beta-Lapachone, a novel DNA topoisomerase I inhibitor with a mode of action different from camptothecin

beta-Lapachone is a plant product that has been found to have many pharmacological effects. To date, very little is known about its biochemical target. In this study, we found that beta-lapachone inhibits the catalytic activity of topoisomerase I from calf thymus and human cells. But, unlike camptot...

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Bibliographic Details
Published in:The Journal of biological chemistry 1993-10, Vol.268 (30), p.22463-22468
Main Authors: Li, C.J., Averboukh, L, Pardee, A.B.
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Biological and medical sciences
Camptothecin - pharmacology
Cattle
Cell Line
DNA, Kinetoplast - metabolism
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Humans
Isomerases
Kinetics
Leukemia, Promyelocytic, Acute
Models, Structural
Molecular Structure
Naphthoquinones - pharmacology
Nucleic Acid Conformation
Plasmids
Protein Binding
Substrate Specificity
Thymus Gland - enzymology
Topoisomerase I Inhibitors
Tumor Cells, Cultured
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Summary:beta-Lapachone is a plant product that has been found to have many pharmacological effects. To date, very little is known about its biochemical target. In this study, we found that beta-lapachone inhibits the catalytic activity of topoisomerase I from calf thymus and human cells. But, unlike camptothecin, beta-lapachone does not stabilize the cleavable complex, indicating a different mechanism of action. beta-Lapachone inhibits topoisomerase I-mediated DNA cleavage induced by camptothecin. Incubation of topoisomerase I with beta-lapachone before adding DNA substrate dramatically increases this inhibition. Incubation of topoisomerase I with DNA prior to beta-lapachone makes the enzyme refractory, and treatment of DNA with beta-lapachone before topoisomerase has no effect. These results suggest a direct interaction of beta-lapachone with topoisomerase I rather than DNA substrate. beta-Lapachone does not inhibit binding of enzyme to DNA substrate. In cells, beta-lapachone itself does not induce a SDS-K(+)-precipitable complex, but it inhibits complex formation with camptothecin. We propose that the direct interaction of beta-lapachone with topoisomerase I does not affect the assembly of the enzyme-DNA complex but does inhibit the formation of cleavable complex.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)41552-9