A new strategy for glioblastoma treatment: In vitro and in vivo preclinical characterization of Si306, a pyrazolo[3,4-d]pyrimidine dual Src/P-Glycoprotein inhibitor

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Abstract

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells' membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.

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Fallacara, A. L., Zamperini, C., Podolski-Renić, A., Dinić, J., Stanković, T., Stepanović, M., … Schenone, S. (2019). A new strategy for glioblastoma treatment: In vitro and in vivo preclinical characterization of Si306, a pyrazolo[3,4-d]pyrimidine dual Src/P-Glycoprotein inhibitor. Cancers, 11(6). https://doi.org/10.3390/cancers11060848

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