Hypersensitive Inhibition of the Proliferation of Cells with Mutated DNA Repair-Related Genes by the Catalytic Topoisomerase II Inhibitor 20-O-IngenolEZ — Oak Academic Publishing
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Hypersensitive Inhibition of the Proliferation of Cells with Mutated DNA Repair-Related Genes by the Catalytic Topoisomerase II Inhibitor 20-O-IngenolEZ
Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
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Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
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Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
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School of Pharmacy, Nihon University, Chiba, Japan
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School of Pharmacy, Nihon University, Chiba, Japan.
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Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
1 Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
2 Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
3 Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
4 School of Pharmacy, Nihon University, Chiba, Japan
5 School of Pharmacy, Nihon University, Chiba, Japan.
6 Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan
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.
KeywordsCatalytic Topo II InhibitorDNA Damage CheckpointDNA Repair-Related GenesIngenol Compound
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