Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne

Barbara Gatto, Marilyn M. Sanders, Chiang Yu, Hong Yan Wu, Darshan Makhey, Edmond J. LaVoie, Leroy-Fong Liu

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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 clearable 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.

Original languageEnglish
Pages (from-to)2795-2800
Number of pages6
JournalCancer Research
Volume56
Issue number12
Publication statusPublished - Jun 15 1996
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gatto, B., Sanders, M. M., Yu, C., Wu, H. Y., Makhey, D., LaVoie, E. J., & Liu, L-F. (1996). Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne. Cancer Research, 56(12), 2795-2800.