2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer Cells

Abstract

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-Dglucose (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-acetylcysteine (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. [Cancer Res 2007;67(7):3364-70]

Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death

“…Although 2-DG alone is poorly effective in vivo, it was successfully used in combination with chemotherapeutic agents, radiotherapy or metformin in vitro and in animal models. 19,38,39 Consequently, the resistance to energetic stress-induced apoptosis is an important issue in cancer biology. Our study demonstrates that Sesn2 mediates this resistance against 2-DG; therefore, a low expression of Sesn2 in tumors should be predictive of a better response to therapies targeting cancer cell metabolism.…”

2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress

“…Recent reports also documented that the combination of ionizing radiation and adenoviral p53 gene therapy increased radiosensitivity of both p53-mutant and wild type cancer cells [7;8;35]. In addition several reports have suggested that p53 over expression can induce oxidative stress and alterations in respiration in cancer cells [1,2,9,10,20,36] and that 2DG can enhance cell killing in malignant cells by agents that induce metabolic oxidative stress [3,4,37]. Finally, several investigators have reported that androgenindependent prostate cancer cells have a high frequency of p53 mutations [38;39].…”

“…The biochemical rationale for this combination to enhance cancer cell killing was based on previous results in other human cancer cells suggesting that 2DG would inhibit glucose metabolism leading to a reduction in intracellular pyruvate and NADPH [3,4,37], limiting the capacity of the tumor cells to metabolize hydroperoxides [4,15,25], and p53 would increase metabolic hydroperoxide production [1,2,20,36] leading to enhanced oxidative stress. As shown in our results the combination of 2DG and Adp53 lead to over expression of p53 (Figure 1), increased clonogenic cell killing (Figure 2 and Figure 3), and increased oxidative stress that appeared to be mediated by increased steady-state levels of hydroperoxides including H 2 O 2 (Fig 4-Fig 6) in prostate cancer cells.…”

The p53/p21WAF/CIP Pathway Mediates Oxidative Stress and Senescence in Dyskeratosis Congenita Cells with Telomerase Insufficiency

“…GSH levels were measured as described previously (45). Briefly, fibroblasts were scraped harvested, spun down, and homogenized in 50 mmol=L potassium phosphate buffer (pH 7.8) containing 1.34 mmol=L diethylenetriaminepentaacetic acid buffer.…”