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

Research output: Contribution to journalArticle

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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

Fingerprint

coralyne
Type I DNA Topoisomerase
Alkaloids
Camptothecin
Benzophenanthridines
Type II DNA Topoisomerase
Recombinant DNA
Poisons
Poisoning
protoberberine
Animal Models
Yeasts
nitidine

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.

Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne. / Gatto, Barbara; Sanders, Marilyn M.; Yu, Chiang; Wu, Hong Yan; Makhey, Darshan; LaVoie, Edmond J.; Liu, Leroy-Fong.

In: Cancer Research, Vol. 56, No. 12, 15.06.1996, p. 2795-2800.

Research output: Contribution to journalArticle

Gatto, B, Sanders, MM, Yu, C, Wu, HY, Makhey, D, LaVoie, EJ & Liu, L-F 1996, 'Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne', Cancer Research, vol. 56, no. 12, pp. 2795-2800.
Gatto B, Sanders MM, Yu C, Wu HY, Makhey D, LaVoie EJ et al. Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne. Cancer Research. 1996 Jun 15;56(12):2795-2800.
Gatto, Barbara ; Sanders, Marilyn M. ; Yu, Chiang ; Wu, Hong Yan ; Makhey, Darshan ; LaVoie, Edmond J. ; Liu, Leroy-Fong. / Identification of topoisomerase I as the cytotoxic target of the protoberberine alkaloid coralyne. In: Cancer Research. 1996 ; Vol. 56, No. 12. pp. 2795-2800.
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