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Molecular Pharmacology

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Research ArticleArticle

Miltefosine Induces Apoptosis-Like Cell Death in Yeast via Cox9p in Cytochrome c Oxidase

Xiaoming Zuo, Julianne T. Djordjevic, Johanes Bijosono Oei, Desmarini Desmarini, Stephen D. Schibeci, Katrina A. Jolliffe and Tania C. Sorrell
Molecular Pharmacology September 2011, 80 (3) 476-485; DOI: https://doi.org/10.1124/mol.111.072322
Xiaoming Zuo
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Julianne T. Djordjevic
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Johanes Bijosono Oei
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Desmarini Desmarini
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Stephen D. Schibeci
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Katrina A. Jolliffe
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Tania C. Sorrell
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Abstract

Miltefosine has antifungal properties and potential for development as a therapeutic for invasive fungal infections. However, its mode of action in fungi is poorly understood. We demonstrate that miltefosine is rapidly incorporated into yeast, where it penetrates the mitochondrial inner membrane, disrupting mitochondrial membrane potential and leading to an apoptosis-like cell death. COX9, which encodes subunit VIIa of the cytochrome c oxidase (COX) complex in the electron transport chain of the mitochondrial membrane, was identified as a potential target of miltefosine from a genomic library screen of the model yeast Saccharomyces cerevisiae. When overexpressed in S. cerevisiae, COX9, but not COX7 or COX8, led to a miltefosine-resistant phenotype. The effect of miltefosine on COX activity was assessed in cells expressing different levels of COX9. Miltefosine inhibited COX activity in a dose-dependent manner in Cox9p-positive cells. This inhibition most likely contributed to the miltefosine-induced apoptosis-like cell death.

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 Health and Medical Research Council, Australia [Project Grant 570891] and by a Fellowship from the Sydney Medical School Foundation (to T.C.S.).

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

    doi:10.1124/mol.111.072322.

  • ABBREVIATIONS:

    PC
    phosphatidylcholine
    PE
    phosphatidylethanolamine
    COX
    cytochrome c oxidase
    MIC
    minimum inhibitory concentration
    YPD
    yeast extract peptone dextrose
    YPGly
    yeast extract peptone glycerol
    YNB
    yeast nitrogen base
    PBS
    phosphate-buffered saline
    DiOC6
    3,3′-dihexyloxacarbocyanine iodide
    DAPI
    4,6-diamidino-2-phenylindole
    PI
    propidium iodide
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    kb
    kilobase(s)
    PCR
    polymerase chain reaction
    qRT
    quantitative real-time
    TES
    N-tris-[hydroxymethyl]methyl-2-aminoethanesulfonic acid
    AEBSF
    4-[2-aminoethyl]-benzene-sulfonylfluoride·HCl
    KCN
    potassium cyanide
    WT
    wild type
    FP
    forward primer
    RP
    reverse primer.

  • Received March 17, 2011.
  • Accepted May 24, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Miltefosine Induces Apoptosis-Like Cell Death in Yeast via Cox9p in Cytochrome c Oxidase

Xiaoming Zuo, Julianne T. Djordjevic, Johanes Bijosono Oei, Desmarini Desmarini, Stephen D. Schibeci, Katrina A. Jolliffe and Tania C. Sorrell
Molecular Pharmacology September 1, 2011, 80 (3) 476-485; DOI: https://doi.org/10.1124/mol.111.072322

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Research ArticleArticle

Miltefosine Induces Apoptosis-Like Cell Death in Yeast via Cox9p in Cytochrome c Oxidase

Xiaoming Zuo, Julianne T. Djordjevic, Johanes Bijosono Oei, Desmarini Desmarini, Stephen D. Schibeci, Katrina A. Jolliffe and Tania C. Sorrell
Molecular Pharmacology September 1, 2011, 80 (3) 476-485; DOI: https://doi.org/10.1124/mol.111.072322
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