title: Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II.
abstract: We have identified a small library of novel substituted 9-aminoacridine derivatives that inhibit cell proliferation of pancreatic cancer cell lines by inducing apoptosis [Goodell, J.R. et al., 2008. J. Med. Chem. 51, 179-182.]. To further investigate their antiproliferative activities, we have assessed the antiproliferative activity of these acridine-based compounds against several pancreatic cancer cell lines. All four compounds used in this study inhibited the proliferation of pancreatic cancer cell lines in vitro. In addition, we have employed a xenograft tumor model and found that these compounds also inhibit the proliferation of pancreatic cancer in vivo. In light of the potential importance of the anticancer activity of these acridine-based compounds, we have conducted a series of biochemical assays to determine the effect of these compounds on human topoisomerase II. Unlike amsacrine, these compounds do not poison topoisomerase II. Similar to amsacrine, however, these compounds intercalate into DNA in a way that they would alter the apparent topology of the DNA substrate. Thus, inhibition of the relaxation activity of topoisomerase II by these compounds has been reexamined using a DNA strand passage assay. We have found that these compounds, indeed, inhibit the catalytic activity of topoisomerase II. Thus, these novel acridine-based compounds with anti-pancreatic cancer activity are catalytic inhibitors, not poisons, of human topoisomerase II.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School-Twin Cities, Minneapolis, Minnesota 55455, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Oppegard
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Ougolkov
authors.forename: Doris N
authors.initials: DN
authors.lastname: Luchini
authors.forename: Renee A
authors.initials: RA
authors.lastname: Schoon
authors.forename: John R
authors.initials: JR
authors.lastname: Goodell
authors.forename: Harneet
authors.initials: H
authors.lastname: Kaur
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.forename: David M
authors.initials: DM
authors.lastname: Ferguson
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiasa
mesh_terms: D000166:Acridines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II