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).

Primasová Primasová,Paul Paul,Vermathen Vermathen,Diserens Diserens,Furrer Furrer

doi:10.3390/metabo9070146

Primasová Primasová, Paul Paul + Show 3 more

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https://doi.org/10.3390/metabo9070146

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Journal: Metabolites	Publication Date: Jul 18, 2019
Citations: 9	License type: CC BY 4.0

Affiliation: University of Bern, University Hospital of Bern

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.

Highlights

Fifty years after the discovery of its antiproliferative properties, Cis-platin (Cis-Pt) is the most used metal-based drug in cancer treatment
There is a significant difference in observable signals such as the ones corresponding to the ω-CH3, (–CH2 )n, and α-CH2 groups
The 1 H high resolution magic angle spinning (HR-MAS) NMR 1-D NOESY and T2 -filtered PROJECT [23] spectra of the lysed and untreated cells are shown in Figure 2 and Figures S1 and S2, respectively

Summary

Introduction

Fifty years after the discovery of its antiproliferative properties, Cis-platin (Cis-Pt) is the most used metal-based drug in cancer treatment. It has been used over decades for the treatment of ovarian, testicular, and other types of cancer and is still used today in combination with other drugs in more than 50% of all chemotherapies [1]. The numerous side effects and the emergence of resistance have encouraged further development of platinum compounds as well as of other metal-based compounds as anticancer drug candidates. Out of the numerous arene ruthenium (II) compounds synthesized and evaluated so far, RAPTA-C from the RAPTA family and RM175

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