Primasová Hedvika, Paul Lydia E H, Diserens Gaëlle, Primasová Ester, Vermathen Peter, Vermathen Martina, Furrer Julien
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
Department of BioMedical Research and Radiology, University of Bern and Inselspital, Erlachstrasse 9a, 3012 Bern, Switzerland.
Metabolites. 2019 Jul 18;9(7):146. doi: 10.3390/metabo9070146.
The trithiolato bridged diruthenium complex DiRu-1 [(p-MeCHPr)Ru(SCH-p-Bu)] is highly cytotoxic against various cancer cell lines, but its exact mode of action remains unknown. The present H HR-MAS NMR-based metabolomic study was performed on ovarian cancer cell line A2780, on its cis-Pt resistant variant A2780cisR, and on the cell line HEK-293 treated with 0.03 µM and 0.015 µM of DiRu-1 corresponding to full and half IC doses, respectively, to investigate the mode of action of this ruthenium complex. The resulting changes in the metabolic profile of the cell lines were studied using HR-MAS NMR of cell lysates and a subsequent statistical analysis. We show that DiRu-1 in a 0.03 µM dose has significant impact on the levels of a number of metabolites, such as glutamine, glutamate, glutathione, cysteine, lipid, creatine, lactate, and acetate, especially pronounced in the A2780cisR cell line. The IC/2 dose shows some significant changes, but full IC appears to be necessary to observe the full effect. Overall, the metabolic changes observed suggest that redox homeostasis, the Warburg effect, and the lipid metabolism are affected by DiRu-1.
三硫醇桥联二钌配合物DiRu-1 [（对甲基环己基）钌（硫代对叔丁基苯）] 对多种癌细胞系具有高度细胞毒性，但其确切作用方式尚不清楚。本研究基于高分辨魔角旋转核磁共振（HR-MAS NMR）的代谢组学方法，对卵巢癌细胞系A2780、其顺铂耐药变体A2780cisR以及分别用0.03 μM和0.015 μM的DiRu-1处理的人胚肾细胞系HEK-293（分别对应完全抑制浓度和半数抑制浓度）进行了研究，以探究这种钌配合物的作用方式。利用细胞裂解物的HR-MAS NMR和随后的统计分析，研究了细胞系代谢谱的变化。我们发现，0.03 μM剂量的DiRu-1对多种代谢物水平有显著影响，如谷氨酰胺、谷氨酸、谷胱甘肽、半胱氨酸、脂质、肌酸、乳酸和乙酸盐，在A2780cisR细胞系中尤为明显。半数抑制浓度剂量显示出一些显著变化，但似乎需要完全抑制浓度才能观察到全部效果。总体而言，观察到的代谢变化表明，氧化还原稳态、瓦伯格效应和脂质代谢受到DiRu-1的影响。
