title: In-vitro and in-vivo evaluation of the anticancer activity of diruthenium-2, a new trithiolato arene ruthenium complex [(η6-p-MeC6H4Pri)2Ru2(μ-S-p-C6H4OH)3]Cl.
abstract: In the present study, we investigated the anticancer action of the trithiolato arene ruthenium complex, [(η-p-MeC6H4Pr)2Ru2(μ-S-p-C6H4OH)3]Cl, named diruthenium-2, both in vitro and in vivo. The mechanism of antiproliferative, cytotoxic, and DNA-damaging activity, and the effect on expressions of cell cycle regulatory proteins were investigated using a WST-1-based proliferation assay, lactate dehydrogenase leakage assay, comet assay, flow cytometry, and western blot analysis. In-vivo anticancer activity was evaluated using Ehrlich tumor-bearing NMRI mice. Diruthenium-2 inhibited the growth of all cancer cell lines used, the most sensitive being gastric (AGS), breast cancer (BT-549, MCF-7, MDA-MB-231), and leukemic (HL-60, MOLT-4) cells. In MCF-7 cells, it caused a G1/S cell cycle arrest, along with an increase in the expression of protein p21 and cyclin B1. We also observed increased levels of MRN complex proteins, which, together with the results from the comet assay, indicate the formation of DNA double-strand breaks. In tumor-bearing mice, diruthenium-2 at doses of 3 and 5 mg/kg inhibits the growth of solid Ehrlich tumor, although weaker than cisplatin. However, it did not prolong the post-therapeutic survival. Our results suggest the in-vitro potential of diruthenium-2 should be further evaluated in studies using other in-vivo models.
authors.affiliation: aDepartment of Medical Biochemistry bDepartment of Medical Biophysics, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové cDepartment of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Pardubice, Czech Republic dInstitute of Chemistry, University of Neuchâtel, Neuchâtel, Switzerland.
authors.forename: Darina
authors.initials: D
authors.lastname: Muthná
authors.forename: Pavel
authors.initials: P
authors.lastname: Tomšík
authors.forename: Radim
authors.initials: R
authors.lastname: Havelek
authors.forename: Renata
authors.initials: R
authors.lastname: Köhlerová
authors.forename: Vidhya
authors.initials: V
authors.lastname: Kasilingam
authors.forename: Eva
authors.initials: E
authors.lastname: Čermáková
authors.forename: David
authors.initials: D
authors.lastname: Stíbal
authors.forename: Martina
authors.initials: M
authors.lastname: Řezáčová
authors.forename: Georg
authors.initials: G
authors.lastname: Süss-Fink
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D061986:MCF-7 Cells; D051379:Mice; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012428:Ruthenium