Gottschalk Sven, Anderson Nora, Hainz Carsten, Eckhardt S Gail, Serkova Natalie J
Department of Biology/Chemistry, University of Bremen, Bremen, Germany.
Clin Cancer Res. 2004 Oct 1;10(19):6661-8. doi: 10.1158/1078-0432.CCR-04-0039.
The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1-13C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC50, 0.69 +/- 0.06 micromol/L) and K562 cells (IC50, 0.47 +/- 0.04 micromol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 micromol/L) decreased glucose uptake from the media by suppressing glycolytic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 micromol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 micromol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.
甲磺酸伊马替尼（格列卫）的治疗效果基于其对BCR-ABL癌基因蛋白的特异性抑制，该蛋白是慢性粒细胞白血病（CML）细胞中广泛表达的一种酪氨酸激酶。本研究的目的是评估对伊马替尼敏感的BCR-ABL阳性细胞中的葡萄糖代谢。将两个人类BCR-ABL阳性细胞系（CML-T1和K562）和一个BCR-ABL阴性细胞系（HC-1）与不同浓度的伊马替尼孵育96小时。对细胞酸提取物进行磁共振波谱分析，以评估与伊马替尼孵育后的[1-13C]葡萄糖代谢、能量状态和内源性代谢物的变化。伊马替尼对CML-T1细胞（IC50，0.69±0.06微摩尔/升）和K562细胞（IC50，0.47±0.04微摩尔/升）的细胞增殖具有浓度依赖性抑制作用，但对HC-1细胞无此作用。伊马替尼处理的HC-1细胞没有代谢变化。在BCR-ABL阳性细胞中，伊马替尼的相关治疗浓度（0.1 - 1.0微摩尔/升）通过抑制糖酵解细胞活性降低了从培养基中摄取葡萄糖的量（在0.25毫摩尔/升时，K562细胞中C3-乳酸降低65%，CML-T1细胞中降低77%，与对照组相比）。此外，线粒体三羧酸循环的活性增加（在0.25微摩尔/升时，K562细胞中C4-谷氨酸增加147%，CML-T1细胞中增加170%）。线粒体葡萄糖代谢的改善导致能量状态增加（在0.25微摩尔/升时，K562细胞中三磷酸核苷/二磷酸核苷增加130%，CML-T1细胞中增加125%）。在较高浓度下观察到细胞凋亡。与标准化疗药物不同，伊马替尼没有杀细胞活性，它通过从糖酵解转变为线粒体葡萄糖代谢来逆转BCR-ABL阳性细胞中的瓦伯格效应，从而导致葡萄糖摄取减少和能量状态升高。
