title: A topoisomerase II inhibitor, NK109, induces DNA single- and double-strand breaks and apoptosis.
abstract: 2,3-(Methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthr idinium hydrogensulfate dihydrate, called NK109, is a benzo[c]phenanthridine derivative, which inhibits DNA topoisomerase II activity by stabilizing the DNA-enzyme-drug complex, and shows strong growth-inhibitory effects on several human cancer cells. In the present study, NK109 treatment induced DNA fragmentation and a rise in the level of cytoplasmic nucleosomes, which are markers of apoptosis, in human small-cell lung carcinoma SBC-3 cells. These effects were inhibited by zinc ions and enhanced by cycloheximide or actinomycin D. Dose-dependent single- and double-strand DNA breaks were observed, using alkaline and neutral elution assays, in SBC-3 cells treated with more than 0.2 microM NK109 for 4 h. Treatment with NK109 caused more DNA single- and double-strand breaks than treatment with an equimolar amount of VP-16. These results suggest that NK109 induces DNA strand breaks and apoptosis. In addition, it appears that this process does not require protein or RNA synthesis, but involves a specific endonuclease which is inhibited by zinc ions.
authors.affiliation: Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: M
authors.initials: M
authors.lastname: Inomata
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.forename: K
authors.initials: K
authors.lastname: Fukuoka
authors.forename: F
authors.initials: F
authors.lastname: Kanzawa
authors.forename: H
authors.initials: H
authors.lastname: Arioka
authors.forename: T
authors.initials: T
authors.lastname: Ishida
authors.forename: H
authors.initials: H
authors.lastname: Fukumoto
authors.forename: H
authors.initials: H
authors.lastname: Kurokawa
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: N
authors.initials: N
authors.lastname: Saijo
mesh_terms: D004247:DNA / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D009707:Nucleosomes; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D009707:Nucleosomes; D059005:Topoisomerase II Inhibitors; D004247:DNA