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Pharmacological PDGFRβ inhibitors imatinib and sunitinib cause human brain pericyte death in vitro
journal contribution
posted on 2023-05-21, 07:25 authored by Natalie KingNatalie King, Jo-Maree CourtneyJo-Maree Courtney, Lachlan BrownLachlan Brown, Catherine Foster, Jake CashionJake Cashion, Emily AttrillEmily Attrill, Dino PremilovacDino Premilovac, David Howells, Brad SutherlandBrad SutherlandCapillary 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.
Funding
Rebecca L Cooper Medical Research Foundation
History
Publication title
Toxicology and Applied PharmacologyVolume
444Pagination
1-9ISSN
0041-008XDepartment/School
Tasmanian School of MedicinePublisher
Academic Press Inc Elsevier SciencePlace of publication
525 B St, Ste 1900, San Diego, USA, Ca, 92101-4495Rights statement
© 2022 Elsevier Inc. All rights reserved.Repository Status
- Restricted