COPPER(II)-PHENANTHROLINE COMPLEXES AS MULTI-TARGET ANTITUMOR AGENTS: LINKING COMPLEXATION AND CYTOTOXIC MECHANISMS IN OVARIAN AND BREAST CANCER MODELS

Cancer remains a major global health challenge. The development of new and more effective pharmacological treatments is therefore still needed. Platinum-based coordination compounds containing chemotherapy constitute one cornerstone of cancer treatment. However, drug resistance limits their efficacy.  Complexes with 1,10-phenanthroline (phen) and its methylated derivatives neocuproine (neo) and 3,4,7,8-tetramethylphenanthroline (tmp) offer a chemically tunable platform to develop antitumor metallodrugs. This work integrates studies of Cu-diimine and Cu-diimine-dipeptide (Ala-Gly, Ala-Phe) systems evaluated in ovarian cancer cells (A2780, cisplatin-resistant A2780-cisR) and in breast cancer cells (MCF-7, both monolayer and 3D spheroids), looking to understand the molecular basis of the cytotoxic activity. All complexes outperformed cisplatin cytotoxicity, with distinct structure-activity patterns. In ovarian cells, neo complexes were the most active, whereas in breast cancer models, tmp complexes were most potent, showing that the methyl substitution pattern on the diimine scaffold modulates both potency and cell-type selectivity. The presence of copper potentiated ligand activity, as speciation equilibria shifted toward fully copper-bound species. This effect was attenuated in resistant cells, possibly due to altered CTR1-mediated copper uptake as part of the resistance mechanism. Mechanistically, reactive oxygen species generation was ligand- specific rather than general: only tmp-based complexes significantly elevated superoxide and peroxide content in breast cells, yet antioxidant rescue failed to restore viability, indicating oxidative stress operates as a parallel rather than causal pathway. DNA damage (evaluated by the comet assay) was induced across the family, supporting genotoxicity as a shared mechanism. A key finding was inhibition of the Na+/H+ exchanger NHE1 by all the complexes, identifying a novel ion-transport target linked to intracellular pH regulation. Spheroid assays confirmed activity against 3D architectures. Together, these results frame copper-phenanthroline antitumor activity as a result of the coupled genotoxic and redox mechanisms and ion-transport interference, with a marked influence of copper coordination on the activity of phen and its derivatives.