title: Block of purinergic P2X7R inhibits tumor growth in a C6 glioma brain tumor animal model.
abstract: We examined the expression and pharmacological modulation of the purinergic receptor P2X7R in a C6 glioma model. Intrastriatal injection of C6 cells induced a time-dependent growth of tumor; at 2 weeks postinjection immunohistochemical analysis demonstrated higher levels of P2X7R in glioma-injected versus control vehicle-injected brains. P2X7R immunoreactivity colocalized with tumor cells and microglia, but not endogenous astrocytes. Intravenous administration of the P2X7R antagonist brilliant blue G (BBG) inhibited tumor growth in a spatially dependent manner from the C6 injection site. Treatment with BBG reduced tumor volume by 52% versus that in controls. Double immunostaining indicated that BBG treatment did not alter microgliosis, astrogliosis, or vasculature vessels in C6-injected animals. In vitro, BBG reduced the expression of P2X7R and glioma chemotaxis induced by the P2X7R ligand, 2',3'-O-(4-benzoyl-benzoyl)adenosine triphosphate (BzATP). Immunohistochemical staining of human glioblastoma tissue samples demonstrated greater expression of P2X7R compared to control nontumor samples. These results suggest that the efficacy of BBG in inhibiting tumor growth is primarily mediated by direct actions of the compound on P2X7R in glioma cells and that pharmacological inhibition of this purinergic receptor might serve as a strategy to slow the progression of brain tumors.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, British Columbia, Canada.
authors.forename: Jae K
authors.initials: JK
authors.lastname: Ryu
authors.forename: Nattinee
authors.initials: N
authors.lastname: Jantaratnotai
authors.forename: Maria C
authors.initials: MC
authors.lastname: Serrano-Perez
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
authors.forename: James G
authors.initials: JG
authors.lastname: McLarnon
mesh_terms: D000368:Aged; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000096:biosynthesis / Q000235:genetics; D012394:Rosaniline Dyes / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D006131:Growth Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; C004692:coomassie Brilliant Blue