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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

12 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)E848-N/A
RivistaCancers
Volume11
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • P-gp inhibitors
  • Src inhibitors
  • brain distribution
  • glioblastoma
  • in vitro ADME
  • multidrug resistance
  • pharmacokinetics
  • tolerability

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