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 Mn 2 L 2 Ac and Mn 2 L 2 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 Mn 2 ‐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 Mn 2 SOD mimics and Pt(II) complexes. Specifically, we synthesized and characterized the self‐assembled Mn 2 ‐Pt adducts ( isolated Mn 2 L 2 Pt and in situ Mn 2 L 2 Pt’) , linking Mn 2 L 2 ‐core with the carboxylate group of PtDAPCl 2 (dichloro(2,3‐diaminopropionic acid) platinum(II)). The SOD activity of the isolated Mn 2 L 2 Pt adduct (k SOD =1.7×10 7 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 Mn 2 ‐containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H 2 S 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.