Preprint Article Version 1 This version is not peer-reviewed

New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme

Version 1 : Received: 13 May 2018 / Approved: 14 May 2018 / Online: 14 May 2018 (12:50:18 CEST)

A peer-reviewed article of this Preprint also exists.

Salaroglio, I.C.; Gazzano, E.; Kopecka, J.; Chegaev, K.; Costamagna, C.; Fruttero, R.; Guglielmo, S.; Riganti, C. New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro. Molecules 2018, 23, 1401. Salaroglio, I.C.; Gazzano, E.; Kopecka, J.; Chegaev, K.; Costamagna, C.; Fruttero, R.; Guglielmo, S.; Riganti, C. New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro. Molecules 2018, 23, 1401.

Journal reference: Molecules 2018, 23, 1401
DOI: 10.3390/molecules23061401

Abstract

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs in glioblastoma multiforme (GB) because it is highly expressed in GB stem cells and in brain-blood barrier (BBB), the peculiar endothelium surrounding brain. Inhibiting Pgp activity in BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC50 for Pgp < 50 nM, in primary human BBB cells and in patients-derived GB, from which we isolated differentiated/adherent cells (AC, i.e. Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e. Pgp-positive/doxorubicin-resistant cells). At 1 nM, 3 compounds increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring necrosis, apoptosis and reduction in cell viability induced by doxorubicin. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations, that effectively reduce Pgp activity in BBB and GB, and can improve chemotherapy efficacy in this tumor.

Subject Areas

P-glycoprotein; glioblastoma multiforme; brain-blood barrier; doxorubicin

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