Vol. 305, Issue 2, 725-732, May 2003

Distinct Effects of Dinuclear Ruthenium(III) Complexes on Cell Proliferation and on Cell Cycle Regulation in Human and Murine Tumor Cell Lines

Alberta Bergamo, Gabriele Stocco, Barbara Gava, Moreno Cocchietto, Enzo Alessio, Barbara Serli, Elisabetta Iengo and Gianni Sava

Foundation Callerio-Onlus (A.B., Ga.S., B.G., M.C., Gi.S.), Trieste, Italy; and Departments of Chemical Sciences (E.A., B.S.) and Biomedical Sciences (Gi.S.), University of Trieste, Trieste, Italy

We have examined the biological and antitumor activity of a series of dinuclear ruthenium complexes. The aim of this study was to compare the in vitro effects of these new compounds on cell proliferation, cell distribution among cell cycle phases, and the expression of some proteins involved in cell cycle regulation. Results obtained show a mild cytotoxic activity against human and murine cell lines, more evident after prolonged exposure of cell challenge. Two of the eight dinuclear complexes [namely, compounds D3 (Na₂[{RuCl₄(dmso-S)}₂(µ-bipy)]) and D7 ([NH₄][{RuCl₄(dmso-S)}(µ-pyz){RuCl₃(dmso-S)(dmso-O)}]) modify cell cycle distribution similarly to imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A), whereas the others have a low or negligible effect on this parameter. If we correlate the induction of cell cycle modifications with ruthenium uptake by tumor cells and with the modulation of proteins regulating cell cycle, we may stress that the induction of G₂-M cell cycle arrest is related to the achievement of a threshold concentration of ruthenium inside the cells, which is dependent on the cell line being used, and that only cyclin B, among cell cycle regulating proteins examined by immunoblotting assays, appears to be significantly modified. This in vitro study shows that dinuclear ruthenium complexes may have a behavior similar to that of the monomer NAMI-A. These results encourage the future experimentation of their pharmacological properties in in vivo models.