Neoamphimedine circumvents metnase-enhanced DNA topoisomerase IIα activity through ATP-competitive inhibition

Jessica Ponder, Byong Hoon Yoo, Adedoyin D. Abraham, Qun Li, Amanda K. Ashley, Courtney L. Amerin, Qiong Zhou, Brian G. Reid, Philip Reigan, Robert Hromas, Jac A. Nickoloff, Daniel V. LaBarbera

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 TopoIIá-dependent DNA decatenation in the presence of Metnase. Cell proliferation assays demonstrate that neoamphimedine can inhibit Metnase-enhanced cell growth with an IC 50 of 0.5 μM. Additionally, we find that the apparent K m 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.

Original languageEnglish (US)
Pages (from-to)2397-2408
Number of pages12
JournalMarine Drugs
Volume9
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery

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    Ponder, J., Yoo, B. H., Abraham, A. D., Li, Q., Ashley, A. K., Amerin, C. L., Zhou, Q., Reid, B. G., Reigan, P., Hromas, R., Nickoloff, J. A., & LaBarbera, D. V. (2011). Neoamphimedine circumvents metnase-enhanced DNA topoisomerase IIα activity through ATP-competitive inhibition. Marine Drugs, 9(11), 2397-2408. https://doi.org/10.3390/md9112397