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

Autor: King NE; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Courtney JM; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Brown LS; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Foster CG; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Cashion JM; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Attrill E; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Premilovac D; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Howells DW; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia., Sutherland BA; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia. Electronic address: brad.sutherland@utas.edu.au.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2022 Jun 01; Vol. 444, pp. 116025. Date of Electronic Publication: 2022 Apr 17.
DOI: 10.1016/j.taap.2022.116025
Abstrakt: 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.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: