Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation.
Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation.
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DOI：
10.1042/bj20081258
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发表时间：
2009-02-15
期刊：
影响因子：
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通讯作者：
Spitz DR
中科院分区：
文献类型：
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作者：
Aykin-Burns N;Ahmad IM;Zhu Y;Oberley LW;Spitz DR
相对于正常细胞，癌细胞表现出对葡萄糖剥夺诱导的细胞毒性的敏感性增加。为了确定由O2·−和氢过氧化物介导的氧化应激是否有助于人类上皮癌细胞对葡萄糖剥夺的不同敏感性，（DHE;表示O2·−）和5-（和-6）-羧基-2 '，7'-二氯二氢荧光素二乙酸酯在人结肠癌和乳腺癌细胞（HT 29、HCT 116、SW 480、MB 231）中测量了细胞因子（CDCFH 2;对于氢过氧化物），并与正常人细胞（FHC、33 Co、HMEC）进行了比较。癌细胞显示DHE（2-20倍）和CDCFH 2（1.8-10倍）氧化的显著增加，相对于在线粒体电子传递链阻断剂抗霉素A存在下更明显的正常细胞。此外，HCT 116和MB 231细胞更容易受到葡萄糖剥夺诱导的细胞毒性和氧化应激，相对于33 Co和HMEC。HT-29细胞也更容易受到2-脱氧葡萄糖（2DG）诱导的细胞毒性，相对于FHC。过表达锰超氧化物歧化酶和过氧化氢酶显著保护HCT 116和MB 231细胞免受葡萄糖剥夺诱导的细胞毒性和氧化应激，以及保护HT-29细胞免受2DG诱导的细胞毒性。这些结果表明，癌细胞（相对于正常细胞）表现出活性氧（ROS，即O2·−和H2 O2）的稳态水平增加，这有助于对葡萄糖剥夺诱导的细胞毒性和氧化应激的不同敏感性。这些研究支持癌细胞增加葡萄糖代谢以补偿ROS的过量代谢产生以及葡萄糖和氢过氧化物代谢的抑制可以提供用于选择性地增强人类癌细胞中的细胞毒性和氧化应激的生化靶标的假设。
Cancer cells, relative to normal cells, demonstrate increased sensitivity to glucose deprivation-induced cytotoxicity. To determine if oxidative stress mediated by O2•− and hydroperoxides contributed to the differential susceptibility of human epithelial cancer cells to glucose deprivation, oxidation of dihydroethidine (DHE; for O2•−) and 5-(and-6)-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (CDCFH2; for hydroperoxides) were measured in human colon and breast cancer cells (HT29, HCT116, SW480, MB231) and compared to normal human cells (FHC, 33Co, HMEC). Cancer cells showed significant increases in DHE (2–20 fold) and CDCFH2 (1.8–10 fold) oxidation, relative to normal cells that were more pronounced in the presence of the mitochondrial electron transport chain blocker, antimycin A. Furthermore, HCT116 and MB231 cells were more susceptible to glucose deprivation-induced cytotoxicity and oxidative stress, relative to 33Co and HMEC. HT-29 cells were also more susceptible to 2-deoxyglucose-(2DG)-induced cytotoxicity, relative to FHC. Over expression of manganese superoxide dismutase and mitochondrially targeted catalase significantly protected HCT116 and MB231 cells from glucose deprivation-induced cytotoxicity and oxidative stress, as well as protecting HT-29 cells from 2DG-induced cytotoxicity. These results show cancer cells (relative to normal cells) demonstrate increased steady-state levels of reactive oxygen species (ROS, i.e. O2•− and H2O2) that contribute to differential susceptibility to glucose deprivation-induced cytotoxicity and oxidative stress. These studies support the hypotheses that cancer cells increase glucose metabolism to compensate for excess metabolic production of ROS as well as that inhibition of glucose and hydroperoxide metabolism may provide a biochemical target for selectively enhancing cytotoxicity and oxidative stress in human cancer cells.