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Research ArticleArticle

C-Myc Down-Regulation Increases Susceptibility to Cisplatin through Reactive Oxygen Species-Mediated Apoptosis in M14 Human Melanoma Cells

Annamaria Biroccio, Barbara Benassi, Sarah Amodei, Chiara Gabellini, Donatella Del Bufalo and Gabriella Zupi
Molecular Pharmacology July 2001, 60 (1) 174-182; DOI: https://doi.org/10.1124/mol.60.1.174
Annamaria Biroccio
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Barbara Benassi
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Sarah Amodei
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Chiara Gabellini
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Donatella Del Bufalo
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Gabriella Zupi
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Abstract

Our aim in this work was to define the role of c-Myc in the susceptibility to cisplatin [cis-diamminedichloroplatinum(II) (CDDP)] in human melanoma cells. Two M14 melanoma cell clones obtained by transfection and expressing six to ten times lower c-Myc protein levels than the parental cells and the control clone were employed. Analysis of survival curves demonstrates an increase in CDDP sensitivity in c-Myc low-expressing clones if compared with the control clone and the parental line. The enhanced sensitivity is unrelated to the impairment in enzymatic DNA repair activity. Cell cycle analysis demonstrates that although the control clone is able to completely recover from the CDDP-induced S-G2/M block, this arrest is prolonged in c-Myc low-expressing clones and a fraction of cells undergoes apoptosis. Although no changes in P53, Bax, Bcl-2, and Bcl-xL/S protein levels are observed, apoptosis is associated with the formation of reactive oxygen species (ROS), activation of caspase-1, caspase-3 and cleavage of the specific caspase substrate poly-ADP-ribose polymerase. The use of the antioxidantN-acetyl cysteine and caspase inhibitors prevents CDDP-induced apoptosis in c-Myc low-expressing clones, demonstrating that ROS, caspase-1, and caspase-3 are required for apoptotic cell death. Moreover, ROS generation depends on caspase-1-like activation because the Ac-YVAD-cho inhibitor abrogates CDDP-induced ROS in the c-Myc low-expressing clones.

  • Abbreviations

    CPP32
    caspase-3
    CDDP
    cisplatin [cis-diamminedichloroplatinum(II)]
    ODN
    oligodeoxynucleotide
    ICE
    caspase-1
    ROS
    reactive oxygen species
    ADR
    doxorubicin (Adriamycin)
    CPT
    camptothecin
    Z-VAD-fmk
    Z-Val-Ala-Asp (OMe)-fluoromethylketone
    Ac-YVAD-cho
    N-acetyl-Tyr-Val-Ala-Asp-CHO
    Ac-DEVD-cho
    N-acetyl-Asp-Glu-Val-Asp-CHO
    β-gal
    β-galactosidase
    BrdU
    bromodeoxyuridine
    NAC
    N-acetyl-l-cysteine
    LUC
    luciferase
    PARP
    poly-ADP-ribose polymerase
    PI
    propidium iodide
    CHO
    Chinese hamster ovary
    • Received November 28, 2000.
    • Accepted March 30, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    C-Myc Down-Regulation Increases Susceptibility to Cisplatin through Reactive Oxygen Species-Mediated Apoptosis in M14 Human Melanoma Cells

    Annamaria Biroccio, Barbara Benassi, Sarah Amodei, Chiara Gabellini, Donatella Del Bufalo and Gabriella Zupi
    Molecular Pharmacology July 1, 2001, 60 (1) 174-182; DOI: https://doi.org/10.1124/mol.60.1.174

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    Research ArticleArticle

    C-Myc Down-Regulation Increases Susceptibility to Cisplatin through Reactive Oxygen Species-Mediated Apoptosis in M14 Human Melanoma Cells

    Annamaria Biroccio, Barbara Benassi, Sarah Amodei, Chiara Gabellini, Donatella Del Bufalo and Gabriella Zupi
    Molecular Pharmacology July 1, 2001, 60 (1) 174-182; DOI: https://doi.org/10.1124/mol.60.1.174
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