Voxtalisib Hydrochloride

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.

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.

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.

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.

Background. Necrotizing enterocolitis (NEC) is a devastating disease affecting the gastrointestinal tract in the newborn period. In recent years, the role of apoptosis and autophagy in intestinal mucosal barrier dysfunction has come into prominence in research regarding the pathogenesis of NEC. β-Carotene is a well-known vitamin A precursor, and its content in breast milk is relatively high, especially in the colostrum. In the present study, we investigated the protective effect of β-carotene on necrotizing enterocolitis model cells IEC-6 induced by lipopolysaccharide (LPS). Methods. CCK-8 assay was performed to evaluate cell viability. The Annexin V-FITC/PI method was used to detect apoptosis. Western blotting was utilized to measure the expression levels of proteins. Immunofluorescence analysis was used to assess the autophagy of IEC-6 cells. Results. Our findings indicated that β-carotene inhibited the apoptosis of IEC-6 cells by downregulating cleaved caspase-3 levels and Bax levels and upregulating Bcl-2 levels, reducing cell autophagy via downregulating LC3II/I ratio and upregulating p62 levels. In addition, the expression of p-PI3K, p-AKT, and p-mTOR was upregulated after β-carotene treatment. Interestingly, these changes induced by β-carotene were partially reversed by rapamycin and voxtalisib. Conclusion. In conclusion, our findings indicated that β-carotene can attenuate apoptosis and autophagy of IEC-6 cells induced by LPS via activating the PI3K/AKT/mTOR signaling pathway. Therefore, β-carotene may be a promising drug used in the clinical treatment of NEC.