Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression

Robert H. Berndsen, C. dric Castrogiovanni, Andrea Weiss, Magdalena Rausch, Marchien G. Dallinga, Marijana Miljkovic-Licina, Ingeborg Klaassen, Patrick Meraldi, Judy R. van Beijnum, Patrycja Nowak-Sliwinska

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)139-149
Number of pages11
JournalBritish Journal of Cancer
Volume121
Issue number2
DOIs
Publication statusPublished - 16 Jul 2019

Cite this

Berndsen, Robert H. ; Castrogiovanni, C. dric ; Weiss, Andrea ; Rausch, Magdalena ; Dallinga, Marchien G. ; Miljkovic-Licina, Marijana ; Klaassen, Ingeborg ; Meraldi, Patrick ; van Beijnum, Judy R. ; Nowak-Sliwinska, Patrycja. / Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression. In: British Journal of Cancer. 2019 ; Vol. 121, No. 2. pp. 139-149.
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abstract = "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.",
author = "Berndsen, {Robert H.} and Castrogiovanni, {C. dric} and Andrea Weiss and Magdalena Rausch and Dallinga, {Marchien G.} and Marijana Miljkovic-Licina and Ingeborg Klaassen and Patrick Meraldi and {van Beijnum}, {Judy R.} and Patrycja Nowak-Sliwinska",
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doi = "10.1038/s41416-019-0498-2",
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Berndsen, RH, Castrogiovanni, CD, Weiss, A, Rausch, M, Dallinga, MG, Miljkovic-Licina, M, Klaassen, I, Meraldi, P, van Beijnum, JR & Nowak-Sliwinska, P 2019, 'Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression' British Journal of Cancer, vol. 121, no. 2, pp. 139-149. https://doi.org/10.1038/s41416-019-0498-2

Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression. / Berndsen, Robert H.; Castrogiovanni, C. dric; Weiss, Andrea; Rausch, Magdalena; Dallinga, Marchien G.; Miljkovic-Licina, Marijana; Klaassen, Ingeborg; Meraldi, Patrick; van Beijnum, Judy R.; Nowak-Sliwinska, Patrycja.

In: British Journal of Cancer, Vol. 121, No. 2, 16.07.2019, p. 139-149.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Anti-angiogenic effects of crenolanib are mediated by mitotic modulation independently of PDGFR expression

AU - Berndsen, Robert H.

AU - Castrogiovanni, C. dric

AU - Weiss, Andrea

AU - Rausch, Magdalena

AU - Dallinga, Marchien G.

AU - Miljkovic-Licina, Marijana

AU - Klaassen, Ingeborg

AU - Meraldi, Patrick

AU - van Beijnum, Judy R.

AU - Nowak-Sliwinska, Patrycja

PY - 2019/7/16

Y1 - 2019/7/16

N2 - 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.

AB - 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.

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