2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells

Glucose deprivation has been hypothesized to cause cytotoxicity by inducing metabolic oxidative stress in human cancer cells. The current work tests the hypothesis that 2-deoxy-D-glucose (2DG) combined with cisplatin [cis-diamminedichloroplatinum(II)] can enhance cytotoxicity in human head and neck cancer cells (FaDu) by mechanisms involving oxidative stress. Exposure of FaDu cells to the combination of 2DG and cisplatin resulted in a significant decrease in cell survival when compared with 2DG or cisplatin alone. Treatment with 2DG and cisplatin also caused perturbations in parameters indicative of oxidative stress, including decreased intracellular total glutathione and increased percentage of glutathione disulfide. Simultaneous treatment with the thiol antioxidant N-acetyl-cysteine (NAC) inhibited parameters indicative of oxidative stress, as well as protected FaDu cells from the cytotoxic effects of cisplatin alone and the combination of 2DG and cisplatin. In addition, polyethylene glycol-conjugated antioxidant enzymes (PEG-superoxide dismutase and PEG-catalase) also protected FaDu cells from 2DG toxicity. An inhibitor of glutathione synthesis, L-buthionine-[S,R]-sulfoximine (BSO), sensitized FaDu cells to the cytotoxic effects of 2DG and cisplatin, and these effects were inhibited by NAC. Furthermore, the combination of 2DG, cisplatin, and BSO significantly increased the percentage of glutathione disulfide, which was also inhibited by NAC. These results support the hypothesis that exposure of human head and neck cancer cells to 2DG combined with cisplatin enhances cytotoxicity via metabolic oxidative stress. These findings provide a strong biochemical rationale for evaluating inhibitors of glucose and hydroperoxide metabolism in combination with cisplatin for the treatment of head and neck cancer.