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Molecular Pharmacology

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Research ArticleArticle

Apoptosis Induced by the Homocamptothecin Anticancer Drug BN80915 in HL-60 Cells

Amelie Lansiaux, Michael Facompré, Nicole Wattez, Marie-Paule Hildebrand, Christine Bal, Daniéle Demarquay, Olivier Lavergne, Dennis C. H. Bigg and Christian Bailly
Molecular Pharmacology September 2001, 60 (3) 450-461;
Amelie Lansiaux
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Michael Facompré
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Nicole Wattez
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Marie-Paule Hildebrand
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Christine Bal
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Daniéle Demarquay
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Olivier Lavergne
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Dennis C. H. Bigg
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Christian Bailly
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Abstract

The homocamptothecin (hCPT) derivative BN80915 containing a seven-membered lactone ring represents one of the most potent topoisomerase I inhibitors described. This anticancer agent, currently undergoing phase I clinical trials, has been shown to produce a greater number of DNA strand breaks than conventional camptothecins with a six-membered lactone ring. To shed light on the mechanism of action of hCPT at the cellular level, we compared the effects of BN80915 and the classic camptothecin SN-38, the active metabolite of irinotecan, on HL-60 human promyelocytic cancer cells. A variety of biochemical events, at both the mitochondrial and the nuclear levels, were characterized to determine how and to what extent the hCPT derivative can induce apoptotic cell death. The use of cytometry, Western blot analysis, confocal microscopy, and different colorimetric assays enabled us to demonstrate that BN80915 is a potent inducer of apoptosis in HL-60 cells. This induction of apoptosis is associated with cell cycle changes, a marked decrease of intracellular pH, activation of caspase-3 and -8, DNA fragmentation, and externalization of phosphatidylserine lipids but no significant changes of the mitochondrial membrane potential or the expression of Bcl-2. The interconnections between these different events are discussed. Collectively, the results indicate that the superior activity expressed at the topoisomerase I level leads to a more pronounced induction of apoptosis by BN80915 compared with SN-38. The study identifies and delineates signaling factors involved in BN80915-induced apoptosis in HL-60 cells.

Footnotes

  • This work was performed with the support of research grants (to C.Bailly) from the Institut de Recherches sur le Cancer de Lille and the Ligue Nationale Française Contre le Cancer (Comitédu Nord).

  • Abbreviations:
    CPT
    camptothecin
    hCPT
    homocamptothecin
    DiOC6
    3-dihexyloxacarbocyanine iodide
    JC-1
    tetrachloro-tetraethylbenzimidazolcarbocyanine iodide
    SNARF-AM
    carboxy-seminaphthorhodafluor-1-acetoxymethyl ester
    CCCP
    carbonyl cyanide p-chlorophenylhydrazone
    WST1
    4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate
    EthD-1
    ethidium homodimer-1
    BrdU
    5-bromo-2-deoxyuridine
    FITC
    fluorescein isothiocyanate
    DEVD-pNA
    N-acetyl-Asp-Glu-Val-Asp-pNA
    IETD-pNA
    N-acetyl-Ile-Glu-Thr-Asp-pNA
    PARP
    poly(ADP-ribose) polymerase
    PBST
    phosphate-buffered saline/Tween 20
    TUNEL
    terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling
    PI
    propidium iodide
    PS
    phosphatidylserine
    TPT
    topotecan
    PAGE
    polyacrylamide gel electrophoresis
    • Received February 5, 2001.
    • Accepted May 23, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Apoptosis Induced by the Homocamptothecin Anticancer Drug BN80915 in HL-60 Cells

Amelie Lansiaux, Michael Facompré, Nicole Wattez, Marie-Paule Hildebrand, Christine Bal, Daniéle Demarquay, Olivier Lavergne, Dennis C. H. Bigg and Christian Bailly
Molecular Pharmacology September 1, 2001, 60 (3) 450-461;

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Research ArticleArticle

Apoptosis Induced by the Homocamptothecin Anticancer Drug BN80915 in HL-60 Cells

Amelie Lansiaux, Michael Facompré, Nicole Wattez, Marie-Paule Hildebrand, Christine Bal, Daniéle Demarquay, Olivier Lavergne, Dennis C. H. Bigg and Christian Bailly
Molecular Pharmacology September 1, 2001, 60 (3) 450-461;
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