Hybrids of harmine and quinoline-based antimalarials show a strong antiproliferative effect on glioblastoma cells and reverse ATP-binding cassette transporter-mediated drug resistance.

Abstract

BACKGROUND: Glioblastomas (GBM) are the most aggressive tumors of the nervous system, with therapy limited by multidrug resistance (MDR) and poor drug penetration across the blood-brain barrier (BBB). The BBB expresses ATP-binding cassette (ABC) transporters, particularly ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which reduce intracellular drug concentrations and contribute to MDR. The aim of this study was to evaluate a series of β-carboline-quinoline hybrid compounds as potential glioblastoma therapeutics and modulators of ABC transporter activity. METHODS: Fifteen hybrid compounds, combining harmine and quinoline-based antimalarials via triazole or ureido linkers, were tested for cytotoxicity on U251 glioblastoma and SH-SY5Y neuroblastoma cell lines using cell viability assays. ABC transporter inhibition was assessed with cell-based functional assays measuring intracellular accumulation of fluorescent P-gp and ABCG2 substrates. Selected hybrids were further evaluated for their ability to sensitize chemoresistant cells to the reference drugs doxorubicin (DOXO) and mitoxantrone (MX). RESULTS: Most hybrids exhibited stronger cytotoxic effects on glioblastoma cells than their parent compounds and the reference drug temozolomide. Several compounds significantly inhibited P-gp and ABCG2 function, with ureido-type derivatives PU-9 and MU-9 showing the most pronounced dual inhibition. Importantly, these compounds enhanced the sensitivity of resistant cells to DOXO and MX, suggesting a potential strategy to overcome MDR. CONCLUSIONS: β-Carboline-quinoline hybrids, particularly PU-9 and MU-9, represent promising dual-function agents with both cytotoxic and ABC transporter-modulating activity. Their ability to reduce glioblastoma cell survival and sensitize resistant cells highlights their potential as leads for developing therapeutics that can overcome MDR and improve CNS drug delivery. CLINICAL TRIAL NUMBER: Not applicable.