title: Neoamphimedine circumvents metnase-enhanced DNA topoisomerase IIα activity through ATP-competitive inhibition.
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 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.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ponder
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Byong Hoon
authors.initials: BH
authors.lastname: Yoo
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Adedoyin D
authors.initials: AD
authors.lastname: Abraham
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Ashley
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Amerin
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Reid
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
authors.affiliation: Department of Medicine, University of Florida and Shands Health Care System, Gainesville, FL 32610, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.affiliation: Department of Pharmaceutical Sciences, The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO 80045,USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: LaBarbera
mesh_terms: D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008958:Models, Molecular
chemical_list: D000166:Acridines; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; C474173:neoamphimedine; D000255:Adenosine Triphosphate; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human; D004250:DNA Topoisomerases, Type II