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

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

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 - 2003 Nov 15

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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