TY - JOUR
T1 - A New Strategy for Glioblastoma Treatment
T2 - In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor
AU - Fallacara, Anna Lucia
AU - Zamperini, Claudio
AU - Podolski-Renić, Ana
AU - Dinić, Jelena
AU - Stanković, Tijana
AU - Stepanović, Marija
AU - Mancini, Arianna
AU - Rango, Enrico
AU - Iovenitti, Giulia
AU - Molinari, Alessio
AU - Bugli, Francesca
AU - Sanguinetti, Maurizio
AU - Torelli, Riccardo
AU - Martini, Maurizio
AU - Maccari, Laura
AU - Valoti, Massimo
AU - Dreassi, Elena
AU - Botta, Maurizio
AU - Pešić, Milica
AU - Schenone, Silvia
PY - 2019/6/19
Y1 - 2019/6/19
N2 - 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.
AB - 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.
U2 - 10.3390/cancers11060848
DO - 10.3390/cancers11060848
M3 - Article
C2 - 31248184
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 6
ER -