title: Insights into the in vitro Anticancer Effects of Diruthenium-1.
abstract: The in vitro anticancer activity of the dinuclear trithiolato-bridged arene ruthenium complex diruthenium-1 (DiRu-1) was evaluated against a panel of human cancer cell lines used as in vitro models for hepatocellular carcinoma (HepG2 cells), estrogen-responsive breast adenocarcinoma (MCF-7 cells), and triple-negative breast adenocarcinoma (MDA-MB-231 cells). DiRu-1 is highly cytotoxic to these cell lines, demonstrating half-maximal inhibitory concentrations (IC50) in the low-nanomolar range (77±1.4 to 268.2±4.4 nm). The main molecular mechanisms responsible for the high cytotoxicity of DiRu-1 against the most responsive MCF-7 cell line (IC50=77±1.4 nm) were investigated on the basis of the capacity of DiRu-1 to induce oxidative stress, apoptosis, and DNA damage, and to inhibit the cell cycle and proliferation. The results show that DiRu-1 triggers caspase-dependent apoptosis in MCF-7 cells on both the intrinsic and extrinsic pathways. Moreover, the Ru complex also causes necrosis, mitotic catastrophe, and autophagy. DiRu-1 increases the intracellular levels of reactive oxygen species (ROS), which play a significant role in its cytotoxicity and pro-apoptotic activity. An important mechanism of the anticancer activity of DiRu-1 appears to be the induction of DNA lesions, mainly due to apoptotic DNA fragmentation and cell-cycle arrest at the G2/M checkpoint. These changes are correlated with the concentration of DiRu-1, the duration of the cell treatment, and the post-treatment time.
authors: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska St. 141/143, 90236, Łódź, Poland. koceva.aneta@gmail.com.
authors: Aneta
authors: A
authors: Koceva-Chyła
authors: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska St. 141/143, 90236, Łódź, Poland.
authors: Karolina
authors: K
authors: Matczak
authors: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska St. 141/143, 90236, Łódź, Poland.
authors: Msc Paweł
authors: MP
authors: Hikisz
authors: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska St. 141/143, 90236, Łódź, Poland.
authors: Msc Kamil
authors: MK
authors: Durka
authors: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska St. 141/143, 90236, Łódź, Poland.
authors: Msc Krzysztof
authors: MK
authors: Kochel
authors: Institut de Chimie, Université de Neuchâtel, Avenue de Bellevaux 51, 2000, Neuchâtel, Switzerland.
authors: Georg
authors: G
authors: Süss-Fink
authors: Department für Chemie und Biochemie, Universität Bern, Freiestrasse 3, 3012, Bern, Switzerland. julien.furrer@dcb.unibe.ch.
authors: Julien
authors: 0000-0003-2096-0618
authors: J
authors: Furrer
authors: Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka St. 12, 91403, Łódź, Poland. kondor15@wp.pl.
authors: Konrad
authors: K
authors: Kowalski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D017382:Reactive Oxygen Species; C000620894:diruthenium-1
keywords: DNA damage; anticancer agents; apoptosis; oxidation; ruthenium