Molecular insights into the antineoplastic mechanisms of mono- and bimetallic ruthenium(II) arene diamine complexes: a comprehensive evaluation
Bioorganic Chemistry, vol.181, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 181
- Publication Date: 2026
- Doi Number: 10.1016/j.bioorg.2026.110430
- Journal Name: Bioorganic Chemistry
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO)
- Keywords: Antineoplastic agents, Apoptosis, Bimetallic complex, p53 pathway, ROS, Ru(II) arene complex
- Bursa Uludag University Affiliated: Yes
Abstract
Although platinum-based therapies are of central importance in oncology, their clinical benefits are often limited by systemic toxicity and the emergence of drug resistance. This study, a mechanistic continuation of our previous research on the cytotoxicity of organometallic Ru(II) complexes, presents a comprehensive in vitro investigation of the antineoplastic pathways of monometallic ( Ru1 ) and bimetallic Ru(II) arene complexes ( Ru2 , Ru3 ) carrying diamine ligands. We evaluated their efficacy in prostate (PC-3, DU145) and colorectal (HT-29) cancer models, as well as in non-cancerous Vero cells. Morphological assessments and long-term wound healing tests revealed that the bimetallic complex ( Ru3 ) significantly suppressed cellular motility and caused total cell death over a 7-day period. Immunocytochemical analysis of γ-H2AX foci confirmed that the complexes caused potent DNA double-strand breaks, and Ru3 demonstrated superior genotoxic activity in all cell lines. Mechanistic elucidation via flow cytometry and immunoblotting revealed that these complexes trigger a p53-dependent mitochondrial apoptotic pathway characterized by depolarization of the mitochondrial membrane potential, significant release of Cytochrome C, followed by Caspase-3 and PARP activation. Furthermore, treatment caused a remarkable reduction in anti-apoptotic Bcl-2 and Bcl-xL proteins. In particular, Ru1 exhibited unique antioxidant-like properties by reducing intracellular ROS and 8-OHdG levels in specific cell lines, suggesting a novel protective role in oxidative metabolism as well as its anticarcinogenic potential. Collectively, these results provide a potent molecular map for the activity of these Ru(II) diamine complexes and highlight Ru3 as a strong candidate for the development of next-generation, targeted anticancer therapies.