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Combined VEGF and PDGF inhibition for neovascular AMD: anti-angiogenic properties of axitinib on human endothelial cells and pericytes in vitro

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Abstract

Purpose

Drugs currently approved for neovascular age-related macular degeneration (nAMD) offer anti-VEGF monotherapy only. Platelet-derived growth factor (PDGF) signaling is pivotal to pericyte-induced stabilization of choroidal neovascularizations (CNV), and causes partial anti-VEGF resistance. No combination therapy for VEGF and PDGF has been approved yet. Axitinib is a tyrosine kinase inhibitor interfering with VEGF and PDGF signaling, and has been approved for the treatment of renal cell carcinoma. This study evaluates anti-angiogenic properties of axitinib in an in-vitro model of choroidal neovascularizations in nAMD.

Methods

Human endothelial cells (HUVEC) and human pericytes (hPC-PL) were treated with axitinib doses ranging from 1.0 ng/ml to 10 μg/ml. Cellular viability and proliferation were assessed with a modified MTT assay. VEGF- and PDGF-stimulated migration was observed in modified Boyden chambers. Formation of capillary structures was evaluated on Cultrex basement membrane.

Results

Proliferation was significantly inhibited in both cell lines in a dose-dependent manner. VEGF and PDGF significantly induced, whereas simultaneous axitinib normalized cellular migration in HUVEC and pericytes. On growth-factor-reduced Cultrex, VEGF induced the formation of capillary structures, while axitinib significantly reverted this effect. Axitinib reduced the amount of vessel associated tissue on full growth factor Cultrex. All effects on both cell lines were observed in non-toxic concentrations of axitinib.

Conclusions

Axitinib inhibits angiogenesis in endothelial cells and pericytes via VEGFR and PDGFR modulation in vitro. Further studies are needed to elucidate whether axitinib may also improve therapy of CNV in AMD in vivo by interference with pericyte stabilization of pathological vessels.

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Acknowledgements

This work was presented at the 29th annual meeting of the German Retina Society in Berlin in June 2016, for which the first author (JS) received a travel grant. Part of this work was presented at the 133th annual meeting of the DOG in Berlin in October 2015.

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  1. Department of Ophthalmology, Ludwig-Maximilians-University, Mathildenstrasse 8, 80336, Munich, Germany

    Jakob Siedlecki, Christian Wertheimer, Armin Wolf, Raffael Liegl, Claudia Priglinger, Siegfried Priglinger & Kirsten Eibl-Lindner

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Jakob Siedlecki: NONE, Christian Wertheimer: NONE; Armin Wolf: NONE; Raffael Liegl: NONE; Claudia Priglinger: NONE; Siegfried Priglinger: NONE; Kirsten Eibl-Lindner: NONE

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Siedlecki, J., Wertheimer, C., Wolf, A. et al. Combined VEGF and PDGF inhibition for neovascular AMD: anti-angiogenic properties of axitinib on human endothelial cells and pericytes in vitro. Graefes Arch Clin Exp Ophthalmol 255, 963–972 (2017). https://doi.org/10.1007/s00417-017-3595-z

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