Inhibition of topoisomerase I function by nitidine and fagaronine.
The benzophenanthridine alkaloids nitidine and fagaronine were characterized as inhibitors of topoisomerase I function. In common with the antitumor agent camptothecin, both nitidine and fagaronine stabilized the covalent binary complex formed between calf thymus topoisomerase I and DNA. The effects of these compounds were readily apparent at 0.15-0.3 microM concentrations. Both nitidine and fagaronine inhibited the topoisomerase I-mediated relaxation of supercoiled pSP64 plasmid DNA more effectively than camptothecin; unlike camptothecin, both of these benzophenanthridine alkaloids also bound directly to and mediated the unwinding of B-form DNA. Nitidine and fagaronine were also studied in comparison with camptothecin to determine the sequence specificity of DNA breaks produced from a 32P-end-labeled duplex in the presence of topoisomerase I. All three compounds produced very similar cleavage patterns. The specificity of nitidine and fagaronine for inhibiting topoisomerase I function was studied by measuring the effects of the compounds on the unknotting of P4 DNA by calf thymus topoisomerase II. Moderate inhibition of topoisomerase II-mediated unknotting was obtained, but only in the presence of high (i.e., 40 microM) concentrations of nitidine and fagaronine. In comparison, doxorubicin inhibited topoisomerase II to the same extent as nitidine and fagaronine when it was employed at 2.5 microM concentration and was strongly inhibitory when employed at 10 microM concentration.
Wang
L K
LK
Department of Chemistry, University of Virginia, Charlottesville 22901.
Johnson
R K
RK
Hecht
S M
SM
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D053119:Benzophenanthridines; D002166:Camptothecin / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010617:Phenanthridines / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects; D059004:Topoisomerase I Inhibitors
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D010617:Phenanthridines; D059004:Topoisomerase I Inhibitors; C002066:fagaronine; D004317:Doxorubicin; D004247:DNA; C013615:nitidine; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin