Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, P.O. Box 016960 (R124), Miami, FL, 33101, USA.
Cancer Chemother Pharmacol. 2014 Feb;73(2):417-27. doi: 10.1007/s00280-013-2366-8. Epub 2013 Dec 19.
Although cisplatin is the drug of choice in treating lung cancer patients, relapse and resistance is a common drawback to its clinical effectiveness. Based on cisplatin's reported ability to interfere with numerous cellular components, including mitochondria, we probed alterations in metabolism in cisplatin-resistant tumor cell lines to reveal targets for overcoming this important form of resistance.
Cisplatin-resistant lung and ovarian cancer cell lines were used to evaluate the efficacy of metabolic inhibitors for selectively targeting cisplatin-resistant cells under varying oxygen conditions.
Three cisplatin-resistant cancer cell lines expressed lower HKII protein when compared to the respective cisplatin-sensitive cancer cell lines from which they were derived. Under anaerobic and hypoxic conditions, treatment with the glycolytic inhibitors 2-deoxyglucose (2-DG) and 2-fluorodeoxyglucose (2-FDG) correlated with increased cytotoxicity and more pronounced decreases in lactate production in cisplatin-resistant cells, indicating a greater blockage of glycolysis. Knockdown of HKI or HKII with siRNA in the parental lung cancer cell lines led to increased 2-FDG-induced cell death under anaerobic conditions. Under normal oxygen conditions, blockage of either fatty acid oxidation or deprivation of glutamine resulted in cell death in cisplatin-resistant lung cancer cell lines.
Altered hexokinase levels in cisplatin-resistant cancer cell lines leads to increased sensitivity to glycolytic inhibition under anaerobic conditions, whereas under normoxic conditions, blockage of either fatty acid oxidation or deprivation of glutamine leads to cell death. These findings may be clinically applicable when considering cisplatin resistance.
尽管顺铂是治疗肺癌患者的首选药物，但复发和耐药是其临床疗效的常见缺点。基于顺铂据报道能够干扰包括线粒体在内的许多细胞成分，我们探讨了代谢在顺铂耐药肿瘤细胞系中的变化，以揭示克服这种重要耐药形式的靶点。
使用顺铂耐药的肺癌和卵巢癌细胞系来评估代谢抑制剂在不同氧条件下选择性靶向顺铂耐药细胞的疗效。
与它们衍生的相应顺铂敏感癌细胞系相比，三种顺铂耐药癌细胞系表达的 HKII 蛋白较低。在厌氧和缺氧条件下，用糖酵解抑制剂 2-脱氧葡萄糖（2-DG）和 2-氟脱氧葡萄糖（2-FDG）处理与顺铂耐药细胞中细胞毒性增加和乳酸产生减少更明显相关，表明糖酵解的阻断更明显。用 siRNA 在亲本肺癌细胞系中敲低 HK1 或 HK2 导致在厌氧条件下 2-FDG 诱导的细胞死亡增加。在正常氧条件下，阻断脂肪酸氧化或剥夺谷氨酰胺会导致顺铂耐药肺癌细胞系的细胞死亡。
顺铂耐药癌细胞系中己糖激酶水平的改变导致在厌氧条件下对糖酵解抑制的敏感性增加，而在正常氧条件下，阻断脂肪酸氧化或剥夺谷氨酰胺会导致细胞死亡。这些发现可能在考虑顺铂耐药时具有临床应用价值。
