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Molecular Pharmacology

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Research ArticleArticle

Effect of Cellular ATP Depletion on Topoisomerase II Poisons. Abrogation of Cleavable-Complex Formation by Etoposide But Not by Amsacrine

M. Sorensen, M. Sehested and P. B. Jensen
Molecular Pharmacology March 1999, 55 (3) 424-431;
M. Sorensen
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M. Sehested
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P. B. Jensen
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Abstract

Topoisomerase (topo) II poisons have been categorized into ATP-independent and -dependent drugs based on in vitro studies. We investigated drug-induced topoII-DNA complexes in intact cells almost completely depleted of ATP. Virtually no DNA single-strand breaks (SSBs), as measured by alkaline elution, were detected in energy-depleted cells treated with the topoII poisons etoposide, teniposide, daunorubicin, doxorubicin, mitoxantrone, or clerocidin. This inhibition was reversible; subsequent incubation with glucose restored the level of DNA SSBs. The effect of ATP depletion was specific for topoII, because topoI-mediated cleavable complexes induced by camptothecin were unaffected by ATP depletion. Furthermore, etoposide-induced DNA-protein complexes and DNA double-strand breaks, as measured by filter elution techniques, and topoIIα and -β trapping, as measured by a band depletion assay, were completely inhibited by energy depletion. Differences in drug transport could not explain the effect of ATP depletion. The topoII poison amsacrine (m-AMSA) was unique with respect to ATP dependence. In ATP-depleted cells, m-AMSA-induced DNA SSBs, DNA double-strand breaks, DNA-protein complexes, topoIIα and -β trapping were only modestly reduced. The accumulation ofm-AMSA was reduced in ATP-depleted cells, which indicates that drug transport could contribute to the modest decrease in m-AMSA-induced cleavable complexes. In conclusion, drug-induced topoII-DNA complexes were completely antagonized in ATP-depleted cells, except in the case of m-AMSA. One possible interpretation is that m-AMSA mainly produces prestrand passage DNA lesions, whereas the other topoII poisons tested exclusively stabilize poststrand passage DNA lesions in intact cells.

Footnotes

  • Send reprint requests to: Dr. Morten Sorensen, Laboratory of Experimental Medical Oncology, The Finsen Center, 5074, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. E-mail:msorensen{at}dadlnet.dk

  • This work was supported financially by the Faculty of Health, University of Copenhagen, and by the Danish Cancer Society.

  • Abbreviations:
    topo
    topoisomerase
    SSBs
    single-strand breaks
    DPCs
    DNA protein complexes
    DSBs
    double-strand-breaks
    FCS
    fetal calf serum
    DMSO
    dimethyl sulfoxide
    m-AMSA
    amsacrine
    VP-16
    etoposide
    DNP
    2,4-dinitro-phenol
    • Received August 27, 1998.
    • Accepted November 30, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (3)
Molecular Pharmacology
Vol. 55, Issue 3
1 Mar 1999
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Research ArticleArticle

Effect of Cellular ATP Depletion on Topoisomerase II Poisons. Abrogation of Cleavable-Complex Formation by Etoposide But Not by Amsacrine

M. Sorensen, M. Sehested and P. B. Jensen
Molecular Pharmacology March 1, 1999, 55 (3) 424-431;

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Research ArticleArticle

Effect of Cellular ATP Depletion on Topoisomerase II Poisons. Abrogation of Cleavable-Complex Formation by Etoposide But Not by Amsacrine

M. Sorensen, M. Sehested and P. B. Jensen
Molecular Pharmacology March 1, 1999, 55 (3) 424-431;
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