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Molecular Pharmacology

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Research ArticleArticle

Obatoclax and Lapatinib Interact to Induce Toxic Autophagy through NOXA

Yong Tang, Hossein A. Hamed, Nichola Cruickshanks, Paul B. Fisher, Steven Grant and Paul Dent
Molecular Pharmacology April 2012, 81 (4) 527-540; DOI: https://doi.org/10.1124/mol.111.076851
Yong Tang
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Hossein A. Hamed
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Nichola Cruickshanks
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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 demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclax-initiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL-2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclax-induced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function.

Footnotes

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

  • This work was supported by the Department of Defense [Breast Cancer Idea Award W81XWH-10-1-0009]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK52825]; National Institutes of Health National Cancer Institute [Grants CA141703, CA150218, F32-CA85159] (the last of these to Y.T. by way of the Massey Cancer Center).

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

    http://dx.doi.org/10.1124/mol.111.076851.

  • ABBREVIATIONS:

    HER
    human epidermal growth factor receptor
    PI3K
    phosphatidylinositol 3-kinase
    MAPK
    mitogen-activated protein kinase
    BCL-2/Bcl-2
    B-cell CLL/lymphoma-2
    MCL-1
    myeloid cell leukemia-1
    BCL-XL
    BCL-2-related gene long isoform
    BAX
    BCL-2-associated x protein
    BAK
    BCL-2 antagonist killer
    mTOR
    mammalian target of rapamycin
    3-MA
    3-methyladenine
    FBS
    fetal bovine serum
    GFP
    green fluorescent protein
    LC3
    microtubule-associated protein light chain 3
    ATG
    autophagy related
    ATM
    ataxia telangiectasia mutated
    shRNA
    short hairpin RNA
    BAD
    BCL-2 antagonist of cell death
    BIM
    BCL-2-interacting mediator of cell death
    BID
    BCL-2-interacting domain death agonist
    LAMP-2
    lysosomal associated membrane protein 2
    NAC
    N-acetylcysteine
    ROS
    reactive oxygen species
    DCFDA
    dichlorofluorescein diacetate
    si
    small interfering
    PBS
    phosphate-buffered saline
    PI
    propidium iodide
    DMSO
    dimethyl sulfoxide
    COX IV
    cytochrome c oxidase
    AT-101
    (R-(−)-gossypol acetic acid
    ABT-263
    4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide
    Δψ
    mitochondrial membrane potential
    AVOs
    acidic vesicular organelles
    MOMP
    mitochondrial outer membrane permeabilization
    ER
    Estrogen receptor
    GX
    obatoclax (GX15–070).

  • Received November 17, 2011.
  • Accepted January 4, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (4)
Molecular Pharmacology
Vol. 81, Issue 4
1 Apr 2012
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Research ArticleArticle

Lapatinib and Obatoclax

Yong Tang, Hossein A. Hamed, Nichola Cruickshanks, Paul B. Fisher, Steven Grant and Paul Dent
Molecular Pharmacology April 1, 2012, 81 (4) 527-540; DOI: https://doi.org/10.1124/mol.111.076851

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Research ArticleArticle

Lapatinib and Obatoclax

Yong Tang, Hossein A. Hamed, Nichola Cruickshanks, Paul B. Fisher, Steven Grant and Paul Dent
Molecular Pharmacology April 1, 2012, 81 (4) 527-540; DOI: https://doi.org/10.1124/mol.111.076851
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