Ligand-Engineered Cu(II) Complexes Suppress Stemness and Drug Resistance in Triple-Negative Breast Cancer

Area of Science:

• Medicinal Chemistry
• Oncology
• Materials Science

Background:

• Triple-negative breast cancer (TNBC) is aggressive, with enriched cancer stem cells (CSCs) and multidrug resistance.
• Existing treatments face challenges due to CSCs and chemoresistance.

Purpose of the Study:

• To design and evaluate novel copper(II) complexes for TNBC treatment.
• To investigate the impact of ligand engineering on anticancer efficacy and mechanisms.

Main Methods:

• Synthesis and characterization of Cu(II) complexes (Cu1-Cu4) with engineered ligands.
• In vitro antiproliferative assays against TNBC cell lines.
• Mechanistic studies including cell-cycle analysis, apoptosis assays, EMT marker assessment, and CSC marker evaluation.
• Investigation of drug-resistance modulation via ABC transporter expression analysis.

Main Results:

• Lead complexes Cu3 and Cu4 demonstrated submicromolar antiproliferative activity against TNBC cells, surpassing oxaliplatin.
• Cu3 and Cu4 induced cell-cycle arrest and apoptosis, suppressed epithelial-mesenchymal transition (EMT) and migration.
• Both complexes reduced 3D tumor spheroid formation and CSC markers (CD44high/CD24low).
• Cu3 and Cu4 enhanced doxorubicin retention by downregulating ABC transporters, overcoming drug resistance.

Conclusions:

• Ligand-engineered Cu(II) complexes (Cu3, Cu4) are effective against TNBC.
• These complexes reduce CSC populations and spheroid formation capacity.
• The novel complexes show potential for overcoming chemoresistance in TNBC by modulating drug efflux mechanisms.