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Research ArticleArticle

Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress

Nichola Cruickshanks, Yong Tang, Laurence Booth, Hossein Hamed, Steven Grant and Paul Dent
Molecular Pharmacology December 2012, 82 (6) 1217-1229; DOI: https://doi.org/10.1124/mol.112.081539
Nichola Cruickshanks
Departments of Neurosurgery (N.C., Y.T., L.B., P.D.) and Internal Medicine (S.G.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Yong Tang
Departments of Neurosurgery (N.C., Y.T., L.B., P.D.) and Internal Medicine (S.G.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Laurence Booth
Departments of Neurosurgery (N.C., Y.T., L.B., P.D.) and Internal Medicine (S.G.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Hossein Hamed
Departments of Neurosurgery (N.C., Y.T., L.B., P.D.) and Internal Medicine (S.G.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Steven Grant
Departments of Neurosurgery (N.C., Y.T., L.B., P.D.) and Internal Medicine (S.G.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Paul Dent
Departments of Neurosurgery (N.C., Y.T., L.B., P.D.) and Internal Medicine (S.G.), School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Abstract

Previous studies showed 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. Lapatinib and obatoclax killed multiple tumor cell types, and cells lacking phosphatase and tensin homolog (PTEN) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null breast cancer cells restored drug sensitivity. Coadministration of lapatinib with obatoclax elicited autophagic cell death that was attributable to the actions of mitochondrial reactive oxygen species. Wild-type cells but not mitochondria-deficient rho-zero cells were radiosensitized by lapatinib and obatoclax treatment. Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase 1/2 (JNK1/2) by the drug combination was enhanced by radiation, and signaling by p38 MAPK and JNK1/2 promoted cell killing. In immunohistochemical analyses, the autophagosome protein p62 was determined to be associated with protein kinase-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1, as well as with binding immunoglobulin protein/78-kDa glucose-regulated protein, in drug combination-treated cells. Knockdown of PERK suppressed drug-induced autophagy and protected tumor cells from the drug combination. Knockdown of PERK suppressed the reduction in Mcl-1 expression after drug combination exposure, and overexpression of Mcl-1 protected cells. Our data indicate that mitochondrial function plays an essential role in cell killing by lapatinib and obatoclax, as well as radiosensitization by this drug combination.

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], the Department of Defense [Grant W81XWH-10-1-0009], and the Lind-Lawrence Foundation. P.D. is the holder of the Universal Inc. Professorship in Signal Transduction Research.

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

    http://dx.doi.org/10.1124/mol.112.081539.

  • ABBREVIATIONS:

    BAX
    Bcl-2–associated X protein
    S6K
    S6 kinase
    siRNA
    small interfering RNA
    MAPK
    mitogen-activated protein kinase
    JNK
    c-Jun NH2-terminal kinase
    PI3K
    phosphoinositide 3-kinase
    PTEN
    phosphatase and tensin homolog
    PERK
    protein kinase-like endoplasmic reticulum kinase
    ASK1
    apoptosis signaling kinase 1
    BiP
    binding immunoglobulin protein
    GRP78
    78-kDa glucose-regulated protein
    IRE1
    inositol-requiring enzyme 1
    BAK
    Bcl-2–homologous antagonist/killer
    BH
    Bcl-2 homology
    mTOR
    mammalian target of rapamycin
    DMSO
    dimethylsulfoxide
    ER
    endoplasmic reticulum
    ROS
    reactive oxygen species
    GFP
    green fluorescent protein
    PBS
    phosphate-buffered saline
    PAGE
    polyacrylamide gel electrophoresis
    BEZ235
    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.

  • Received July 25, 2012.
  • Accepted September 18, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Lapatinib and Obatoclax

Nichola Cruickshanks, Yong Tang, Laurence Booth, Hossein Hamed, Steven Grant and Paul Dent
Molecular Pharmacology December 1, 2012, 82 (6) 1217-1229; DOI: https://doi.org/10.1124/mol.112.081539

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Research ArticleArticle

Lapatinib and Obatoclax

Nichola Cruickshanks, Yong Tang, Laurence Booth, Hossein Hamed, Steven Grant and Paul Dent
Molecular Pharmacology December 1, 2012, 82 (6) 1217-1229; DOI: https://doi.org/10.1124/mol.112.081539
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