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Research ArticleCellular and Molecular

Epoxyeicosatrienoic Acids Attenuate Reactive Oxygen Species Level, Mitochondrial Dysfunction, Caspase Activation, and Apoptosis in Carcinoma Cells Treated with Arsenic Trioxide

Liu Liu, Chen Chen, Wei Gong, Yuanjing Li, Matthew L. Edin, Darryl C. Zeldin and Dao Wen Wang
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 451-463; DOI: https://doi.org/10.1124/jpet.111.180505
Liu Liu
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Chen Chen
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Wei Gong
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Yuanjing Li
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Matthew L. Edin
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Darryl C. Zeldin
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Dao Wen Wang
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Abstract

Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1–2 μM). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction.

Footnotes

  • This work was supported by the China Natural Science Foundation Committee [Grants 30700377, 30770882, 30430320]; the 973 Project [Grant 2007 CB512004]; and the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01-ES025034].

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

    doi:10.1124/jpet.111.180505.

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

  • ABBREVIATIONS:

    EET
    epoxyeicosatrienoic acid
    ERK
    extracellular signal-regulated kinase
    ATO
    arsenic trioxide
    ROS
    reactive oxygen species
    DCFH-DA
    2,7-dichlorodihydrofluorescein diacetate
    SOD
    superoxide dismutase
    SRB
    sulforhodamine B
    MAPK
    mitogen-activated protein kinase
    JNK
    c-Jun NH2-terminal kinase
    C26
    compound 26
    PI
    propidium iodide
    NAC
    N-acetyl-l-cysteine
    FITC
    fluorescein isothiocyanate
    siRNA
    small interfering RNA
    ΔΨm
    mitochondrial transmembrane potential
    SP600125
    anthra[1–9-cd]pyrazol-6(2H)-one
    PD98059
    2′-amino-3′-methoxyflavone
    SB203580
    4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine.

  • Received February 11, 2011.
  • Accepted August 11, 2011.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleCellular and Molecular

EETs, ROS, and Apoptosis

Liu Liu, Chen Chen, Wei Gong, Yuanjing Li, Matthew L. Edin, Darryl C. Zeldin and Dao Wen Wang
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 451-463; DOI: https://doi.org/10.1124/jpet.111.180505

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Research ArticleCellular and Molecular

EETs, ROS, and Apoptosis

Liu Liu, Chen Chen, Wei Gong, Yuanjing Li, Matthew L. Edin, Darryl C. Zeldin and Dao Wen Wang
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 451-463; DOI: https://doi.org/10.1124/jpet.111.180505
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