On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents

Marina Gálvez-Peralta, Jennifer S. Hackbarth, Karen S. Flatten, Scott H. Kaufmann, Hiroshi Hiasa, Chenguo Xing, David M. Ferguson

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.

Original languageEnglish (US)
Pages (from-to)4459-4462
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number15
DOIs
StatePublished - Aug 1 2009

Keywords

  • Acridine
  • Anticancer agents
  • Catalytic inhibitor
  • Cleavable complex
  • Cytotoxicity
  • DNA
  • Doxorubicin
  • Etoposide
  • Mechanism of action
  • Topoisomerase
  • siRNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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