Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds

Eur J Pharm Sci. 2015 Aug 30;76:192-202. doi: 10.1016/j.ejps.2015.04.023. Epub 2015 May 8.

Abstract

HL-60 cancer cells were treated with a series of novel acridine derivatives (derivatives 1-4) in order to test the compounds' ability to inhibit both cancer cell growth and topoisomerase I and II activity. Binding studies of derivatives 1-4 with calf thymus DNA were also performed using a number of techniques (UV-Vis and fluorescence spectroscopy, thermal denaturation, linear dichroism and viscometry) to determine the nature of the interaction between the compounds and ctDNA. The binding constants for the complexes of the studied acridine derivatives with DNA were calculated from UV-Vis spectroscopic titrations (K=3.1×10(4)-2.0×10(3)M(-1)). Some of the compounds showed a strong inhibitory effect against Topo II at the relatively low concentration of 5μM. Topo I/II inhibition mode assays were also performed and verified that the novel compounds are topoisomerase suppressors rather than poisons. The biological activities of derivatives were studied using MTT assay and flow cytometric methods (detection of mitochondrial membrane potential, measurement of cell viability) after 24 and 48h incubation. The ability of derivatives to impair cell proliferation was tested by an analysis of cell cycle distribution.

Keywords: Acridine derivatives; DNA-binding; HL-60 cells; Topoisomerases I and II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemical synthesis
  • Acridines / metabolism
  • Acridines / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Chemistry, Pharmaceutical
  • DNA / chemistry
  • DNA / metabolism
  • DNA Topoisomerases, Type I / metabolism*
  • DNA Topoisomerases, Type II / metabolism*
  • Dose-Response Relationship, Drug
  • HL-60 Cells
  • Hot Temperature
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / enzymology
  • Leukemia, Promyelocytic, Acute / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Nucleic Acid Conformation
  • Nucleic Acid Denaturation
  • Spectrometry, Fluorescence
  • Spectrophotometry, Ultraviolet
  • Technology, Pharmaceutical / methods
  • Time Factors
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / metabolism
  • Topoisomerase I Inhibitors / pharmacology*
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / metabolism
  • Topoisomerase II Inhibitors / pharmacology*
  • Viscosity

Substances

  • Acridines
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • DNA
  • calf thymus DNA
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • DNA Topoisomerases, Type II