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

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.

Funding

Rebecca L Cooper Medical Research Foundation

History

Publication title

Toxicology and Applied Pharmacology

Volume

444

Pagination

1-9

ISSN

0041-008X

Department/School

Tasmanian School of Medicine

Publisher

Academic Press Inc Elsevier Science

Place of publication

525 B St, Ste 1900, San Diego, USA, Ca, 92101-4495

Rights statement

© 2022 Elsevier Inc. All rights reserved.

Repository Status

  • Restricted

Socio-economic Objectives

Treatment of human diseases and conditions; Expanding knowledge in the biomedical and clinical sciences