Efficient Nuclear DNA Cleavage in Human Cancer Cells by Synthetic Bleomycin Mimics

Abstract

Iron complexes of N,N-bis(2-pyridylmethyl)-N-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.