Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells

We
previously described the development of a DNA-alkylating compound
that showed selective toxicity in breast cancer cells. This compound
contained an estrogen receptor α (ERα)-binding ligand
and a DNA-binding/methylating component that could selectively methylate
the N3-position of adenines at adenine–thymine rich regions
of DNA. Herein, we describe mechanistic investigations that demonstrate
that this class of compounds facilitate the translocation of the ERα-compound
complex to the nucleus and induce the expression of ERα target
genes. We confirm that the compounds show selective toxicity in ERα-expressing
cells, induce ERα localization in the nucleus, and verify the
essential role of ERα in modulating the toxicity. Minor alterations
in the compound structure significantly affects the DNA binding ability,
which correlates to the DNA-methylating ability. These studies demonstrate
the utility of DNA-alkylating compounds to accomplish targeted inhibition
of the growth of specific cancer cells; an approach that may overcome
shortcomings of currently used chemotherapy agents.