INHIBITION OF TOPOISOMERASE-II BY LIRIODENINE

The cytotoxic oxoaporphine alkaloid liriodenine, isolated from Cananga odorata, mas found to be a potent inhibitor of topoisomerase II (EC 5 .99.1.3) both in vivo and in vitro. Liriodenine treatment of SV40 (sim ian virus 40)-infected CV-1 cells caused highly catenated SV40 daughte r chromosomes, a signature of topoisomerase II inhibition. Strong cata lytic inhibition of topoisomerase II by liriodenine was confirmed by i n vitro assays with purified human topoisomerase II and kinetoplast DN A. Liriodenine also caused low-lever protein-DNA cross-links to purse labeled SV40 chromosomes in vivo, suggesting that it may be a weak top oisomerase II poison. This was supported by the finding that liriodeni ne caused topoisomerase II-DNA cross-links in an in vitro assay for to poisomerase II poisons. Verapamil did not increase either liriodenine- induced protein-DNA cross-links or catalytic inhibition of topoisomera se II in SV40-infected cells. This indicates that liriodenine is not a substrate for the verapamil-sensitive drug efflux pump in CV-1 cells. (C) 1997 Elsevier Science Inc.