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The method demonstrated that activation of A2A adenosine receptors potently downregulated P-gp expression in brain endothelial cells and in cancer cell.
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Invention Summary This invention describes a novel method to down-modulate P-glycoprotein (P-gp) in cells, by targeting adenosine receptor A2A with agonists. Technology Overview P-gp is an efflux transporter protein with a broad substrate spectrum that is expressed in many different cell types that actively pumps foreign substances, including drugs, out of cells. In some cancer cells, P-gp is highly expressed and leads to multi-drug resistance, while P-gp expression in brain endothelial cells makes more challenging drug delivery into the central nervous system. Using selective A2A receptor agonists Lexiscan (Regadenoson) or NECA, it was demonstrated that activation of A2A adenosine receptors potently downregulated P-gp expression in brain endothelial cells and in cancer cell In vivo experiments further demonstrated accumulation of epirubicin, an anti-cancer chemotherapy drug, in the brain of mice treated with Lexiscan or NECA which correlated with the kinetics of downregulation of P-gp. Specifically, down-regulation of P-gp occurred later with NECA treatment compared to treatment with Lexiscan due to the half-life of each molecule, 5 hours and 2.5 minutes, respectively. In addition, fluorescent microscopic analysis revealed that epirubicin accumulated in the cerebral cortex, the cerebellum, and the hippocampus. Potential Applications Delivery of therapeutics into the brain for treatment of central nervous system (CNS) diseases Treatment of multi-drug resistant cancers. Advantages Reversible modulation of P-gp Tunable modulation – dependent on the half-life of adenosine receptor agonists.