Inhibition of topoisomerase II by liriodenine.

The cytotoxic oxoaporphine alkaloid liriodenine, isolated from Cananga odorata, was found to be a potent inhibitor of topoisomerase II (EC 5.99.1.3) both in vivo and in vitro. Liriodenine treatment of SV40 (simian virus 40)-infected CV-1 cells caused highly catenated SV40 daughter chromosomes, a signature of topoisomerase II inhibition. Strong catalytic inhibition of topoisomerase II by liriodenine was confirmed by in vitro assays with purified human topoisomerase II and kinetoplast DNA. Liriodenine also caused low-level protein-DNA cross-links to pulse-labeled SV40 chromosomes in vivo, suggesting that it may be a weak topoisomerase II poison. This was supported by the finding that liriodenine caused topoisomerase II-DNA cross-links in an in vitro assay for topoisomerase II poisons. Verapamil did not increase either liriodenine-induced protein-DNA cross-links or catalytic inhibition of topoisomerase II in SV40-infected cells. This indicates that liriodenine is not a substrate for the verapamil-sensitive drug efflux pump in CV-1 cells.