title: Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds.
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.
authors.affiliation: Department of Biochemistry, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Janočková
authors.affiliation: Department of Biochemistry, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Plšíková
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 11, 78371 Olomouc, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kašpárková
authors.affiliation: Department of Biophysics, Faculty of Science, Palacky University in Olomouc, Slechtitelu 11, 78371 Olomouc, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Jendželovský
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Jaromír
authors.initials: J
authors.lastname: Mikeš
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Kovaľ
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Slávka
authors.initials: S
authors.lastname: Hamuľaková
authors.affiliation: Department of Cellular Biology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Fedoročko
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Sokolovska 581, Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuča
authors.affiliation: Department of Biochemistry, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovak Republic; Biomedical Research Center, University Hospital Hradec Kralove, Sokolovska 581, Hradec Kralove, Czech Republic. Electronic address: maria.kozurkova@upjs.sk.
authors.forename: Mária
authors.initials: M
authors.lastname: Kožurková
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006358:Hot Temperature; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D014783:Viscosity
chemical_list: D000166:Acridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; C427203:calf thymus DNA; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D004250:DNA Topoisomerases, Type II
keywords: Acridine derivatives; DNA-binding; HL-60 cells; Topoisomerases I and II