Abstract
[Purpose] The upregulation of aerobic glycolysis, known as Warburg effect, is one of the metabolic changes prevalent in solid tumors. Warburg effect is characterized by reliance on glycolysis, which is mitochondrial-independent, regardless of oxygen availability. We have recently observed that X-irradiation activated mitochondrial electron transport chain, leading to the activation of apoptosis signaling pathway. In this study, we examined whether the modulation of cellular energy metabolism could enhance radiation-induced cell death.
[Materials and Methods] SCC VII cells derived from mice floor of the mouth squamous carcinoma were used in this study. Two pharmacological inhibitors: 2-deoxy-D-glucose (2DG) as a glycolysis inhibitor and dichroloacetate (DCA) as a pyruvate dehydrogenase kinase (PDK) inhibitor, were used. The effect of these drugs on the radiation-induced reproductive cell death was evaluated by clonogenic assay. Furthermore, in vivo experiment, the effect of 2DG combined with X-irradiation on the tumor growth was examined in SCC VII cells transplanted in C3H/HeJ mice.
[Result] Radiation-induced reproductive cell death was significantly enhanced by 2DG and DCA, respectively. This result suggested that the potential of these drugs as radiosensitizers for tumor cells. We also observed distinct suppression of tumor growth by 2DG combined with X-irradiation in vivo experiment. Since DCA was known to activate pyruvate dehydrogenase by inhibiting PDK and promote the following production of acetyl-CoA for the activation of mitochondrial function, it was suggested that the modification of cellular energy metabolism, i.e., inhibition of glycolysis and activation of mitochondrial energy metabolism, induced the enhancement of the radiation-induced cell death.
