Mixed copper (II)-phenanthroline complexes induce cell death of ovarian cancer cells by evoking unfolded protein response

There is an ongoing need for development of new cancer therapeutics that combine high cytotoxic efficiency with low side effects, and also override resistance to the first-line chemotherapeutics. Copper (II)-phenanthroline complexes are promising compounds that were shown previously to induce an immediate cytotoxic response over a panel of tumor cell lines in vitro. The molecular mechanism, however, remained unresolved. In this study we performed a thorough study of the copper (II)-phenanthroline complexes containing different imidazolidine-2-thione ligands in ovarian cancer cells, and revealed that these complexes induce the endoplasmic reticulum (ER) stress and subsequently the cell death mediated by unfolded protein response. Alleviation of the ER-stress by tauroursodeoxycholic acid (TUDCA) attenuated the cytotoxic effects. In summary, we have identified a novel, ER-dependent, molecular mechanism mediating cytotoxic effects of copper (II)-phenanthroline complexes.