title: Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne.
abstract: Protoberberine alkaloids (coralyne and its derivatives), which exhibit antileukemic activity in animal models, have been shown to be potent inducers of topoisomerase (topo) I-DNA cleavable complexes using purified recombinant human DNA topo I. Different from the structurally similar benzophenanthridine alkaloid nitidine (a dual poison of both topos I and II), coralyne and its derivatives have marginal poisoning activity against DNA topo II. Yeast cells expressing human DNA topo I are shown to be specifically sensitive to killing by coralyne derivatives and nitidine, suggesting that cellular DNA topo I is their cytotoxic target. Two human camptothecin-resistant cell lines, CPT-K5 and A2780/CPT-2000, which are known to express highly camptothecin-resistant topo I, are only marginally resistant to coralyne derivatives and nitidine. Purification of human topo I from Escherichia coli cells overexpressing CPT-K5 recombinant topo I has demonstrated similar marginal cross-resistance to nitidine. It seems possible to develop coralyne and nitidine derivatives as new topo I-targeted therapeutics to overcome aspects of camptothecin-related resistance.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gatto
authors.forename: M M
authors.initials: MM
authors.lastname: Sanders
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.forename: H Y
authors.initials: HY
authors.lastname: Wu
authors.forename: D
authors.initials: D
authors.lastname: Makhey
authors.forename: E J
authors.initials: EJ
authors.lastname: LaVoie
authors.forename: L F
authors.initials: LF
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001483:Base Sequence; D053119:Benzophenanthridines; D001600:Berberine Alkaloids / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D002417:Cattle; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008969:Molecular Sequence Data; D010617:Phenanthridines / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D015003:Yeasts / Q000187:drug effects / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D001600:Berberine Alkaloids; D010617:Phenanthridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C000666:coralyne; C013615:nitidine; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin