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

Marine Drugs

Jessica Ponder²  Byong Hoon Yoo²  Adedoyin D. Abraham²  Qun Li²  Amanda K. Ashley¹  Courtney L. Amerin¹  Qiong Zhou²  Brian G. Reid²  Philip Reigan²  Robert Hromas³  Jac A. Nickoloff¹ 

[1] Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA; E-Mails:;Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045, USA; E-Mails:;Department of Medicine, University of Florida and Shands Health Care System, Gainesville, FL 32610, USA; E-Mail:

关键词: neoamphimedine;    topoisomerase II;    Metnase;    cancer therapeutics;   

DOI  :  10.3390/md9112397

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland