Efficient Nuclear DNA Cleavage in Human Cancer Cells
by Synthetic Bleomycin Mimics
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Abstract
Iron complexes of <i>N</i>,<i>N</i>-bis(2-pyridylmethyl)-<i>N</i>-bis(2-pyridyl)-methylamine
(N4Py) have proven to be excellent
synthetic mimics of the Bleomycins (BLMs), which are a family of natural
antibiotics used clinically in the treatment of certain cancers. However,
most investigations of DNA cleavage activity of these and related
metal complexes were carried out in cell-free systems using plasmid
DNA as substrate. The present study evaluated nuclear DNA cleavage
activity and cell cytotoxicity of BLM and its synthetic mimics based
on the ligand N4Py. The N4Py-based reagents induced nuclear DNA cleavage
in living cells as efficiently as BLM and Fe(II)-BLM. Treatment of
2 cancer cell lines and 1 noncancerous cell line indicated improved
cytotoxicity of N4Py when compared to BLM. Moreover, some level of
selectivity was observed for N4Py on cancerous versus noncancerous
cells. It was demonstrated that N4Py-based reagents and BLM induce
cell death via different mechanistic pathways. BLM was shown to induce
cell cycle arrest, ultimately resulting in mitotic catastrophe. In
contrast, N4Py-based reagents were shown to induce apoptosis effectively.
To the best of our knowledge, the present study is the first demonstration
of efficient nuclear DNA cleavage activity of a synthetic BLM mimic
within cells. The results presented here show that it is possible
to design synthetic bioinorganic model complexes that are at least
as active as the parent natural product and thereby are potentially
interesting alternatives for BLM to induce antitumor activity