Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives—eleutherin, α lapachone, and β lapachone∗
Section snippets
Materials
pBR322 was prepared by standard methods. Topoisomerase II (p170 isoform) was purchased from TopoGEN, Inc. HindIII-digested pBR322 was labeled with [α-32P]dCTP (3000 Ci/mmol, ICN Radiochemicals) using T4 DNA polymerase (GIBCO-BRL). Eleutherin (compound 1) was isolated from the bulb of E. americana, and was a gift from Dr. Y. Imakura (Naruto University of Education) [5]. β Lapachone and α lapachone were prepared according to methods published by Hooker [14]. Etoposide was provided by the Natural
Catalytic inhibition of topoisomerase II
Relaxation of supercoiled pBR322 by either topoisomerase I or II was measured in the presence of the three pyranonaphthoquinone derivatives to evaluate catalytic inhibition and DNA unwinding activities. Compounds 1-3 did not inhibit topoisomerase I, nor did they possess unwinding activities, suggesting that compounds 1-3 did not bind to DNA (data not shown). The compounds, however, were selective inhibitors of topoisomerase II. Figure 2 shows inhibition of the enzyme analyzed in a gel
Discussion
Several structurally diverse natural and synthetic compounds inhibit topoisomerase II at different steps of the catalytic cycle. A few such examples of catalytic inhibitors include aclarubicin and acridones (which inhibit the initial enzyme–DNA interactions 16, 20), merbarone (which inhibits enzyme-mediated DNA cleavage [21]), staurosporine (which inhibits strand passage by competing at the ATP binding site [22]), novobiocin (which inhibits ATP hydrolysis and prevents enzyme turnover [23]), and
Acknowledgements
This work was performed by P. K. in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
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