A novel antitumor compound, NC-190, induces topoisomerase II-dependent DNA cleavage and DNA fragmentation.
A novel benzophenazine derivative, NC-190, is a potent antitumor compound. NC-190 has been shown to inhibit the DNA strand-passing activity of DNA topoisomerase II. We investigated further the mode of action of NC-190 against DNA topoisomerase II and DNA fragmentation. NC-190 inhibited the decatenation activity of purified topoisomerase II, but had only a weak inhibitory effect against topoisomerase I. A topoisomerase II-dependent DNA cleavage assay showed that NC-190 inhibited the enzyme activity by stabilizing a topoisomerase II-DNA cleavable complex. NC-190 induced growth inhibition, protein-linked DNA breaks, and DNA fragmentation in cultured HL-60 cells in a dose-dependent manner. These activities of NC-190 in HL-60 cells were comparable to those of etoposide (VP-16). These results demonstrate a good correlation among growth inhibition, topoisomerase II-dependent DNA cleavage, and DNA fragmentation induced by NC-190. A DNA unwinding assay showed that NC-190 had intercalating activity, but its activity appeared to be weaker than those of ethidium bromide and adriamycin. These results indicate that the mechanism by which NC-190 exhibits antitumor activity may be the inhibition of topoisomerase II.
Yamagishi
T
T
Research Center, Taisho Pharmaceutical Co. Ltd., Ohmiya-shi, Saitama, Japan.
Nakaike
S
S
Ikeda
T
T
Ikeya
H
H
Otomo
S
S
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D010446:Peptide Fragments; D010619:Phenazines / Q000008:administration & dosage / Q000633:toxicity*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014343:Trypan Blue / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D010619:Phenazines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C059048:NC 190; D004247:DNA; D014343:Trypan Blue