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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

1
Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, Italy
2
Lead Discovery Siena S.r.l., via Vittorio Alfieri 31, Castelnuovo Berardenga, 53019 Siena, Italy
3
Department of Neurobiology, Institute for Biological Research “Siniša Stanković” (IBISS), University of Belgrade, 11060 Belgrade (RS), Serbia
4
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
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Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
6
Istituto di Microbiologia, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
7
Dipartimento Scienze della Vita, Università degli Studi di Siena, 53100 Siena, Italy
8
Department of Pharmacy, Università degli Studi di Genova, 16132 Genova, Italy
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(6), 848; https://doi.org/10.3390/cancers11060848
Received: 16 May 2019 / Revised: 17 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)
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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. View Full-Text
Keywords: glioblastoma; multidrug resistance; P-gp inhibitors; Src inhibitors; in vitro ADME; pharmacokinetics; brain distribution; tolerability glioblastoma; multidrug resistance; P-gp inhibitors; Src inhibitors; in vitro ADME; pharmacokinetics; brain distribution; tolerability
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Fallacara, A.L.; Zamperini, C.; Podolski-Renić, A.; Dinić, J.; Stanković, T.; Stepanović, M.; Mancini, A.; Rango, E.; Iovenitti, G.; Molinari, A.; Bugli, F.; Sanguinetti, M.; Torelli, R.; Martini, M.; Maccari, L.; Valoti, M.; Dreassi, E.; Botta, M.; Pešić, M.; Schenone, S. 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 2019, 11, 848.

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