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Molecular Pharmacology

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Research ArticleArticle

Lapatinib and Obatoclax Kill Tumor Cells through Blockade of ERBB1/3/4 and through Inhibition of BCL-xL and MCL-1

Nichola Cruickshanks, Hossein A. Hamed, M. Danielle Bareford, Andrew Poklepovic, Paul B. Fisher, Steven Grant and Paul Dent
Molecular Pharmacology May 2012, 81 (5) 748-758; DOI: https://doi.org/10.1124/mol.112.077586
Nichola Cruickshanks
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Hossein A. Hamed
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M. Danielle Bareford
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Andrew Poklepovic
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Paul B. Fisher
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Steven Grant
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Paul Dent
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Abstract

Prior studies in breast cancer cells have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses to the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1–4), we discovered that the inhibition of ERBB1/3/4 receptors were most important for enhancing obatoclax lethality rather than ERBB2. In parallel, we noted in CNS tumor cells that knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib- and obatoclax-prolonged survival. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Cancer Institute [Grants R01-CA141704, R01-CA150214]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK52825]; and the Department of Defense [Grant DAMD17-03-1-0262].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.077586.

  • ABBREVIATIONS:

    GBM
    glioblastoma
    ERBB1-4
    erythroblastic leukemia viral oncogene homolog 1–4
    BCL
    B-cell lymphoma
    BCL-xL
    B-cell lymphoma-extra large
    MCL
    MCL-1, myeloid cell leukemia-1
    GX15-070
    obatoclax
    ERK
    extracellular-regulated kinase
    MEK
    mitogen-activated extracellular regulated kinase
    PI3K
    phosphatidylinositol 3-kinase
    z-VAD
    N-benzyloxycarbonyl-Val-Arg-Asp
    siRNA
    small interfering RNA
    PTEN
    phosphatase and tensin homolog on chromosome 10
    PAGE
    polyacrylamide gel electrophoresis
    DMSO
    dimethyl sulfoxide
    GFP
    green fluorescent protein
    BEZ-235
    2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile
    PBS
    phosphate-buffered saline
    ABT-263
    navitoclax
    CNS
    central nervous system.

  • Received January 3, 2012.
  • Accepted February 22, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (5)
Molecular Pharmacology
Vol. 81, Issue 5
1 May 2012
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Research ArticleArticle

Lapatinib, Obatoclax, and CNS Tumors

Nichola Cruickshanks, Hossein A. Hamed, M. Danielle Bareford, Andrew Poklepovic, Paul B. Fisher, Steven Grant and Paul Dent
Molecular Pharmacology May 1, 2012, 81 (5) 748-758; DOI: https://doi.org/10.1124/mol.112.077586

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Research ArticleArticle

Lapatinib, Obatoclax, and CNS Tumors

Nichola Cruickshanks, Hossein A. Hamed, M. Danielle Bareford, Andrew Poklepovic, Paul B. Fisher, Steven Grant and Paul Dent
Molecular Pharmacology May 1, 2012, 81 (5) 748-758; DOI: https://doi.org/10.1124/mol.112.077586
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