Unlocking Selective Anticancer Mechanisms: Dinuclear Manganese Superoxide Dismutase Mimetics Combined with Pt(II) Complexes

We conducted an in-depth exploration of the in vitro activities of the dinuclear Mn₂L₂Ac and Mn₂L₂ complexes (where HL=2-{[di(2-pyridyl)methylamino]-methyl}phenol), possessing dual superoxide dismutase (SOD) and catalase (CAT) activity. We investigated these complexes both individually and in conjunction with various Pt(II)-complexes, either as mixtures or as the Mn₂-Pt adducts. Our findings revealed a notable up to 50 % enhancement in the viability of healthy human breast cells, contrasted with a viability decrease as low as 50 % in breast cancer cells upon combined treatments with Mn₂ SOD mimics and Pt(II) complexes. Specifically, we synthesized and characterized the self-assembled Mn₂-Pt adducts (isolated Mn₂L₂Pt and in situ Mn₂L₂Pt'), linking Mn₂L₂-core with the carboxylate group of PtDAPCl₂ (dichloro(2,3-diaminopropionic acid) platinum(II)). The SOD activity of the isolated Mn₂L₂Pt adduct (k_SOD=1.7×10⁷ M^-1 s^-1) remained intact. Through in vitro cell viability assessments, ROS levels, cellular Mn uptake and proteomics measurements, we elucidated key mechanisms underlying the observed biological effects. We demonstrated that Mn₂-containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H₂S signaling and expression of mitochondrial complex I and III, as well as increased oxidative phosphorylation pathways and upregulation of EGFR in cancer cells. In contrast, healthy cells showed a decrease in EGFR expression and a moderate enrichment in oxidative phosphorylation pathways.