Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne.
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.
Gatto
B
B
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
Sanders
M M
MM
Yu
C
C
Wu
H Y
HY
Makhey
D
D
LaVoie
E J
EJ
Liu
L F
LF
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
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