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• Ponder, J
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• Nickoloff, J
• LaBarbera, D
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• Nickoloff, J
• LaBarbera, D
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Mar. Drugs 2011, 9(11), 2397-2408; doi:10.3390/md9112397

Article

Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase IIα Activity Through ATP-Competitive Inhibition

Jessica Ponder ¹ , Byong Hoon Yoo ¹ , Adedoyin D. Abraham ¹ , Qun Li ¹ , Amanda K. Ashley ² , Courtney L. Amerin ² , Qiong Zhou ¹ , Brian G. Reid ¹ , Philip Reigan ¹ , Robert Hromas ³ , Jac A. Nickoloff ²  and Daniel V. LaBarbera ^1,*

¹ Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA ² Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA ³ Department of Medicine, University of Florida and Shands Health Care System, Gainesville, FL 32610, USA

* Author to whom correspondence should be addressed.

Received: 6 September 2011; in revised form: 8 November 2011 / Accepted: 9 November 2011 / Published: 18 November 2011

(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)

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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 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 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.

Keywords: neoamphimedine; topoisomerase II; Metnase; cancer therapeutics

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