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.
Cagir
Ali
A
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, USA.
Jones
Shannon H
SH
Gao
Rong
R
Eisenhauer
Brian M
BM
Hecht
Sidney M
SM
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D011758:Pyrroles; D011809:Quinones; D059004:Topoisomerase I Inhibitors; C480761:luotonin A; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin