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The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II

Identifieur interne : 002D65 ( Main/Exploration ); précédent : 002D64; suivant : 002D66

The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II

Auteurs : Annette Kragh Larsen [France] ; Lucile Grondard [France] ; Jeannine Couprie ; Bernard Desoize ; Leopold Comoe ; Jean-Claude Jardillier ; Jean-François Riou [France]

Source :

Biochemical Pharmacology [ 0006-2952 ] ; 1993.

RBID : ISTEX:3964EE5BAD8FDFB072D84C0444565F869776803E

English descriptors

Abstract

Abstract: 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 Kapp of 2.1 × 105 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 μM. Fagaronine also inhibits the catalytic activity of purified calf thymus topoisomerase II at concentrations above 25 μM 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 μM. Further increase of the fagaronine concentration leads to a progressive decrease in the cleavable complex formation, which is totally inhibited at 100 μM. In contrast, up to 1 μM 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.

Url:

https://api.istex.fr/ark:/67375/6H6-0VFZXMGM-6/fulltext.pdf

DOI: 10.1016/0006-2952(93)90105-6

Affiliations:

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Le document en format XML

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<term>CPT, camptothecin</term>
<term>SDS, sodium dodecyl sulfate</term>
<term>mAMSA, 4′-(9-acridinylamino)-methanesulfon-m-anisidide</term>
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<keywords scheme="Teeft" xml:lang="en"><term>Agarose</term>
<term>Assay</term>
<term>Biol chem</term>
<term>Bromide</term>
<term>Calf thymus</term>
<term>Calf thymus topoisomerase</term>
<term>Camptothecin</term>
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<term>Catalytic activity</term>
<term>Cell line</term>
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<term>Final concentrations</term>
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<term>Nucleic acids</term>
<term>Protein synthesis</term>
<term>Proteinase</term>
<term>Reaction mixture</term>
<term>Riou</term>
<term>Strand breakage</term>
<term>Strand breaks</term>
<term>Supercoiled</term>
<term>Thymus</term>
<term>Topoisomerase</term>
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<front><div type="abstract" xml:lang="en">Abstract: 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 Kapp of 2.1 × 105 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 μM. Fagaronine also inhibits the catalytic activity of purified calf thymus topoisomerase II at concentrations above 25 μM 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 μM. Further increase of the fagaronine concentration leads to a progressive decrease in the cleavable complex formation, which is totally inhibited at 100 μM. In contrast, up to 1 μM 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.</div>
</front>
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The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II

The antileukemic alkaloid fagaronine is an inhibitor of DNA topoisomerases I and II

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English descriptors

Abstract

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