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.