Induction of topoisomerase II-mediated DNA cleavage by the plant naphthoquinones plumbagin and shikonin.
Plumbagin and shikonin, plant metabolites which have naphthoquinone structures, induced mammalian topoisomerase II-mediated DNA cleavage in vitro. Treatment of a reaction mixture containing these naphthoquinones and topoisomerase II at an elevated temperature (65 degrees C) resulted in a great reduction in DNA cleavage, suggesting that the mechanism of the topoisomerase II-mediated DNA cleavage induced by these naphthoquinones is through formation of a cleavable complex, as seen with antitumor agents such as 4'-(9-acridinylamino)methanesulfon-m-anisidide and demethylepipodophyllotoxin ethylidene-beta-glucoside. Lawson and lapacol, which are structurally related plant metabolites with naphthoquinone moieties, could not induce topoisomerase II-mediated DNA cleavage. Plumbagin and shikonin induced a similar DNA cleavage pattern with topoisomerase II which was different from the cleavage patterns induced with other known topoisomerase II-active drugs. A DNA-unwinding assay with T4 DNA ligase showed that shikonin, lawson, and lapacol did not intercalate into DNA, while plumbagin and 2-methyl-1,4-naphthoquinone intercalate into DNA, but to a lower degree than 4'-(9-acridinylamino)methanesulfon-m-anisidide does.
Fujii
N
N
Kyowa Hakko Kogyo Co. Ltd., Tokyo Research Laboratories, Japan.
Yamashita
Y
Y
Arima
Y
Y
Nagashima
M
M
Nakano
H
H
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000378:metabolism*; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D007364:Intercalating Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology* / Q000633:toxicity
D000972:Antineoplastic Agents, Phytogenic; D007364:Intercalating Agents; D009285:Naphthoquinones; C016101:shikonin; D004250:DNA Topoisomerases, Type II; C014758:plumbagin