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Tomsik 2015 J Organomet Chem

From Bioblast
Publications in the MiPMap
Tomsík P, Muthna D, Rezacova M, Micuda S, Cmielova J, Hroch M, Endlicher R, Cervinkova Z, Rudolf E, Hann S, Stíbal D, Therrien B, Süss-Fink G (2015) [(p-MeC6H4Pri)2Ru2(SC6H4-p-But)3]Cl (diruthenium-1), a dinuclear arene ruthenium compound with very high anticancer activity: An in vitro and in vivo study. J Organomet Chem 782:42-51.

» Science Direct

Tomsik P, Muthna D, Rezacova M, Micuda S, Cmielova J, Hroch M, Endlicher R, Cervinkova Z, Rudolf E, Hann S, Stibal D, Therrien B, Suess-Fink G (2015) J Organomet Chem

Abstract: Dinuclear p-cymene ruthenium complexes of the type [(p-MeC6H4Pri)2Ru2(SC6H4-p-But)3]+, accessible from the reaction of p-cymene ruthenium dichloride dimer with the corresponding thiophenol and isolated in high yield as the chloride salts, were found to be highly cytotoxic towards human ovarian cancer cells, the IC50 values being in the nanomolar range. Remarkably, the in vitro anticancer activity of these complexes is at least as good for the cisplatin-resistant mutant A2780cisR as for the normal A2780 cancer cell line. The most active compound of this series, [(p-MeC6H4Pri)2Ru2(SC6H4-p-But)3]Cl (diruthenium-1) with an IC50 value of only 30 nM for both cell lines, was selected for an in vivo anticancer study using a mouse model. The effects of diruthenium-1 on the growth of a solid Ehrlich tumour, inoculated subcutaneously in female NMRI mice, and on the survival rate of the tumour-bearing mice were studied. The maximum tolerated dose of diruthenium-1 for healthy animals was 2 mg/kg. Diruthenium-1 at doses of 0.4 and 0.6 mg/kg administered i.p. twice within 8 days inhibited the tumour growth, although somewhat less than cisplatin (5 mg/kg i.p.) in the positive control group. However, it was only diruthenium-1 at a dose of 0.6 mg/kg that prolonged significantly the survival rate of the tumour-bearing mice as compared to the untreated control group.

A biodistribution study by ICP-MS showed ruthenium to be present in the tumour and particularly in the excretion organs but not in the brain; the elimination half-life of diruthenium-1 was estimated to be approximately 30 h. In human breast cancer cells MCF-7 and BT-549, diruthenium-1 exhibited antiproliferative and cytotoxic effects, stimulated the expression and phosphorylation of p53, and modulated the expression of MAP kinases. The levels of ATP decreased but the lactate production rose. Supported by the observed inhibition of mitochondrial respiration, we assume that diruthenium-1 acts predominantly as an inhibitor of the aerobic metabolism. Contrary to the previous findings concerning the catalytic oxidation of glutathione by this type of complexes in solution, we did not observe any glutathione oxidation by diruthenium-1 in the cancer cells: Diruthenium-1 decreased the intracellular concentrations of both reduced and oxidised gluthathione. Altogether, diruthenium-1 turned out to be a promising compound with a potential as an anticancer drug for a future ruthenotherapy.

Bioblast editor: Plangger M O2k-Network Lab: CZ Hradec Kralove Cervinkova Z

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

Organism: Rat  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS  Pathway: N, S  HRR: Oxygraph-2k 

Labels, 2019-08