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Molecular Pharmacology

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Research ArticleArticle

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Shiliang Yin, Rui Wang, Fan Zhou, Hong Zhang and Yongkui Jing
Molecular Pharmacology June 2011, 79 (6) 1072-1083; DOI: https://doi.org/10.1124/mol.110.068528
Shiliang Yin
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Rui Wang
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Fan Zhou
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Hong Zhang
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Yongkui Jing
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Abstract

Homoharringtonine (HHT) has been reported to be effective in a portion of patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). To investigate its mechanism of action, cell growth inhibition and cytotoxicity of HHT were investigated in three AML cell lines, HL-60, NB4, and U937, and in three CML cell lines, K562, KU812, and KCL22. AML cells were more sensitive than CML cells to HHT-induced cytotoxicity. Using HL-60 cells, it was revealed that HHT decreased the levels of myeloid cell leukemia 1 (Mcl-1), X-linked inhibitor of apoptosis protein (XIAP), survivin, and B-cell lymphoma 2 (Bcl-2)-homology domain 3 (BH3)-only proteins as well as the mitochondrial membrane potential. The levels of Bcl-2, Bcl-2–associated X protein (Bax), and Bcl-2 homologous antagonist/killer (Bak) proteins in HL-60 cells were not changed after HHT treatment. U937, K562, KU812, and KCL22 cells expressed B-cell lymphoma-extra large (Bcl-xL) and were less responsive to HHT-induced apoptosis than HL-60 cells. Silencing Mcl-1 or Bcl-xL, but not XIAP or survivin, enhanced HHT-induced apoptosis in U937 cells. The levels of HHT-induced apoptosis in K562, KCL22, and KU812 cells were inversely correlated with the levels of Bcl-xL but not those of Bcl-2 or Mcl-1. K562 cells expressing high levels of Bcl-xL but no Bcl-2 were less responsive to HHT-induced apoptosis than KCL22 cells that expressed lower levels of Bcl-xL and higher levels of Bcl-2 protein. In K562 cells, knockdown of Bcl-xL, but not of Mcl-1, enhanced HHT-induced apoptosis. Transfection of Bcl-xL into KCL22 cells attenuated HHT-induced apoptosis. These data suggest that Bcl-xL plays a more important role than Bcl-2 and Mcl-1 in protecting against HHT-induced apoptosis.

Footnotes

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

    doi:10.1124/mol.110.068528.

  • ABBREVIATIONS:

    HHT
    homoharringtonine
    AML
    acute myeloid leukemia
    CML
    chronic myeloid leukemia
    Fas
    fatty acid synthase
    FADD
    Fas-associated protein with death domain
    c-FLIP
    cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein
    Mcl-1
    myeloid cell leukemia 1
    XIAP
    X-linked inhibitor of apoptosis protein
    Bcl-xL
    B-cell lymphoma-extra large
    Bcl-2
    B-cell lymphoma 2
    Bax
    Bcl-2–associated X protein
    Bak
    Bcl-2 homologous antagonist/killer
    Rh123
    Rhodamine-123
    PARP
    poly(ADP-ribose) polymerase
    DR4
    death receptor 4
    DR5
    death receptor 5
    Bim
    Bcl-2-like protein 11
    Puma
    p53 up-regulated modulator of apoptosis
    siRNA
    small interfering RNA
    FITC
    fluorescein isothiocyanate
    PI
    propidium iodide
    PBS
    phosphate-buffered saline
    MMP
    mitochondrial membrane potential
    CHAPS
    3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate
    FACS
    fluorescence-activated cell sorting
    VDAC
    voltage-dependent anion channel.

  • Received August 30, 2010.
  • Accepted March 17, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Shiliang Yin, Rui Wang, Fan Zhou, Hong Zhang and Yongkui Jing
Molecular Pharmacology June 1, 2011, 79 (6) 1072-1083; DOI: https://doi.org/10.1124/mol.110.068528

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Research ArticleArticle

Bcl-xL Is a Dominant Antiapoptotic Protein that Inhibits Homoharringtonine-Induced Apoptosis in Leukemia Cells

Shiliang Yin, Rui Wang, Fan Zhou, Hong Zhang and Yongkui Jing
Molecular Pharmacology June 1, 2011, 79 (6) 1072-1083; DOI: https://doi.org/10.1124/mol.110.068528
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