Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase II[alpha] Activity Through ATP-Competitive Inhibition

Type IIα DNA topoisomerase (TopoIIα) is among the most important clinical drug targets for the treatment of cancer. Recently, the DNA repair protein Metnase was shown to enhance TopoIIα activity and increase resistance to TopoIIα poisons. Using in vitro DNA decatenation assays we show that neoamphim...

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Bibliographic Details
Published in:Marine drugs 2011-11, Vol.9 (11), p.2397
Main Authors: Ponder, Jessica, Yoo, Byong Hoon, Abraham, Adedoyin D, Li, Qun, Ashley, Amanda K, Amerin, Courtney L, Zhou, Qiong, Reid, Brian G, Reigan, Philip, Hromas, Robert, Nickoloff, Jac A, LaBarbera, Daniel V
Format: Article
Language:English
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Summary:Type IIα DNA topoisomerase (TopoIIα) is among the most important clinical drug targets for the treatment of cancer. Recently, the DNA repair protein Metnase was shown to enhance TopoIIα activity and increase resistance to TopoIIα poisons. Using in vitro DNA decatenation assays we show that neoamphimedine potently inhibits TopoIIα-dependent DNA decatenation in the presence of Metnase. Cell proliferation assays demonstrate that neoamphimedine can inhibit Metnase-enhanced cell growth with an IC50 of 0.5 µM. Additionally, we find that the apparent Km of TopoIIα for ATP increases linearly with higher concentrations of neoamphimedine, indicating ATP-competitive inhibition, which is substantiated by molecular modeling. These findings support the continued development of neoamphimedine as an anticancer agent, particularly in solid tumors that over-express Metnase.
ISSN:1660-3397
DOI:10.3390/md9112397