Because
radiotherapy significantly increases median survival in patients with
glioblastoma, 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
radiotherapy. Metabolically, the elevated glycolysis in
glioblastoma cells was observed postradiotherapy together with upregulated
hypoxia-inducible factor (HIF)-1α and its target
pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate, 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. Dichloroacetate alone demonstrated modest antitumor effects in both in vitro and in vivo models of
glioblastoma and has the ability to reverse the
radiotherapy-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of
glioblastoma cells was observed when dichloroacetate was combined with
radiotherapy. Further mechanistic investigation revealed that dichloroacetate sensitized
glioblastoma cells to
radiotherapy 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
glioblastoma cells together with
radiotherapy. In vivo, the combinatorial treatment of dichloroacetate and
radiotherapy improved the survival of orthotopic
glioblastoma-bearing mice. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize
glioblastoma cells to
radiotherapy by modulating the metabolic state of
tumor cells. These findings warrant further evaluation of the combination of dichloroacetate and
radiotherapy in clinical trials.