Isodiospyrin as a novel human DNA topoisomerase I inhibitor

Chun Yuan Ting, Chia Tse Hsu, Hsiang Ting Hsu, Jin Shan Su, Tzong Yueh Chen, Woan Yuh Tarn, Yao Haur Kuo, Jacqueline Whang-Peng, Leroy F. Liu, Jaulang Hwang

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Abstract

Isodiospyrin is a natural product from the plant Diospyros morrisiana, which consists of an asymmetrical 1,2-binaphthoquinone chromophore. Isodiospyrin exhibits cytotoxic activity to tumor cell lines but very little is known about its cellular target and mechanism of action. Unlike the prototypic human topoisomerase I (htopo I) poison camptothecin, isodiospyrin does not induce htopo I-DNA covalent complexes. However, isodiospyrin antagonizes camptothecin-induced, htopo I-mediated DNA cleavage. Binding analysis indicated that isodiospyrin binds htopo I but not DNA. These results suggest that isodiospyrin inhibits htopo I by direct binding to htopo I, which limits htopo I access to the DNA substrate. Furthermore, isodiospyrin exhibits strong inhibitory effect on the kinase activity of htopo I toward splicing factor 2/alternate splicing factor in the absence of DNA. Thus, these findings have important implications on naphthoquinone and its derivatives' cellular mode of actions, i.e. these novel DNA topoisomerase I inhibitors can prevent both DNA relaxation and kinase activities of htopo I.

Original languageEnglish
Pages (from-to)1981-1991
Number of pages11
JournalBiochemical Pharmacology
Volume66
Issue number10
DOIs
Publication statusPublished - Nov 15 2003
Externally publishedYes

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Keywords

  • Binaphthoquinone
  • Camptothecin
  • Diospyros morrisiana
  • Human DNA topoisomerase I
  • Isodiospyrin
  • Kinase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ting, C. Y., Hsu, C. T., Hsu, H. T., Su, J. S., Chen, T. Y., Tarn, W. Y., Kuo, Y. H., Whang-Peng, J., Liu, L. F., & Hwang, J. (2003). Isodiospyrin as a novel human DNA topoisomerase I inhibitor. Biochemical Pharmacology, 66(10), 1981-1991. https://doi.org/10.1016/j.bcp.2003.07.003