Abstract
P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhibiting Pgp activity in the 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 patient-derived GB samples, 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). Three compounds used at 1 nM increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering the expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring doxorubicin-induced necrosis and apoptosis, and reducing cell viability. 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. These compounds reduce Pgp activity in BBB and GB and improve in vitro chemotherapy efficacy in this tumor.
Highlights
Glioblastoma multiforme (GB) is considered the most common, aggressive and lethal brain tumor in the adult population, because of its highly infiltrating nature
Compounds 1–5 [18] and 6 [19] were synthesized from MC70, which was prepared according to Compounds 1–5 [18] and 6 [19] were synthesized from MC70, which was prepared according to thethe straightforward metal-freesynthetic synthetic route reported in Scheme straightforward metal-free route reported in Scheme
Many Pgp inhibitors that have displayed excellent in vitro efficacy have failed in pre-clinical and clinical models because of their great toxicity, owing to the high concentrations required to inhibit Pgp, which results in heavy side-effects and toxicities [25]
Summary
Glioblastoma multiforme (GB) is considered the most common, aggressive and lethal brain tumor in the adult population, because of its highly infiltrating nature. GB usually arises from the white matter as a heterogeneous lesion, but it rapidly spreads into the surrounding brain tissue [1]. GB standard therapy is based on surgical resection, followed by radiotherapy and chemotherapy based on temozolomide. The second-line therapy is based on topoisomerase I and II inhibitors or anti-angiogenic drugs. The success of chemotherapy is limited by the tumor polyclonality, the intrinsic resistance to most chemotherapeutic drugs and the presence of blood-brain barrier (BBB) [2,3,4]. Chemotherapy is not efficient to completely eradicate tumor stem cells (SCs) that contribute to GB initiation, progression and recurrence.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
