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Research ArticleArticle

Curcumin Dually Inhibits Both Mammalian Target of Rapamycin and Nuclear Factor-κB Pathways through a Crossed Phosphatidylinositol 3-Kinase/Akt/IκB Kinase Complex Signaling Axis in Adenoid Cystic Carcinoma

Zhi-Jun Sun, Gang Chen, Wei Zhang, Xiang Hu, Yang Liu, Qian Zhou, Ling-Xing Zhu and Yi-Fang Zhao
Molecular Pharmacology January 2011, 79 (1) 106-118; DOI: https://doi.org/10.1124/mol.110.066910
Zhi-Jun Sun
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Gang Chen
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Wei Zhang
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Xiang Hu
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Yang Liu
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Qian Zhou
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Ling-Xing Zhu
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Yi-Fang Zhao
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This article has a correction. Please see:

  • Correction to “Curcumin Dually Inhibits Both Mammalian Target of Rapamycin and Nuclear Factor-κB Pathways through a Crossed Phosphatidylinositol 3-Kinase/Akt/IκB Kinase Complex Signaling Axis in Adenoid Cystic Carcinoma” - March 01, 2011

Abstract

Adenoid cystic carcinoma (ACC) is a highly malignant tumor that is generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus, novel therapeutic strategies and agents are urgently needed to treat this aggressive neoplasm. Curcumin, a component of turmeric (Curcuma longa), has been shown to have a diversity of antitumor activities. We show here that curcumin is a potent inhibitor of ACC progression in vitro and in vivo. Curcumin concentration-dependently inhibited the growth of ACC cells via induction of apoptosis. The ability of ACC cells to migrate/invade and induce angiogenesis was also significantly attenuated by curcumin, accompanied by the down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 and -9. Moreover, our data also demonstrated that the inhibitory effects of curcumin on ACC cells were due to its dual inhibition of both mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB) pathways through a crossed phosphatidylinositol 3-kinase/Akt/IκBα kinase signaling axis. Most importantly, curcumin effectively prevented the in vivo growth and angiogenesis of ACC xenografts in nude mice, as revealed by the induction of cell apoptosis and reduction of microvessel density in tumor tissues. In addition, we further assessed the nature activation status of both mTOR and NF-κB pathways in ACC tissues and confirmed the concurrent high activation of these two pathways in ACC for the first time. Taken together, our findings suggest that further clinical investigation is warranted to apply curcumin as a novel chemotherapeutic regimen for ACC because of its dual suppression of both mTOR and NF-κB pathways.

Footnotes

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

  • This study was supported in part by the National Natural Science Foundation of China [Grants 30872894, 30973330, 81072203], and the National Undergraduate Innovative Experiment Project [Grant 091048654].

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

    doi:10.1124/mol.110.066910.

  • ABBREVIATIONS:

    ACC
    adenoid cystic carcinoma
    mTOR
    mammalian target of rapamycin
    MAPK
    mitogen-activated protein kinase
    JNK
    c-Jun NH2-terminal kinase
    ERK
    extracellular signal-regulated kinase
    NF-κB
    nuclear factor-κB
    IKK
    IκBα kinase
    PI3K
    phosphatidylinositol 3-kinase
    VEGF
    vascular endothelial growth factor
    bFGF
    basic fibroblast growth factor
    IL
    interleukin
    MMP
    matrix metalloproteinase
    CM
    conditioned medium
    NSG
    normal salivary gland
    DMSO
    dimethyl sulfoxide
    PDTC
    pyrrolidine dithiocarbamate
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    PBS
    phosphate-buffered saline
    CAM
    chick chorioallantoic membrane
    TUNEL
    terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
    PARP
    poly(ADP-ribose) polymerase
    PI
    propidium iodide
    CTG
    Cell Titer-Glo
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    ELISA
    enzyme-linked immunosorbent assay
    CA
    constitutively active
    LY294002
    2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
    PS1145
    N-(6-chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide dihydrochloride.

  • Received June 15, 2010.
  • Accepted October 19, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (1)
Molecular Pharmacology
Vol. 79, Issue 1
1 Jan 2011
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Research ArticleArticle

Curcumin Dually Inhibits Both Mammalian Target of Rapamycin and Nuclear Factor-κB Pathways through a Crossed Phosphatidylinositol 3-Kinase/Akt/IκB Kinase Complex Signaling Axis in Adenoid Cystic Carcinoma

Zhi-Jun Sun, Gang Chen, Wei Zhang, Xiang Hu, Yang Liu, Qian Zhou, Ling-Xing Zhu and Yi-Fang Zhao
Molecular Pharmacology January 1, 2011, 79 (1) 106-118; DOI: https://doi.org/10.1124/mol.110.066910

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Research ArticleArticle

Curcumin Dually Inhibits Both Mammalian Target of Rapamycin and Nuclear Factor-κB Pathways through a Crossed Phosphatidylinositol 3-Kinase/Akt/IκB Kinase Complex Signaling Axis in Adenoid Cystic Carcinoma

Zhi-Jun Sun, Gang Chen, Wei Zhang, Xiang Hu, Yang Liu, Qian Zhou, Ling-Xing Zhu and Yi-Fang Zhao
Molecular Pharmacology January 1, 2011, 79 (1) 106-118; DOI: https://doi.org/10.1124/mol.110.066910
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