Isodiospyrin as a novel human DNA topoisomerase I inhibitor.
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.
Ting
Chun-Yuan
CY
Institute of Biochemistry, School of Life Science, National Yang Ming University, Taipei, Taiwan.
Hsu
Chia-Tse
CT
Hsu
Hsiang-Ting
HT
Su
Jin-Shan
JS
Chen
Tzong-Yueh
TY
Tarn
Woan-Yuh
WY
Kuo
Yao-Haur
YH
Whang-Peng
Jacqueline
J
Liu
Leroy F
LF
Hwang
Jaulang
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; C409666:isodiospyrin; D000255:Adenosine Triphosphate; D004247:DNA