Methyl-substituted 1,10-phenanthroline derivatives in copper(II) complexes enhance antitumor activity and inhibit NHE1 in MDA-MB-231 breast cancer cells

Three copper(II) complexes containing 1,10-phenanthroline derivatives - [CuCl2(phen)].0.5H2O (1), [CuCl2(neo)].0.75H2O (2), and [CuCl2(tmp)].H2O (3) - were tested for their potential to treat breast cancer cells. These complexes significantly reduced MDA-MB-231 breast cancer cell viability compared to free ligands, CuCl2, and the chemotherapy drug cisplatin. Interestingly, only complex 1 caused DNA damage at concentrations lower than the IC50 value.

All three complexes induced cytotoxicity by generating reactive oxygen species (ROS) and triggering apoptosis. However, complexes 2 and 3 also promoted necrosis. Besides reducing cell proliferation, they led to increased intracellular copper levels. Moreover, complexes 2 and 3 effectively inhibited Na/H exchanger 1 (NHE1) activity, which in turn decreased cell migration and matrix metalloproteinase-9 (MMP-9) activity.

Further investigation using Western blot analysis revealed that the three complexes altered the expression of NHE1, G protein-coupled estrogen receptor (GPER), and proteins involved in apoptosis. Based on these findings, it appears that methylating the phenanthroline ligand improves the antitumor activity of copper(II) complexes.

Their mechanism of action shifts from DNA damage-driven cytotoxicity to ROS-mediated apoptosis. Crucially, these findings also suggest that inhibiting NHE1 is a key factor behind the enhanced antitumor activity of these methylated phenanthroline copper(II) complexes.