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Molecular Pharmacology

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Research ArticleArticle

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Irina I. Vlasova, Wei-Hong Feng, Julie P. Goff, Angela Giorgianni, Duc Do, Susanne M. Gollin, Dale W. Lewis, Valerian E. Kagan and Jack C. Yalowich
Molecular Pharmacology March 2011, 79 (3) 479-487; DOI: https://doi.org/10.1124/mol.110.068718
Irina I. Vlasova
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Wei-Hong Feng
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Julie P. Goff
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Angela Giorgianni
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Duc Do
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Susanne M. Gollin
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Dale W. Lewis
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Valerian E. Kagan
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Jack C. Yalowich
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Abstract

Etoposide is a widely used anticancer drug successfully used for the treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia involving the mixed-lineage leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by MPO to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34+ myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor-mobilized CD34+ cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in the oxidation of endogenous thiols, thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34+ cells. Together, our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoietic CD34+ cells makes these cells especially prone to the induction of etoposide-related acute myeloid leukemia.

Footnotes

  • This research was supported in part by the National Institutes of Health National Cancer Institute [Grant R01-CA090787].

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

    doi:10.1124/mol.110.068718.

  • ABBREVIATIONS:

    VP-16
    4′-demethyl-epipodophyllotoxin-9-(4,6-O-ethylidene-β-d-gluco-pyranoside)
    MPO
    myeloperoxidase
    SA
    succinylacetone
    3-AT
    3-amino-1,2,4-triazole
    DTPA
    diethylentriaminepentaacetic acid
    CB
    human umbilical cord blood
    MLL
    mixed-lineage leukemia
    MLLR
    MLL gene rearrangements
    t-AML
    treatment-related acute myelogenous leukemia
    EPR
    electron paramagnetic resonance
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    FBS
    fetal bovine serum
    FISH
    fluorescence in situ hybridization
    ACD-A
    anticoagulant citrate dextrose solution.

  • Received September 7, 2010.
  • Accepted November 19, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Irina I. Vlasova, Wei-Hong Feng, Julie P. Goff, Angela Giorgianni, Duc Do, Susanne M. Gollin, Dale W. Lewis, Valerian E. Kagan and Jack C. Yalowich
Molecular Pharmacology March 1, 2011, 79 (3) 479-487; DOI: https://doi.org/10.1124/mol.110.068718

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Research ArticleArticle

Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells

Irina I. Vlasova, Wei-Hong Feng, Julie P. Goff, Angela Giorgianni, Duc Do, Susanne M. Gollin, Dale W. Lewis, Valerian E. Kagan and Jack C. Yalowich
Molecular Pharmacology March 1, 2011, 79 (3) 479-487; DOI: https://doi.org/10.1124/mol.110.068718
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