Hypersensitive Inhibition of the Proliferation of Cells with Mutated DNA Repair-Related Genes by the Catalytic Topoisomerase II Inhibitor 20-O-IngenolEZ

Masahiro Kanbe, Yasuaki Fukuda, Manami Watanabe, Keiichi Matsuzaki, Susumu Kitanaka, Shohei Miyata

Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
School of Pharmacy, Nihon University, Chiba, Japan.
School of Pharmacy, Nihon University, Chiba, Japan..

DOI: 10.4236/pp.2012.32023                

Abstract

We previously reported that many ingenol compounds derived from Euphoria kansui exhibit topoisomerase inhibitory activity. 20-O-ingenolEZ in these compounds exerted inhibitory effects on both topoisomerase II (topo II) activity and cell proliferative activity. Topoisomerase II inhibitors can be divided into the poison and catalytic inhibitor types and 20-O-ingenolEZ is a catalytic inhibitor and inhibits topo IIα through inhibition of ATPase activity, but induces topo II-mediated DNA damage and apoptosis in BLM^-/- DT40 cells through the induction of the DNA damage checkpoint, similar to the poison type inhibitor adriamycin. The ATPase inhibitor of topo II ICRF-193 also showed poison-like characteristics in the same cell line. However, the inhibitory effects of ICRF-193 on the proliferation of BLM^-/- DT40 cells differed from those of 20-O-ingenolEZ, as did the specificity of its inhibition of the proliferation of other cell lines. 20-O-ingenolEZ showed hypersensitive inhibition of the proliferation of MCF-7 cells and BLM^-/- DT40 cells with mutated DNA repair-related genes.

Keywords

Catalytic Topo II Inhibitor; DNA Damage Checkpoint; DNA Repair-Related Genes; Ingenol Compound

Conflicts of Interest

The authors declare no conflicts of interest.

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