Mechanistic Insights into the Antitumor Activity of Cu²⁺-based Complexes: Targeting Apoptosis and Cellular Pathways in MCF-7 Breast Cancer Cells

ABSTRACT: Cancer’s global burden highlights the urgent need for more effective therapies. Metalbased drugs, particularly copper complexes, offer promising alternatives due to copper’s diverse biological functions. This study investigates the antitumor potential of two novel dinuclear Cu²⁺ complexes, [Cu2(µ-CH3COO)(L)(OH2)]·2H2O (R9) and [Cu2(µ-OH)(HL)(OH2)]ClO4·2H2O (R10), in MCF-7 breast cancer cells. Both compounds exhibited greater cytotoxicity than cisplatin, with IC₅₀ values of 1.01 ± 0.09 μM (R9) and 1.27 ± 0.14 μM (R10), while showing selectivity toward cancer cells, as indicated by higher IC₅₀ values in healthy MCF10A cells. Treated MCF-7 cells showed increased granularity, mitochondrial membrane depolarization, and elevated reactive oxygen species. At IC₅₀ concentrations, cell cycle analysis revealed Sub-G1 accumulation and DNA fragmentation (TUNEL assay), indicating apoptosis via intrinsic pathways, supported by caspase 9 activation. Label-free proteomics revealed distinct mechanisms for R10 compared to cisplatin. In R10-treated cells, key downregulated pathways included actin cytoskeleton regulation, viral carcinogenesis, and PI3K-Akt signaling; upregulated pathways involved ribosome biogenesis, necroptosis, and metabolism. Apoptosis-related proteins such as lamin B1, NRAS, and MAPKs were downregulated, while AIFM1 was upregulated. These findings support the potential of dinuclear Cu²⁺ complexes as effective antitumor agents with mechanisms distinct from cisplatin, possibly offering superior efficacy through apoptosis induction.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Proteomics Unit  

LAB HEAD: Fábio César Sousa Nogueira

PROVIDER: PXD064464 | Pride | 2025-11-24

REPOSITORIES: Pride