¹H HR-MAS NMR-Based Metabolomics of Cancer Cells in Response to Treatment with the Diruthenium Trithiolato Complex [(p-MeC₆H₄ⁱPr)₂Ru₂(SC₆H₄- p-Bu^t)₃]⁺ (DiRu-1)

The trithiolato bridged diruthenium complex DiRu-1 [(p-MeC₆H₄ⁱPr)₂Ru₂(SC₆H₄-p-Bu^t)₃]⁺ is highly cytotoxic against various cancer cell lines, but its exact mode of action remains unknown. The present ¹H 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 IC₅₀ 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 IC₅₀/2 dose shows some significant changes, but full IC₅₀ 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.