[(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
Abstract
A newly synthesised derivative [(p-MeC6H4Pri)2Ru2(SC6H4-p-But)3]Cl (diruthenium-1) with an IC50 value of only 30 nM for both cisplatin-resistant mutant A2780cisR and the normal A2780 cancer cells, was selected for an in vivo anticancer study using a mouse model. In a solid Ehrlcih tumour, diruthenium-1 at doses of 0.4 and 0.6 mg/kg i.p. 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 MCF-7 and BT-549 cells, 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.
It also inhibited the mitochondrial respiration and decreased the intracellular concentrations of both reduced and oxidised gluthathione.