and subsequently organ dysfunction. With the exception of the pulmonary drugs, nintedanib and pirfenidone, drugs specifically targeting anti-fibrotic pathways are scarce. We recently performed large library screenings of natural occurring compounds and identified first lead structures with anti-fibrotic properties in vitro and in vivo. In line, we now aimed to improve efficacy of these anti-fibrotic lead structures by combining in vitro validation studies and in silico prediction. Next to this combined approach, we performed large OMICs-multi-panel-based mechanistic studies. Applying human cardiac fibroblasts (HCF), we analyzed 26 similars of the initially identified anti-fibrotic lead molecules bufalin and lycorine and determined anti-proliferative activity and potential toxicity in an array of in vitro and ex vivo studies. Of note, even at lower concentrations, certain similars were more effective at inhibiting HCF proliferation than nintedanib and pirfenidone. Additionally, selected similars showed low cytotoxicity on human iPS-derived cardiomyocytes and anti-fibrotic gene regulation in human ex vivo living myocardial slices. Further, array and RNA sequencing studies of coding and non-coding RNAs in treated HCFs revealed strong anti-fibrotic properties, especially with the lycorine similar lyco-s (also known as homoharringtonine), that led to a nearly complete shutdown of ECM production at concentrations 100-fold lower than the previously identified anti-fibrotic compound lycorine without inducing cellular toxicity. We thus identified a new natural compound similar with strong anti-fibrotic properties in human cardiac fibroblasts and human living heart tissue potentially opening new anti-fibrotic treatment strategies.
Aktuelle Publikation in »Basic Research in Cardiology«: