Cancer Stem Cell and Bulk Cancer Cell Active Copper(II) Complexes with Vanillin Schiff Base Derivatives and Naproxen

5 years ago

Cancer Stem Cell and Bulk Cancer Cell Active Copper(II) Complexes with Vanillin Schiff Base Derivatives and Naproxen

Arvin Eskandari, Paul B. Cressey, Kogularamanan Suntharalingam, Chunxin Lu

Four copper(II) complexes, 1–4 containing regioisomeric vanillin Schiff base derivatives and the nonsteroidal anti-inflammatory drug (NSAID), naproxen, were synthesised and characterised. All complexes effectively cleave DNA in cell-free systems, with 4 displaying the highest nuclease activity. DNA binding studies suggest that 4 binds to DNA via the grooves prior to inducing oxidative DNA cleavage. Three of the complexes (1, 3, and 4) indiscriminately kill cancer stem cell (CSC)-enriched cells (HMLER-shEcad) and bulk cancer cells (HMLER) at micromolar concentrations. The most effective complex, 4 also reduced the formation and size of mammospheres to a similar extent as salinomycin, a well-established CSC-potent agent. Mechanistic studies show that 4 is readily taken up by CSCs, elevates intracellular reactive oxygen species (ROS) levels, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 4 inhibits cyclooxygenase-2 (COX-2) expression and causes COX-2-dependent CSC death. The advantage of 4 over bulk cancer cell- or CSC-selective agents is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose. Two birds with one copper stone: We present a series of copper(II) complexes containing vanillin Schiff base derivatives and the nonsteroidal anti-inflammatory drug, naproxen. Three of the complexes kill bulk cancer cells and cancer stem cells with similar doses. The most effective complex evokes cell death by inducing DNA damage and inhibiting cyclooxygenase-2.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701939