The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II
| Autor: | Annette K. Larsen, Jean-François Riou, Leopold Comoe, Jeannine Couprie, Lucile Grondard, Bernard Desoize, Jean-Claude Jardillier |
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| Rok vydání: | 1993 |
| Předmět: |
Fibrosarcoma
Drug Resistance Biochemistry Catalysis chemistry.chemical_compound Mice Alkaloids Cricetulus Cricetinae medicine Tumor Cells Cultured Animals Topoisomerase II Inhibitors Pharmacology chemistry.chemical_classification Benzophenanthridines biology Leukemia P388 Topoisomerase DNA Molecular biology Antineoplastic Agents Phytogenic Intercalating Agents Phenanthridines Enzyme DNA Topoisomerases Type II Mechanism of action chemistry Enzyme inhibitor Kinetoplast Fagaronine biology.protein Camptothecin Cattle Topoisomerase-II Inhibitor medicine.symptom |
| Zdroj: | Biochemical pharmacology. 46(8) |
| ISSN: | 0006-2952 |
| Popis: | The antileukemic alkaloid, fagaronine, is a potent differentiation inducer of various hematopoietic cell lines. We show here that fagaronine is a DNA base-pair intercalator with a K(app) of 2.1 x 10(5) M-1 for calf thymus DNA. Fagaronine inhibits the catalytic activity of purified calf thymus topoisomerase I as shown by relaxation of supercoiled plasmid DNA followed by electrophoresis in neutral as well as in chloroquine-containing gels. The catalytic activity of topoisomerase I is inhibited at concentrations above 30 microM. Fagaronine also inhibits the catalytic activity of purified calf thymus topoisomerase II at concentrations above 25 microM as shown by decatenation of kinetoplast DNA. Fagaronine stabilizes the covalent DNA-enzyme reaction intermediate (the cleavable complex) between topoisomerase I and linear pBR322 DNA at concentrations up to 1 microM. Further increase of the fagaronine concentration leads to a progressive decrease in the cleavable complex formation, which is totally inhibited at 100 microM. In contrast, up to 1 microM fagaronine has no effect on cleavable complex formation between purified calf thymus topoisomerase II and linear pBR322 DNA, whereas cleavable complex formation is inhibited at higher concentrations. Exposure to fagaronine results in an increase in DNA-protein complex formation in intact P388 murine leukemia cells. P388CPT5 cells, which have an altered topoisomerase I activity, are 4-fold resistant to the growth inhibitory effects of fagaronine compared to the parental cell line. Similarly, DC-3F/9-OH-E Chinese hamster fibrosarcoma cells, which have an altered topoisomerase II activity, are about 5-fold resistant to the growth inhibitory effects of fagaronine. We conclude that fagaronine is an inhibitor of both DNA topoisomerase I and II and propose that this might play a role in the cytotoxic activity. |
| Databáze: | OpenAIRE |
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