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

Two new ‘hybrid’ metallodrugs of Au(III)
(AuTAML)
and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore
to ideally synergize the anticancer activity of both the metal center
and the organic ligand. The compounds have antiproliferative effects
against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular
dynamics studies suggest that the compounds retain the binding activity
to estrogen receptor (ERα). In vitro and in silico studies showed that the Au(III) derivative is
an inhibitor of the seleno-enzyme thioredoxin reductase, while the
Cu(II) complex may act as an oxidant of different intracellular thiols.
In breast cancer cells treated with the compounds, a redox imbalance
characterized by a decrease in total thiols and increased reactive
oxygen species production was detected. Despite their different reactivities
and cytotoxic potencies, a great capacity of the metal complexes to
induce mitochondrial damage was observed as shown by their effects
on mitochondrial respiration, membrane potential, and morphology.