Voxtalisib and low intensity pulsed ultrasound combinatorial effect on glioblastoma multiforme cancer stem cells via PI3K/AKT/mTOR

Background: Glioblastoma (GBM) is the most aggressive brain tumor contributed to tumor growth by cancer stem cells (CSCs). Targeting CSCs is vital to preventing differentiation into cancer cells, their proliferation, and treatment resistance. According to research, PI3K/AKT/mTOR signaling is active in GBM and GBMCSCs. Anticancer medications combined with ultrasound application have been proposed as a strategy to increase the drug intake of cancer cells. This study aims to investigate the effects of inhibition of PI3K/ AKT/ mTOR pathway with dual inhibitor Voxtalisib (Vox; also known as XL765) and low intensity pulsed ultrasound (LIPUS) combinations in GBM and GBMCSCs in the point of cell survival. F-actin was also used to evaluate cell motility.

Materials and methods: GBMCSCs were isolated from the human glioblastoma U87 MG cell line using the fluorescence-activated cell sorting (FACS) method. Cells were exposed to various concentrations of Vox, LIPUS, and their combinations. Cell count and viability assay was used to determine drug delivery doses. F-actin and mTOR immunofluorescence staining were used to identify cytoskeletal alterations and PI3K/AKT/mTOR signal pathway suppression, respectively. Additionally, the migration capacity of cells was shown with standard wound-healing experiments.

Results: High doses of Vox+LIPUS inhibited mTOR and decreased the viability in both cell groups. Inhibiting mTOR activated autophagy, and LIPUS increased autophagy in GBM cells. However, GBMCSCs were resistant to autophagy even at high drug dosages. Both in GBM and GBMCSCs, combinations of Vox and LIPUS were observed to decrease F-actin density and cell motility.

Conclusions: The combination of Vox+LIPUS has increased drug effectiveness in targeted GBM and GBMCSCs. Combinatory treatment with PI3K/AKT/mTOR signaling pathway and LIPUS has been thought to help develop more effective therapeutic approaches for GBM.

Comments：

The study found that the combination of Voxtalisib (Vox) and low intensity pulsed ultrasound (LIPUS) increased drug efficacy in glioblastoma (GBM) and glioblastoma cancer stem cells (GBMCSCs), inhibiting the PI3K/AKT/mTOR signaling pathway and decreasing cell viability, F-actin density and motility.

Related Products

Cat.No.	Product Name	Information
S1523	Voxtalisib (XL765) Analogue	Voxtalisib (SAR245409, XL765) Analogue is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.

Related Targets

mTOR PI3K