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

• Published in: Chemistry : a European journal 2024-10, Vol.30 (56), p.e202402685-n/a
• Main Authors: Squarcina, Andrea, Maier, Philipp, Vignane, Thibaut, Senft, Laura, Filipovic, Milos R., Ivanović‐Burmazović, Ivana
• Format: Article
• Language: English
• Subjects: Adducts; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agents; Biological activity; Biological effects; Breast cancer; Catalase; Catalase - chemistry; Catalase - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cell viability; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; dinuclear manganese catalysts; Electron transport chain; Epidermal growth factor receptors; Formulations; Humans; Hydrogen sulfide; Manganese; Manganese - chemistry; NADH-ubiquinone oxidoreductase; Oxidative phosphorylation; Phenols; Phosphorylation; platinum; Platinum - chemistry; Proteomes; Proteomics; Reactive Oxygen Species - metabolism; Self-assembly; Superoxide dismutase; Superoxide Dismutase - metabolism; superoxide dismutases
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202402685

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 (kSOD=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. Dinuclear manganese complexes (Mn2), known for their SOD and CAT mimetic properties, enhance healthy breast cell viability by up to 50 % and reduce breast cancer cell viability by up to 50 % when combined with Pt(II) complexes. These Mn2‐containing formulations primarily target mitochondrial processes, affecting cancerous and healthy cells differently. This suggests their potential use for combined SOD‐active and cytostatic treatments.