Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria

Abstract

Two new 'hybrid' metallodrugs of Au(III)(AuTAML)and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophoreto ideally synergize the anticancer activity of both the metal centerand the organic ligand. The compounds have antiproliferative effectsagainst human MCF-7 and MDA-MB 231 breast cancer cells. Moleculardynamics studies suggest that the compounds retain the binding activityto estrogen receptor (ER & alpha;). In vitro and in silico studies showed that the Au(III) derivative isan inhibitor of the seleno-enzyme thioredoxin reductase, while theCu(II) complex may act as an oxidant of different intracellular thiols.In breast cancer cells treated with the compounds, a redox imbalancecharacterized by a decrease in total thiols and increased reactiveoxygen species production was detected. Despite their different reactivitiesand cytotoxic potencies, a great capacity of the metal complexes toinduce mitochondrial damage was observed as shown by their effectson mitochondrial respiration, membrane potential, and morphology.