Ben-Horin H, Tassini M, Vivi A, Navon G, Kaplan O
School of Chemistry, Tel-Aviv University, Israel.
Cancer Res. 1995 Jul 1;55(13):2814-21.
The mechanism of action of the antineoplastic drug lonidamine (LND) on MCF-7 human breast cancer cells was studied with the use of 31P and 13C nuclear magnetic resonance (NMR) spectroscopy. The cells were embedded in alginate microcapsules, perfused with growth media and LND at physiological conditions in the NMR tube, and continuously monitored in vivo for the effects of LND. 31P NMR demonstrated intracellular acidification after LND perfusion concomitant with ATP depletion and changes in phospholipid metabolites. 13C NMR showed marked LND-induced accumulation of lactate, and spectra of the perfusate disclosed that LND inhibited lactate transport. Kinetic 13C NMR also furnished information on LND effects on glucose metabolism; LND decreased initial glucose uptake and lactate formation, although the final intracellular glucose levels were higher compared with those in controls. Combined administration of LND and the metabolic inhibitor 2-deoxyglucose yielded additive but not synergistic cytotoxicity and enabled assessment of hexokinase activity. Overall, the results indicate that the major metabolic changes induced by LND are inhibition of lactate transport and its accumulation, which lead to intracellular acidification.
利用磷-31(31P)和碳-13(13C)核磁共振(NMR)波谱技术研究了抗肿瘤药物氯尼达明(LND)对MCF-7人乳腺癌细胞的作用机制。将细胞包埋于藻酸盐微胶囊中,在核磁共振管内的生理条件下用生长培养基和LND进行灌注,并在体内持续监测LND的作用效果。磷-31核磁共振显示,LND灌注后细胞内发生酸化,同时伴有三磷酸腺苷(ATP)耗竭以及磷脂代谢产物的变化。碳-13核磁共振显示,LND显著诱导乳酸蓄积,灌注液的波谱表明LND抑制乳酸转运。动态碳-13核磁共振还提供了LND对葡萄糖代谢影响的信息;LND降低了初始葡萄糖摄取和乳酸生成,尽管最终细胞内葡萄糖水平高于对照组。联合给予LND和代谢抑制剂2-脱氧葡萄糖产生了相加而非协同的细胞毒性作用,并能够评估己糖激酶活性。总体而言,结果表明LND诱导的主要代谢变化是抑制乳酸转运及其蓄积,进而导致细胞内酸化。