Mar. Drugs 2011, 9(11), 2397-2408; doi:10.3390/md9112397
Article

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

1email, 1email, 1email, 1email, 2email, 2email, 1email, 1email, 1email, 3email, 2email and 1,* email
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)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 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.
Keywords: neoamphimedine; topoisomerase II; Metnase; cancer therapeutics
PDF Full-text Download PDF Full-Text [904 KB, uploaded 18 November 2011 10:37 CET]

Export to BibTeX |
EndNote


MDPI and ACS Style

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. Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase IIα Activity Through ATP-Competitive Inhibition. Mar. Drugs 2011, 9, 2397-2408.

AMA Style

Ponder J, Yoo BH, Abraham AD, Li Q, Ashley AK, Amerin CL, Zhou Q, Reid BG, Reigan P, Hromas R, Nickoloff JA, LaBarbera DV. Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase IIα Activity Through ATP-Competitive Inhibition. Marine Drugs. 2011; 9(11):2397-2408.

Chicago/Turabian Style

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. 2011. "Neoamphimedine Circumvents Metnase-Enhanced DNA Topoisomerase IIα Activity Through ATP-Competitive Inhibition." Mar. Drugs 9, no. 11: 2397-2408.

Mar. Drugs EISSN 1660-3397 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert