Simons Andrean L, Ahmad Iman M, Mattson David M, Dornfeld Kenneth J, Spitz Douglas R
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USA.
Cancer Res. 2007 Apr 1;67(7):3364-70. doi: 10.1158/0008-5472.CAN-06-3717.
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-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.
葡萄糖剥夺被认为可通过在人类癌细胞中诱导代谢性氧化应激而导致细胞毒性。目前的研究检验了这样一个假设，即2-脱氧-D-葡萄糖（2DG）与顺铂[顺二氨二氯铂（II）]联合使用可通过涉及氧化应激的机制增强对人类头颈癌细胞（FaDu）的细胞毒性。与单独使用2DG或顺铂相比，将FaDu细胞暴露于2DG和顺铂的联合作用下会导致细胞存活率显著降低。用2DG和顺铂处理还会引起指示氧化应激的参数发生扰动，包括细胞内总谷胱甘肽减少和谷胱甘肽二硫化物百分比增加。同时用硫醇抗氧化剂N-乙酰半胱氨酸（NAC）处理可抑制指示氧化应激的参数，并保护FaDu细胞免受单独顺铂以及2DG和顺铂联合作用的细胞毒性影响。此外，聚乙二醇共轭抗氧化酶（聚乙二醇超氧化物歧化酶和聚乙二醇过氧化氢酶）也保护FaDu细胞免受2DG毒性的影响。谷胱甘肽合成抑制剂L-丁硫氨酸-[S，R]-亚砜胺（BSO）使FaDu细胞对2DG和顺铂的细胞毒性作用敏感，而这些作用可被NAC抑制。此外，2DG、顺铂和BSO的联合使用显著增加了谷胱甘肽二硫化物的百分比，这也被NAC抑制。这些结果支持了这样一个假设，即人类头颈癌细胞暴露于2DG和顺铂联合作用下可通过代谢性氧化应激增强细胞毒性。这些发现为评估葡萄糖和过氧化氢代谢抑制剂与顺铂联合用于头颈癌治疗提供了强有力的生化依据。
