Reversal of Multidrug Resistance by the Synergistic Effect of Reversan and Hyperthermia to Potentiate the Chemotherapeutic Response of Doxorubicin in Glioblastoma and Glioblastoma Stem Cells

Abstract

The glioblastoma stem cell (GSC) population in glioblastoma multiforme (GBM) poses major complication in clinical oncology owing to increased resistance to chemotherapeutic drugs, thereby limiting treatment in patients with recurring glioblastoma. To completely eradicate glioblastoma, a single therapy module is not enough; therefore, there is a need to develop a multimodal approach to eliminate bulk tumors along with the CSC population. With an aim to target transporters associated with multidrug resistance (MDR), such as Pglycoprotein (P-gp), a small-molecule inhibitor, reversan (RV) was used along with multifunctional magnetic nanoparticles (MNPs) for hyperthermia (HT) therapy and targeted drug delivery. Higher efflux of free doxorubicin (Dox) from the cells was stabilized by encapsulation in PPS-MnFe nanoparticles, whose physicochemical properties were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Treatment with RV also enhanced the cellular uptake of PPS-MnFe-Dox, whereas RV and magnetic hyperthermia (MHT) together showed prolonged retention of fluorescence dye, Rhodamine123 (R123), in glioblastoma cells compared with individual treatment. Overall, in this work, we demonstrated the synergistic action of RV and HT to combat MDR in GBM and GSCs, and chemo-hyperthermia therapy enhanced the cytotoxic effect of the chemotherapeutic drug Dox (with lower effective concentration) and induced a higher degree of apoptosis compared to single-drug dosage.

Overcoming challenges in glioblastoma treatment: targeting infiltrating cancer cells and harnessing the tumor microenvironment

“…Interestingly, the presence of stem cells in the bulk of glioblastomas has been also strongly associated to cancer multidrug resistance (MDR) (Mattei et al, 2021), which remains a serious challenge in GB therapy as it seriously limits the effects of different chemotherapeutic drugs (Tian et al, 2023). Indeed, as MDR has been often associated with the expression of p-glycoprotein (pgp), an ATP-binding cassette (ABC) transporter that promotes efflux of chemotherapeutics from tumor cells, this protein has been recently suggested as a druggable therapeutic target (Hasan et al, 2023). Indeed, the p-gp inhibitor reversan, in association with magnetic nanoparticle-mediated hyperthermia, was able to increase the cytotoxic effect of Doxorubicine treatment to eliminate bulk tumors along with the GSC population (Hasan et al, 2023).…”

“…Indeed, as MDR has been often associated with the expression of p-glycoprotein (pgp), an ATP-binding cassette (ABC) transporter that promotes efflux of chemotherapeutics from tumor cells, this protein has been recently suggested as a druggable therapeutic target (Hasan et al, 2023). Indeed, the p-gp inhibitor reversan, in association with magnetic nanoparticle-mediated hyperthermia, was able to increase the cytotoxic effect of Doxorubicine treatment to eliminate bulk tumors along with the GSC population (Hasan et al, 2023).…”