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: Aneta Koceva-Chyła, Karolina Matczak, Msc Paweł Hikisz, Msc Kamil Durka, Msc Krzysztof Kochel, Georg Süss-Fink, Julien Furrer, Konrad Kowalski
• Journal: ChemMedChem (ChemMedChem) Vol. 11 Issue 19 Pg. 2171-2187 (10 06 2016) ISSN: 1860-7187 [Electronic] Germany
• PMID: 27561129 (Publication Type: Journal Article)
• Copyright: © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Reactive Oxygen Species
• diruthenium-1

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Coordination Complexes (chemical synthesis, chemistry, pharmacology)
• DNA Damage
• DNA Repair
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship
• Tumor Cells, Cultured