Glioma cancer stem cells (gCSCs) are known to play an essential role in tumor formation, maintenance, and progression. Treatment outcome of a glioblastoma, the most malignant form of gliomas, is still unsatisfactory in spite of any combination of current best treatment modalities. Because the presence of residual surviving gCSCs is thought to be a main reason for treatment-resistance and the source of recurrence, new and innovative therapeutic approaches targeting gCSCs could be an important

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... rapeutic modality to overcome resistance to current anti-cancer treatments. It's known that deprivation of tumor bioenergetics by dual inhibition of aerobic and anaerobic pathways may work for cancer treatment. This study investigated whether the combination of 2-deoxygluxose (2-DG) and metformin inhibit gCSCs. We evaluated the antitumor activity of 2-DG, metformin alone, and combination of 2-DG and metformin. 2-DG alone did hardly affect cell viability, however, metformin alone showed dose-dependent antitumor effect on gCSC line. Moreover, 2-DG in combination either with 5mmol/L or 15mmol/L of metformin induced 100% of cell death. When gCSC line was treated with combined 2-DG and metformin, surface markers of gCSC such as Nestin, CD133 and stemness-regulating transcription factors including Sox-2 and Notch4 were both suppressed. On the contrary, adherent cells expressing Olig2, GFAP, Tuj1 were newly formed from neurospheres under treatment of combined 2-DG and metformin, which implies neuro-glial differentiation. 3D invasion test showed that treatment of combined 2-DG and metformin significantly reduced invasiveness of gCSCs with decreased expression of surface markers for invasion like Snail, zeb1, b-catenin and N-cadherin. In mouse xenograft models, 2-DG plus metformin treatment effectively inhibited tumor growth. The combination of 2-DG and metformin may be helpful in the treatment of gliomas by targeting gCSCs.