Abstract
Despite available treatment approaches, including surgical resection along with chemotherapy and radiotherapy, glioblastoma (GBM), the most prevalent primary brain tumor, remains associated with a grim prognosis. Although radiotherapy is central to GBM treatment, its combination with bioenergetics regulators has not been validated in clinical practice. Here, we hypothesized that bioenergetics regulators can enhance the radio-sensitivity of GBM tumorspheres (TSs). Gene expression profiles of GBM patient-derived TSs were obtained through microarray and RNA-seq. In vitro treatment efficacy was assessed using clonogenic assay, 3D invasion assay, neurosphere formation assay, and flow cytometry. Protein expression was measured via western blot, and γH2AX foci were detected via immunofluorescence. In vivo efficacy was confirmed in an orthotopic xenograft model. Based on radiation response-associated gene expression, GBM TSs were classified into high- or low-radioresistant groups. Among the five bioenergetics regulators, the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG notably enhanced the efficacy of ionizing radiation (IR) efficacy in vitro, reducing the survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. Combination with 2-DG further stimulated IR-induced DNA damage response and apoptosis in low-radioresistant GBM TSs. RNA-seq analysis revealed a downregulation of bioenergetics- and cell cycle-associated genes, whereas extracellular matrix- and cell adhesion-associated genes were enhanced by combined IR and 2-DG treatment. This therapeutic regimen extended survival and diminished tumor size in mouse xenograft models. Our data suggest that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen.
Overview
- The study aims to investigate the potential of bioenergetics regulators to enhance the radio-sensitivity of glioblastoma (GBM) tumorspheres (TSs).
- The study used gene expression profiles of GBM patient-derived TSs obtained through microarray and RNA-seq, and in vitro and in vivo assays to assess treatment efficacy. The study classified GBM TSs into high- or low-radioresistant groups based on radiation response-associated gene expression. The study tested five bioenergetics regulators, including the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG, and found that these regulators enhanced the efficacy of ionizing radiation (IR) in vitro and in vivo, reducing survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. The study also identified downregulation of bioenergetics- and cell cycle-associated genes and enhancement of extracellular matrix- and cell adhesion-associated genes by combined IR and 2-DG treatment. The study suggests that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen.
Comparative Analysis & Findings
- The study compared the outcomes observed under different experimental conditions or interventions, including radiation response-associated gene expression, in vitro and in vivo assays, and gene expression profiles. The study identified high- and low-radioresistant GBM TSs based on radiation response-associated gene expression. The study found that the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG enhanced the efficacy of ionizing radiation (IR) in vitro and in vivo, reducing survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. The study also identified downregulation of bioenergetics- and cell cycle-associated genes and enhancement of extracellular matrix- and cell adhesion-associated genes by combined IR and 2-DG treatment.
Implications and Future Directions
- The study's findings suggest that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen. The study identifies downregulation of bioenergetics- and cell cycle-associated genes and enhancement of extracellular matrix- and cell adhesion-associated genes by combined IR and 2-DG treatment. The study's findings could lead to the development of new therapeutic strategies for GBM, which remains associated with a grim prognosis despite available treatment approaches. Future research could further explore the mechanisms underlying the enhanced radio-sensitivity of GBM TSs by bioenergetics regulators and identify potential biomarkers for response to this combined regimen.