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Research ArticleCellular and Molecular

Naltrindole Inhibits Human Multiple Myeloma Cell Proliferation In Vitro and in a Murine Xenograft Model In Vivo

Jyoti Joshi Mundra, Alexandra Terskiy and Richard D. Howells
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 273-287; DOI: https://doi.org/10.1124/jpet.112.194159
Jyoti Joshi Mundra
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Alexandra Terskiy
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Richard D. Howells
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Abstract

It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrindole, a nonpeptidic δ-opioid receptor-selective antagonist; therefore, we hypothesized that human multiple myeloma (MM) would be a valuable model for studying potential antineoplastic properties of naltrindole. [3H]naltrindole exhibited saturable, low-affinity binding to intact human MM cells; however, the pharmacological profile of the binding site differed considerably from the properties of δ-, κ-, and μ-opioid receptors, and opioid receptor mRNA was not detected in MM cells by reverse transcriptase-polymerase chain reaction. Naltrindole inhibited the proliferation of cultured human U266 MM cells in a time- and dose-dependent manner with an EC50 of 16 μM. The naltrindole-induced inhibition of U266 cell proliferation was not blocked by a 10-fold molar excess of naltrexone, a nonselective opioid antagonist. Additive inhibition of MM cell proliferation was observed when using a combination of naltrindole with the histone deacetylase inhibitor sodium valproate, the proteasome inhibitor bortezomib, the glucocorticoid receptor agonist dexamethasone, and the HMG CoA reductase inhibitor simvastatin. Treatment of U266 cells with naltrindole significantly decreased the level of the active, phosphorylated form of the kinases, extracellular signal-regulated kinase and Akt, which may be related to its antiproliferative activity. The antiproliferative activity of naltrindole toward MM cells was maintained in cocultures of MM and bone marrow-derived stromal cells, mimicking the bone marrow microenvironment. In vivo, naltrindole significantly decreased tumor cell volumes in human MM cell xenografts in severe combined immunodeficient mice. We hypothesize that naltrindole inhibits the proliferation of MM cells through a nonopioid receptor-dependent mechanism.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant 09113]; the New Jersey Commission on Cancer Research; and the Foundation of the University of Medicine and Dentistry of New Jersey.

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

    http://dx.doi.org/10.1124/jpet.112.194159.

  • ABBREVIATIONS:

    MM
    multiple myeloma
    ANOVA
    analysis of variance
    BNTX
    7-benzylidenenaltrexone
    bp
    base pairs
    BTz
    bortezomib
    Dex
    dexamethasone
    DMEM
    Dulbecco's modified Eagle's medium
    DOR
    δ-opioid receptor
    DTNB
    5,5′-dithiobis-2-nitrobenzoic acid
    DTT
    dithiothreitol
    ERK
    extracellular signal-regulated kinase
    FITC
    fluorescein isothiocyanate
    HDAC
    histone deacetylase
    HEK
    human embryonic kidney
    IL-6
    interleukin-6
    KOR
    κ-opioid receptor
    MAPK
    mitogen-activated protein kinase
    MG132
    N-(benzyloxycarbonyl)leucinylleucinylleucinal
    MOPS
    4-morpholinepropanesulfonic acid
    MOR
    μ-opioid receptor
    NEM
    N-ethylmaleimide
    NF-κB
    nuclear factor-κB
    Nti
    naltrindole
    PBMC
    peripheral blood mononuclear cell
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    PI
    propidium iodide
    PS
    phosphatidylserine
    RBC
    red blood cell
    RT
    reverse transcriptase
    SCID
    severe combined immunodeficient
    Smvstn
    simvastatin
    SNC80
    4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide
    VPA
    valproic acid.

  • Received March 9, 2012.
  • Accepted April 20, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleCellular and Molecular

Naltrindole Inhibits Multiple Myeloma Cell Proliferation

Jyoti Joshi Mundra, Alexandra Terskiy and Richard D. Howells
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 273-287; DOI: https://doi.org/10.1124/jpet.112.194159

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Research ArticleCellular and Molecular

Naltrindole Inhibits Multiple Myeloma Cell Proliferation

Jyoti Joshi Mundra, Alexandra Terskiy and Richard D. Howells
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 273-287; DOI: https://doi.org/10.1124/jpet.112.194159
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