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

Abstract

We exploration the in vitro activities of the dinuclearMn2L2AcandMn2L2complexes (where HL = 2-{[di(2-pyridyl)methylamino]-methyl}phenol), possessing dual superoxide dismutase (SOD) and catalase (CAT) activity, both individually and in conjunction with various Pt(II)-complexes, either as mixtures or astheMn2-Ptadducts. 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 withMn2SOD mimics and Pt(II) complexes.Specifically, we synthesized and characterized the self-assembledMn2-Ptadducts(isolatedMn2L2Ptandin situMn2L2Pt'), linkingMn2L2-core with the carboxylate group ofPtDAPCl2(dichloro(2,3-diaminopropionic acid) platinum(II)). The SOD activity of the isolatedMn2L2Ptadduct (kSOD= 1.7 × 107M-1s-1) remained intact. We elucidated key mechanisms underlying the observed biological effects.We demonstrated thatMn2-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.