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

Abstract

The trithiolato bridged diruthenium complex DiRu-1 [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)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.

1H HR-MAS NMR Based Metabolic Profiling of Lung Cancer Cells with Induced and De-Induced Cisplatin Resistance to Reveal Metabolic Resistance Adaptations

“…This was ascribed in part to the activation of cellular anti-oxidative reactions through GSH synthesis compensating GSH loss [12,13]. Unlike cisPt, ruthenium-based surrogates [15,16] and other anti-cancer drugs [31] induced increased GSH levels in cisPt-sensitive A2780 cells upon treatment. Since these drugs are proposed to follow alternative cell death pathways other than DNA-damage, their GSH consumption may be reduced.…”

“…In particular, the impact of cisPt on the metabolic profile of various cancer cell lines has been addressed by HR-MAS NMR-based chemometric analyses and has led to the identification of biomarkers for treatment response [12][13][14]. Recently, the metabolic alterations in cisPt sensitive and resistant A2780 cells following treatment with Ruthenium complexes as alternatives to cisPt were shown [15,16].…”

Dinuclear thiolato-bridged arene ruthenium complexes: from reaction conditions and mechanism to synthesis of new complexes

“…13,19,21,22 Recent in vivo studies have demonstrated that these complexes indeed have potential as anticancer drugs, since for instance the compound [(h 6 -p-MeC 6 H 4 Pr i ) 2 Ru 2 (m 2 -S-p-C 6 H 4 Bu t ) 3 ]Cl (termed diruthenium-1) signicantly prolongs the survival of tumour-bearing mice 25 and substantially inuences metabolism of A2780cisR cells involving changes related to redox homeostasis, Warburg effect and lipid metabolism. 45 Other derivatives appear less promising. 44,46 Dinuclear thiolato-bridged arene ruthenium complexes are also promising as antiprotozoal agents, with IC 50 values of up to 1.2 nM against T. gondii, N. caninum and T. brucei and IC 50 values against human foreskin broblasts >800 mM, leading to selectivity indexes >20 000.…”

Synthetic Route of Trithiolato-Bridged Dinuclear Arene Ruthenium(II) Complexes [(η6-P-MeC6H4Pri)2Ru2(μ2-SR)3]+

“…13,19,21,22 Recent in vivo studies have demonstrated that these complexes indeed have potential as anticancer drugs, since for instance the compound [(η 6 -p-MeC6H4Pr i )2Ru2(µ2-S-p-C6H4Bu t )3]Cl (termed diruthenium-1) significantly prolongs the survival of tumour-bearing mice 25 and substantially influences metabolism of A2780cisR cells involving changes related to redox homeostasis, Warburg effect and lipid metabolism. 45 Other derivatives appear less promising. 44,46 Dinuclear thiolatobridged arene ruthenium complexes are also promising as antiprotozoal agents, with IC50 values of up to 1.2 nM against T. gondii, N. Caninum and T. Brucei and IC50 values against human foreskin fibroblasts > 800 µM, leading to selectivity indexes > 20'000.…”