Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

Abstract

Background. Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods. Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemnessrelated proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness-and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

“…Dual inhibition of OXPHOS and glycolysis is able to effectively disrupt energy metabolism and has proven to be effective against tumour growth in multiple preclinical cancer models ( Table 1 ). For example, dual inhibition of glycolysis with 2-DG and OXPHOS with metformin-inhibited tumour growth preclinically in a broad spectrum of tumour models, including breast cancer, prostate cancer, GBM, and sarcoma [ 223 , 224 , 225 , 226 , 227 , 228 , 229 ]. Similarly, HK2 depletion in HCC sensitises cells to metformin [ 230 ].…”

Metformin as Potential Therapy for High-Grade Glioma

“…They showed that the simultaneous administration of both drugs was associated with the stronger inhibition of tumor cell growth compared to the control. The effect on energy metabolism has been confirmed by measuring ATP levels [197]. Interestingly, the use of only metformin was associated with a weak response in the form of inhibition of GBM-TS proliferation in both its low (5 mM) and high (15 mM) concentration.…”

“…This allows the drug concentration in cerebrospinal fluid and portal vein to reach 40 µM, while the concentration in the brain tissue reaches 10 µM [4,65,195,196]. While some observations indicate that doses of 50-100 µM are sufficient to inhibit respiration at the cellular level in hepatocytes, in the case of low drug levels, the anti-tumor effect is often not particularly pronounced [14,54,90,197]. In most studies reporting the anti-tumor effects of metformin, the doses used were higher than in the standard antidiabetic treatment [8,35,39,51,52,54,55,198].…”

Inhibition of TFEB oligomerization by co‐treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells

“…Vorinostat is a linear hydroxamic acid that inhibits HDAC classes I/II, causing the deacetylation of histones H2A, H2B, H3, and H4 and nonhistone proteins. [61][62][63] Deacetylation of these proteins alters chromatin structure, ultimately altering the transcription activity of target genes. Vorinostat also increases the acetylation state of certain proteins, including p53 and hsp90.…”