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Molecular Pharmacology

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Research ArticleArticle

Fyn Inhibition by Cycloalkane-Fused 1,2-Dithiole-3-thiones Enhances Antioxidant Capacity and Protects Mitochondria from Oxidative Injury

Ja Hyun Koo, Woo Hyung Lee, Chan Gyu Lee and Sang Geon Kim
Molecular Pharmacology July 2012, 82 (1) 27-36; DOI: https://doi.org/10.1124/mol.111.077149
Ja Hyun Koo
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Woo Hyung Lee
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Chan Gyu Lee
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Sang Geon Kim
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Abstract

Fyn kinase has emerged as a regulator of diverse pathological processes. However, therapeutic Fyn inhibitors are not available. This study investigated the potential of a series of cycloalkane-fused dithiolethiones (CDTs) or other congeners to increase antioxidant capacity in association with Fyn inhibition, as well as the molecular basis for this effect. Treatment of HepG2 cells with each agent protected the mitochondria from oxidative injury elicited by arachidonic acid and iron, which increased cell viability; 4,5,6,7-tetrahydrobenzo-1,2-dithiole-3-thione (SNU1A) and 5,6-dihydro-4H-cyclopenta-1,2-dithiole-3-thione (SNU2A) were the most effective, whereas 5-methyl-1,2-dithiole-3-thione (SNU3A) was less active. 5-(Quinolin-2-yl)-1,2-dithiole-3-thione (SNU3E) had a minimal effect. SNU1A treatment decreased mitochondrial superoxide production and enabled cells to restore mitochondrial membrane permeability. Oxidative injury caused by arachidonic acid and iron enhanced Fyn phosphorylation at a tyrosine residue, which was decreased by SNU1A treatment. 2,3-Dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU6656), a known Fyn inhibitor, had a similar effect. Fyn inhibition contributed to protecting mitochondria from injury through AMP-activated protein kinase (AMPK), as supported by reversal of this effect with Fyn overexpression. Consistently, Fyn overexpression attenuated AMPK activation by SNU1A, which strengthens the inhibitory role of Fyn in AMPK activity. CDTs had antioxidant effects, as shown by increases in GSH contents and inhibition of H2O2 production. They also had the ability to activate nuclear factor E2–related factor 2 (Nrf2), a key antioxidant transcription factor. Fyn overexpression decreased the Nrf2 activation induced by SNU1A. Our results demonstrate that CDTs exert cytoprotective effects by protecting mitochondria and increasing the cellular antioxidant capacity, which may result not only from Fyn inhibition leading to AMPK activation but also from Nrf2 activation.

Footnotes

  • This work was supported by the National Research Foundation of Korea, with grants funded by the Ministry of Education, Science, and Technology [Grant 2011-0001204] and by the World Class University Project [Grant R32-2011-000-10098-0].

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

    http://dx.doi.org/10.1124/mol.111.077149.

  • ABBREVIATIONS:

    ROS
    reactive oxygen species
    AA
    arachidonic acid
    Ad
    adenoviral
    ACC
    acetyl-CoA carboxylase
    AMPK
    AMP-activated protein kinase
    CDT
    cycloalkane-fused dithiolethione
    DCFH-DA
    2′,7′-dichlorofluorescein diacetate
    FACS
    fluorescence-activated cell sorting
    GSK3β
    glycogen synthase kinase 3β
    LKB1
    liver kinase B1
    MMP
    mitochondrial membrane potential
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide
    Nrf2
    nuclear factor E2–related factor 2
    Rh123
    Rhodamine 123
    ARE
    antioxidant-response element
    SNU1A
    4,5,6,7-tetrahydrobenzo-1,2-dithiole-3-thione
    SNU2A
    5,6-dihydro-4H-cyclopenta-1,2-dithiole-3-thione
    SNU3A
    5-methyl-1,2-dithiole-3-thione
    SNU3E
    5-(quinolin-2-yl)-1,2-dithiole-3-thione
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    DN
    dominant-negative
    SU6656
    2,3-dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide.

  • Received December 8, 2011.
  • Accepted April 2, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (1)
Molecular Pharmacology
Vol. 82, Issue 1
1 Jul 2012
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Research ArticleArticle

Mitochondrial Protection through Fyn Inhibition

Ja Hyun Koo, Woo Hyung Lee, Chan Gyu Lee and Sang Geon Kim
Molecular Pharmacology July 1, 2012, 82 (1) 27-36; DOI: https://doi.org/10.1124/mol.111.077149

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Research ArticleArticle

Mitochondrial Protection through Fyn Inhibition

Ja Hyun Koo, Woo Hyung Lee, Chan Gyu Lee and Sang Geon Kim
Molecular Pharmacology July 1, 2012, 82 (1) 27-36; DOI: https://doi.org/10.1124/mol.111.077149
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