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Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression
Robert H Berndsen1,2, Cédric Castrogiovanni3, Andrea Weiss1
1Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet, 1211, Geneva, Switzerland.
Background:
Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-β and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling.
Methods:
The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts. Alterations in cell morphology were determined by immunofluorescence experiments. Flow-cytometry analysis and mRNA expression profiles were used to investigate cell differentiation. In vivo efficacy was investigated in human ovarian carcinoma implanted on the chicken chorioallantoic membrane (CAM).
Results:
Crenolanib was found to inhibit endothelial cell viability, migration and sprout length, and induced apoptosis independently of PDGFR expression. Treated cells showed altered actin arrangement and nuclear aberrations. Mitosis was affected at several levels including mitosis entry and centrosome clustering. Crenolanib suppressed human ovarian carcinoma tumour growth and angiogenesis in the CAM model.
Conclusions:
The PDGFR/FLT3 inhibitor crenolanib targets angiogenesis and inhibits tumour growth in vivo unrelated to PDGFR expression. Based on our findings, we suggest a broad mechanism of action of crenolanib.
Insights
Crenolanib, a tyrosine kinase inhibitor, directly inhibits angiogenesis and tumor growth, independent of PDGFR signaling. This broadens our understanding of its anti-cancer mechanisms.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Crenolanib targets PDGFR-α, PDGFR-β, and FLT3, with PDGFR signaling crucial for angiogenesis.
- Previous understanding suggested PDGFR signaling is key to crenolanib's effects.
Purpose of the Study:
- To investigate the direct angiostatic activity of crenolanib.
- To determine if crenolanib's anti-angiogenic effects are independent of PDGFR signaling.
Main Methods:
- Assessed crenolanib's effects on endothelial cells, tumor cells, and fibroblasts (viability, migration, apoptosis, mitosis).
- Utilized immunofluorescence, flow cytometry, and mRNA profiling.
- Evaluated in vivo efficacy using a human ovarian carcinoma chicken chorioallantoic membrane (CAM) model.
Main Results:
- Crenolanib inhibited endothelial cell viability, migration, and sprout length, inducing apoptosis independent of PDGFR expression.
- Observed altered cell morphology, actin arrangement, and nuclear aberrations.
- Suppressed tumor growth and angiogenesis in the CAM model.
Conclusions:
- Crenolanib exhibits direct anti-angiostatic activity independent of PDGFR signaling.
- The drug effectively inhibits tumor growth and angiogenesis in vivo.
- Findings suggest a broader mechanism of action for crenolanib beyond PDGFR/FLT3 inhibition.
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