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 P2X 7 R in a C6 glioma model. Intrastriatal injection of C6 cells induced a time-dependent growth of tumor; at 2weeks postinjection immunohistochemical analysis demonstrated higher levels of P2X 7 R in glioma-injected versus control vehicle-injected brains. P2X 7 R immunoreactivity colocalized with tumor cells and microglia, but not endogenous astrocytes. Intravenous administration of the P2X 7 R 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 P2X 7 R and glioma chemotaxis induced by the P2X 7 R ligand, 2′,3′-O-(4- benzoyl-benzoyl)adenosine triphosphate (BzATP). Immunohistochemical staining of human glioblastoma tissue samples demonstrated greater expression of P2X 7 R 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 P2X 7 R in glioma cells and that pharmacological inhibition of this purinergic receptor might serve as a strategy to slow the progression of brain tumors. © 2010 by the American Association of Neuropathologists, Inc.