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
2019
Authors:
Fallacara, Ana LuciaZamperini, Claudio
Podolski-Renić, Ana
Dinić, Jelena
Stanković, Tijana
Nešović, Marija
Mancini, Arianna
Rango, Enrico
Iovenitti, Giulia
Molinari, Alessio
Bugli, Francesca
Sanguinetti, Maurizio
Torelli, Riccardo
Martini, Maurizio
Maccari, Laura
Valoti, Massimo
Dreassi, Elena
Botta, Maurizio
Pešić, Milica
Schenone, Silvia
Document Type:
Article (Published version)
Metadata
Show full item recordAbstract:
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.
Keywords:
Glioblastoma; Multidrug resistance; P-gp inhibitors; Src inhibitors; In vitro ADME; Pharmacokinetics; Brain distribution; TolerabilitySource:
Cancers, 2019, 11, 6, 848-Funding / projects:
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- COST Actions CM1106—Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells
- COST Action CM1407—Challenging organic syntheses inspired by nature—from natural products chemistry to drug discovery
- AIRC (Associazione Italiana per la Ricerca sul Cancro) Grant IG-2015, code 17677
DOI: 10.3390/cancers11060848
ISSN: 2072-6694
PubMed: 31248184