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

Anna Lucia Fallacara, Claudio Zamperini, Ana Podolski-Renić, Jelena Dinić, Tijana Stanković, Marija Stepanović, Arianna Mancini, Enrico Rango, Giulia Iovenitti, Alessio Molinari, Francesca Bugli, Maurizio Sanguinetti, Riccardo Torelli, Maurizio Martini, Laura Maccari, Massimo Valoti, Elena Dreassi, Maurizio Botta, Milica Pešić, Silvia Schenone

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalCancers
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 19 2019

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