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Research ArticleArticle

Inhibition of Autophagy as a Strategy to Augment Radiosensitization by the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235

George J. Cerniglia, Jayashree Karar, Sonia Tyagi, Melpo Christofidou-Solomidou, Ramesh Rengan, Constantinos Koumenis and Amit Maity
Molecular Pharmacology December 2012, 82 (6) 1230-1240; DOI: https://doi.org/10.1124/mol.112.080408
George J. Cerniglia
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Jayashree Karar
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Sonia Tyagi
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Melpo Christofidou-Solomidou
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Ramesh Rengan
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Constantinos Koumenis
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Amit Maity
Department of Radiation Oncology (G.J.C., J.K., R.R., C.K., A.M.) and Department of Medicine, Division of Pulmonary, Allergy, and Critical Care (S.T., M.C.-S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Abstract

We investigated the effect of 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 (NVP-BEZ235) (Novartis, Basel Switzerland), a dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor currently being tested in phase I clinical trials, in radiosensitization. NVP-BEZ235 radiosensitized a variety of cancer cell lines, including SQ20B head and neck carcinoma cells and U251 glioblastoma cells. NVP-BEZ235 also increased in vivo radiation response in SQ20B xenografts. Knockdown of Akt1, p110α, or mTOR resulted in radiosensitization, but not to the same degree as with NVP-BEZ235. NVP-BEZ235 interfered with DNA damage repair after radiation as measured by the CometAssay and resolution of phosphorylated H2A histone family member X foci. NVP-BEZ235 abrogated the radiation-induced phosphorylation of both DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia telangiectasia mutated. Knockdown of either p110α or mTOR failed to decrease the phosphorylation of DNA-PKcs, suggesting that the effect of the drug was direct rather than mediated via p110α or mTOR. The treatment of cells with NVP-BEZ235 also promoted autophagy. To assess the importance of this process in radiosensitization, we used the autophagy inhibitors 3-methyladenine and chloroquine and found that either drug increased cell killing after NVP-BEZ235 treatment and radiation. Knocking down the essential autophagy proteins autophagy related 5 (ATG5) and beclin1 increased NVP-BEZ235-mediated radiosensitization. Furthermore, NVP-BEZ235 radiosensitized autophagy-deficient ATG5(−/−) fibroblasts to a greater extent than ATG5(+/+) cells. We conclude that NVP-BEZ235 radiosensitizes cells and induces autophagy by apparently distinct mechanisms. Inhibiting autophagy via pharmacologic or genetic means increases radiation killing after NVP-BEZ235 treatment; hence, autophagy seems to be cytoprotective in this situation. Our data offer a rationale for combining NVP-BEZ235 along with an autophagy inhibitor (i.e., chloroquine) and radiation in future clinical trials.

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 Institute of Cancer [Grants R01-CA093638, R01-CA133470].

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

    http://dx.doi.org/10.1124/mol.112.080408.

  • ABBREVIATIONS:

    PI3K
    phosphatidylinositol 3-kinase
    NVP-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
    ATG5
    autophagy related 5
    ATM
    ataxia telangiectasia mutated
    DER
    dose enhancement ratio
    DNA-PKcs
    DNA-dependent protein kinase catalytic subunit
    4E-BP1
    4E binding protein 1
    E64d
    2S,3S-trans-(ethoxycarbonyloxirane-2-carbonyl)-l-leucine-(3-methylbutyl) amide
    EGFR
    epidermal growth factor receptor
    GFP
    green fluorescent protein
    Gy
    gray
    HR
    homologous recombination
    H2AX
    H2A histone family member X
    γ-H2AX
    phosphorylated H2AX
    LY294002
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
    3-MA
    3-methyladenosine
    MEF
    mouse embryonic fibroblast
    mTOR
    mammalian target of rapamycin
    NHEJR
    nonhomologous end joining repair
    P-
    phosphorylated-
    PAGE
    polyacrylamide gel electrophoresis
    PARP
    poly(ADP-ribose) polymerase
    PI-103
    3–4-(4-morpholinylpyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl-phenol
    PIK3CA
    phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α
    PTEN
    phosphatase and tensin homolog
    RAD001
    dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
    siRNA
    small inhibitory RNA.

  • Received June 7, 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

Inhibiting Autophagy to Radiosensitize Cells with NVP-BEZ235

George J. Cerniglia, Jayashree Karar, Sonia Tyagi, Melpo Christofidou-Solomidou, Ramesh Rengan, Constantinos Koumenis and Amit Maity
Molecular Pharmacology December 1, 2012, 82 (6) 1230-1240; DOI: https://doi.org/10.1124/mol.112.080408

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Research ArticleArticle

Inhibiting Autophagy to Radiosensitize Cells with NVP-BEZ235

George J. Cerniglia, Jayashree Karar, Sonia Tyagi, Melpo Christofidou-Solomidou, Ramesh Rengan, Constantinos Koumenis and Amit Maity
Molecular Pharmacology December 1, 2012, 82 (6) 1230-1240; DOI: https://doi.org/10.1124/mol.112.080408
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