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

Citation

King, NE and Courtney J-M and Brown, LS and Foster, CG and Cashion, JM and Attrill, E and Premilovac, D and Howells, DW and Sutherland, BA, Pharmacological PDGFRβ inhibitors imatinib and sunitinib cause human brain pericyte death in vitro, Toxicology and Applied Pharmacology, 444 pp. 1-9. ISSN 0041-008X (2022) [Refereed Article]


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DOI: doi:10.1016/j.taap.2022.116025

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 Details

Item Type:Refereed Article
Keywords:pericytes, tyrosine kinase inhibitors, imatinib, sunitinib, platelet derived growth factor receptor beta
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell development, proliferation and death
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:King, NE (Ms Natalie King)
UTAS Author:Courtney J-M (Dr Jo-Maree Courtney)
UTAS Author:Brown, LS (Mr Lachlan Brown)
UTAS Author:Foster, CG (Miss Catherine Foster)
UTAS Author:Cashion, JM (Mr Jake Cashion)
UTAS Author:Attrill, E (Ms Emily Attrill)
UTAS Author:Premilovac, D (Dr Dino Premilovac)
UTAS Author:Howells, DW (Professor David Howells)
UTAS Author:Sutherland, BA (Associate Professor Brad Sutherland)
ID Code:149914
Year Published:2022
Deposited By:Medicine
Deposited On:2022-04-28
Last Modified:2022-07-04
Downloads:0

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