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• W2315702582 abstract "Since adjuvant radiotherapy significantly reduces the mortality and increases median survival in patients with glioblastoma (GBM), the radioresistance of GBM cells and targets to modify their radiation tolerance are of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance, thus the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Dichloroacetate (DCA), currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. DCA alone demonstrated modest anti-tumor effects on both in vitro and in vivo models of GBM. However, we herein describe a better efficacy when DCA is combined with radiotherapy. An enhanced inhibition of clonogenicity of a panel of GBM cells was observed when DCA was combined with irradiation. Further mechanistic investigation revealed that i) DCA sensitized GBM cells to irradiation by inducing the cell cycle arrest at G2/M phase, the most radiosensitive cell cycle phase; ii) DCA reduced mitochondrial reserve capacity, a measure of the ability of cells to resist oxidative stress; iii) DCA and irradiation synergistically boosted the oxidative stress and iv) induced DNA damage in GBM cells at a higher rate compared to each therapy alone. Metabolically, we observed that the glycolysis in GBM cells was induced post-irradiation by stabilizing the hypoxia inducible factor (HIF)-1α, which in turn activated its direct target pyruvate dehydrogenase kinase 1 (PDK1). This irradiation-induced glycolytic metabolism was blocked by the addition of DCA when the combination was administered. In conclusion, this study provides the proof of concept that DCA can effectively sensitize GBM cells to irradiation by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of DCA and radiotherapy in vivo using GBM xenografts." @default.
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• W2315702582 date "2014-11-01" @default.
• W2315702582 modified "2023-09-23" @default.
• W2315702582 title "ET-56 * SENSITIZATION OF GLIOBLASTOMA CELLS TO IRRADIATION BY MODULATING THE GLUCOSE METABOLISM" @default.
• W2315702582 doi "https://doi.org/10.1093/neuonc/nou255.53" @default.
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