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Pharmacological PDGFRβ inhibitors imatinib and sunitinib cause human brain pericyte death in vitro

King, NE, Courtney J-M, ORCID: 0000-0003-4461-4197, Brown, LS ORCID: 0000-0003-3612-8236, Foster, CG, Cashion, JM, Attrill, EH, Premilovac, D ORCID: 0000-0003-2770-4713, Howells, DW ORCID: 0000-0002-2512-7724 and Sutherland, BA ORCID: 0000-0002-0791-0950 2022 , 'Pharmacological PDGFRβ inhibitors imatinib and sunitinib cause human brain pericyte death in vitro' , Toxicology and Applied Pharmacology, vol. 444 , pp. 1-9 , doi: 10.1016/j.taap.2022.116025.

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Abstract

Capillary pericytes have numerous functions important for tissue maintenance. Changes in pericyte function are implicated in diseases such as cancer, where pericyte-mediated angiogenesis contributes to the blood supply that tumors use to survive. Some anti-cancer agents, like imatinib, target platelet-derived growth factor receptor-beta (PDGFRβ). Healthy pericytes rely on PDGFRβ phosphorylation for their survival. Therefore, we hypothesised that pharmacological agents that block PDGFRβ phosphorylation could be used to kill pericytes. We treated human brain vascular pericytes, which express PDGFRβ, with three receptor tyrosine kinase inhibitors: imatinib, sunitinib and orantinib. Imatinib and sunitinib, but not orantinib, inhibited PDGFRβ phosphorylation in pericytes. Imatinib and sunitinib also reduced viability, prevented proliferation, and induced death, while orantinib only blocked pericyte proliferation. Overall, we found that receptor tyrosine kinase inhibitors that block PDGFRβ phosphorylation cause healthy pericytes to die in vitro. While useful in cancer to limit tumor growth, these agents could impair healthy brain pericyte survival and impact brain function.

Item Type: Article
Authors/Creators:King, NE and Courtney J-M, and Brown, LS and Foster, CG and Cashion, JM and Attrill, EH and Premilovac, D and Howells, DW and Sutherland, BA
Keywords: pericytes, tyrosine kinase inhibitors, imatinib, sunitinib, platelet derived growth factor receptor beta
Journal or Publication Title: Toxicology and Applied Pharmacology
Publisher: Academic Press Inc Elsevier Science
ISSN: 0041-008X
DOI / ID Number: 10.1016/j.taap.2022.116025
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© 2022 Elsevier Inc. All rights reserved.

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