Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions
Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions
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DOI：
10.1007/s00280-003-0724-7
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发表时间：
2004-02-01
影响因子：
3
通讯作者：
Lampidis, TJ
中科院分区：
文献类型：
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作者：
Maher, JC;Krishan, A;Lampidis, TJ
目的。为了研究在实体瘤缺氧区发现的细胞比有氧生长的细胞对糖酵解抑制剂更敏感的假设，我们先前描述了模拟这种情况的三个不同的体外模型(A、B和C)。在所有的模型中，都表明在低氧条件下生长的细胞对糖酵解抑制剂2-脱氧-D-葡萄糖(2-DG)高度敏感。然而，在这些研究中，细胞抑制作用和细胞毒性作用并没有相互区分。由于癌症的成功治疗不仅包括减缓而且实际上还包括杀死肿瘤细胞，因此开展了评估2-DG对细胞周期进展和细胞死亡的影响的研究。方法和结果。应用流式细胞术和细胞活力分析发现，与有氧生长的对照细胞相比，2-DG在所有三种低氧模型中都引起了显著的细胞周期抑制和细胞死亡。在A模型(用罗丹明123阻断氧化磷酸化的化学低氧模型)中，1200ug/ml2-DG诱导的细胞周期停滞在S/G晚期(2)，细胞死亡多于3600ug/ml2-dG处理的有氧细胞。在Rho(0)细胞中，当考虑到2-DG对细胞周期停滞和细胞死亡的影响时，发现在基因构建为不能执行氧化磷酸化(模型B)的Rho(0)细胞中，缺氧和有氧细胞之间的选择性窗口更大(超过10倍)。在环境模型(模型C)中，细胞生长在减少的外部氧气(0.1%)下，也观察到了对2-DG的细胞周期停滞和细胞死亡的影响的过敏性。结论。总体而言，这些结果表明，在厌氧条件下生长的细胞对2-DG对细胞周期抑制和细胞死亡的影响比在有氧条件下生长的细胞反应更敏感。这支持了我们的观点，即添加到标准化疗方案中的糖酵解抑制剂应该通过选择性地杀死生长缓慢的细胞来提高治疗效果，这些细胞存在于实体肿瘤的缺氧部分，同时保留了大多数也生长缓慢但生活在有氧条件下的正常细胞。
Purpose. In order to investigate the hypothesis that cells found in hypoxic areas of solid tumors are more sensitive to glycolytic inhibitors than cells growing aerobically, we have previously characterized three distinct in vitro models (A, B and C) that simulate this condition. In all of the models it was shown that cells growing under hypoxic conditions are hypersensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). However, in those studies cytostatic and cytotoxic effects were not distinguished from one another. Since successful treatment of cancer includes not only slowing down but also actually killing tumor cells, studies were undertaken to assess the effects of 2-DG on cell cycle progression and cell death. Methods and results. Using flow cytometry and cell viability assays, it was found that 2-DG caused significantly greater cell cycle inhibition and cell death in all three hypoxic models as compared to aerobically growing control cells. In model A (a chemically induced model of hypoxia in which rhodamine-123 is used to block oxidative phosphorylation), 1200 mug/ml of 2-DG was shown to induce more cell cycle arrest in late S/G(2) and more cell death than in the aerobic cell counterpart treated with 3600 mug/ml 2-DG. In rho(0) cells which are genetically constructed to be unable to perform oxidative phosphorylation (model B), an even greater window of selectivity (more than tenfold) between hypoxic and aerobic cells was found when considering 2-DG's effects on cell cycle arrest and cell death. In the environmental model (model C), where cells were grown under reduced amounts of external oxygen (0.1%), hypersensitivity to the effects of 2-DG with respect to cell cycle arrest and cell death were also observed. Conclusions. Overall, these results indicate that cells growing under anaerobic conditions respond with greater sensitivity to the effects of 2-DG on cell cycle inhibition and cell death than those growing under aerobic conditions. This supports our contention that glycolytic inhibitors added to standard chemotherapeutic protocols should increase treatment efficacy by selectively killing the slow-growing cells, which are found in the hypoxic portions of solid tumors, while sparing most of the normal cells that are also slow-growing but are living under aerobic conditions.