Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism
Menée sur des cellules de glioblastome et à l'aide d'un modèle murin, cette étude montre que le dichloroacétate, un inhibiteur de la pyruvate déshydrogénase kinase 1, peut sensibiliser les cellules tumorales aux rayonnements ionisants en agissant sur le métabolisme du glucose
Since radiotherapy (RT) significantly increases median survival in patients with glioblastoma (GBM), the modulation of radiation resistance is 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 RT. Metabolically, the elevated glycolysis in GBM cells was observed post-RT together with upregulated hypoxia inducible factor (HIF)-1
α and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate (DCA), a PDK inhibitor 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 in both in vitro and in vivo models of GBM and has ability to reverse the RT-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of GBM cells was observed when DCA was combined with RT. Further mechanistic investigation revealed that DCA sensitized GBM cells to RT by inducing the cell cycle arrest at the G2/M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in GBM cells together with RT. In vivo, the combinatorial treatment of DCA and RT improved the survival of orthotopic GBM-bearing mice. In conclusion, this study provides the proof of concept that DCA can effectively sensitize GBM cells to RT by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of DCA and RT in clinical trials.
http://mct.aacrjournals.org/content/early/2015/06/10/1535-7163.MCT-15-0247.abstract