Hypersensitization of tumor cells to glycolytic inhibitors
Hypersensitization of tumor cells to glycolytic inhibitors
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DOI：
10.1021/bi002426w
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发表时间：
2001-05-08
期刊：
影响因子：
2.9
通讯作者：
Lampidis, TJ
中科院分区：
文献类型：
--
作者：
Liu, H;Hu, YP;Lampidis, TJ
实体瘤内核中细胞的缓慢生长呈现出对大多数标准化疗剂的多药耐药形式，其靶向外部更快速分裂的细胞。然而，位于更中心的肿瘤细胞的厌氧环境也提供了利用其对糖酵解的依赖性获得治疗效果的机会。我们已经开发了两种体外模型来研究这种可能性。模型A代表用通过以不同方式与电子传递链的复合物I、III和V相互作用来抑制线粒体氧化磷酸化（Oxphos）的试剂处理的骨肉瘤野生型（wt）细胞，即，罗丹明123（Rho 123）、鱼藤酮、抗霉素A和寡霉素。发现所有这些药剂都使野生型细胞对糖酵解抑制剂2-脱氧葡萄糖超敏。用Rho 123处理的细胞也变得对草氨酸（oxamate）过敏，草氨酸是丙酮酸的类似物，其阻断将丙酮酸转化为乳酸的糖酵解步骤。模型B是rho（0）细胞，其已经失去了它们的线粒体DNA，因此不能经历Oxphos。这些细胞对2-脱氧葡萄糖和草氨酸的敏感性分别是野生型细胞的10倍和4.9倍。乳酸水平是无氧代谢的一个指标，在rho（0）细胞中的乳酸水平比野生型细胞高3倍以上。此外，当用Rho 123处理野生型细胞时，乳酸量随着Rho 123剂量的增加而增加。在类似的Rho 123处理下，rho（0）细胞没有增加其乳酸水平。这些数据证实了细胞模型A和B由于其对厌氧代谢的依赖性而对糖酵解抑制剂具有相似的敏感性。总的来说，我们的体外结果表明，糖酵解抑制剂可用于特异性靶向肿瘤的缓慢生长细胞，从而提高目前设计用于杀死快速分裂细胞的化疗和照射方案的功效。此外，糖酵解抑制剂与抗血管生成剂联合使用可能特别有用，这在先验上应该使肿瘤更厌氧。
The slow growth of cells in the inner core of solid tumors presents a form of multidrug resistance to most of the standard chemotherapeutic agents, which target the outer more rapidly dividing cells. However, the anaerobic environment of the more centrally located tumor cells also provides an opportunity to exploit their dependence on glycolysis for therapeutic gain. We have developed two in vitro models to investigate this possibility. Model A represents osteosarcoma wild-type (wt) cells treated with agents which inhibit mitochondrial oxidative phosphorylation (Oxphos) by interacting with complexes I, III, and V of the electron transport chain in different ways, i.e., rhodamine 123 (Rho 123), rotenone, antimycin A, and oligomycin. All of these agents were found to hypersensitize wt cells to the glycolytic inhibitor 2-deoxyglucose. Cells treated with Rho 123 also become hypersensitive to oxamate, an analogue of pyruvate, which blocks the step of glycolysis that converts pyruvate to lactic acid. Model B is rho (0) cells which have lost their mitochondrial DNA and therefore cannot undergo Oxphos. These cells are 10 and 4.9 times more sensitive to 2-deoxyglucose and oxamate, respectively, than wt cells. Lactic acid levels, which are a measure of anaerobic metabolism, were found to be >3 times higher in rho (0) than in wt cells. Moreover, when wt cells were treated with Rho 123, lactic acid amounts increased as a function of increasing Rho 123 doses. Under similar Rho 123 treatment, rho (0) cells did not increase their lactic acid levels. These data confirm that cell models A and B are similarly sensitive to glycolytic inhibitors due to their dependence on anaerobic metabolism. Overall, our in vitro results suggest that glycolytic inhibitors could be used to specifically target the slow-growing cells of a tumor and thereby increase the efficacy of current chemotherapeutic and irradiation protocols designed to kill rapidly dividing cells. Moreover, glycolytic inhibitors could be particularly useful in combination with anti-angiogenic agents, which, a priori, should make tumors more anaerobic.