Adenosine A2A receptor activation enhances blood-tumor barrier permeability in a rodent glioma model

Amelie Vezina, Monica Manglani, Dree Anna Morris, Brandon Foster, Matthew McCord, Hua Song, Meili Zhang, Dionne Davis, Wei Zhang, Jessica Bills, Kunio Nagashima, Priya Shankarappa, Jessica Kindrick, Stuart Walbridge, Cody J. Peer, William D. Figg, Mark R. Gilbert, Dorian B. McGavern, Leslie L. Muldoon, Sadhana Jackson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma. Poor drug entry across the BTB allows infiltrative glioma stem cells to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier in non-tumor-bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. In vitro, A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, downregulation of junctional protein expression by 4 hours, and reestablishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide concentrations, yet no increased survival noted with combined temozolomide therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes among glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance central nervous system treatment delivery to aggressive brain tumors.

Original languageEnglish (US)
Pages (from-to)2081-2095
Number of pages15
JournalMolecular Cancer Research
Volume19
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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