Luotonin A. A naturally occurring human DNA topoisomerase I poison

Luotonin A is a pyrroloquinazolinoquinoline alkaloid isolated from the Chinese herbal medicinal plant Peganum nigellastrum. Although previously shown to exhibit cytotoxicity against the murine leukemia P-388 cell line, the mechanism of action of luotonin A is unknown. Presently, we demonstrate that luotonin A stabilizes the human DNA Topoisomerase I-DNA covalent binary complex, affording the same pattern of cleavage as the structurally related Topoisomerase I inhibitor camptothecin. Luotonin A also mediated Topoisomerase I-dependent cytotoxicity toward Saccharyomyces cerevisiae lacking yeast Topoisomerase I, but harboring a plasmid having the human Topoisomerase I gene under the control of a galactose promoter. This finding identifies a putative biochemical locus for the cytotoxic action of luotonin A and has important implications for the mechanism of action of camptothecin and the design of camptothecin analogues.