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Research ArticleArticle

Inhibition of Arachidonic Acid and Iron-Induced Mitochondrial Dysfunction and Apoptosis by Oltipraz and Novel 1,2-Dithiole-3-thione Congeners

Sang Mi Shin and Sang Geon Kim
Molecular Pharmacology January 2009, 75 (1) 242-253; DOI: https://doi.org/10.1124/mol.108.051128
Sang Mi Shin
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Sang Geon Kim
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This article has a correction. Please see:

  • Correction to “Resveratrol Protects Mitochondria against Oxidative Stress through AMP-Activated Protein Kinase-Mediated Glycogen Synthase Kinase-3β Inhibition Downstream of Poly(ADP-ribose)polymerase-LKB1 Pathway” - February 01, 2019

Abstract

4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz), a prototype drug candidate containing a 1,2-dithiole-3-thione moiety, has been widely studied as a cancer chemopreventive agent. Oltipraz and other novel 1,2-dithiole-3-thione congeners have the capability to prevent insulin resistance via AMP-activated protein kinase (AMPK) activation. Arachidonic acid (AA, a proinflammatory fatty acid) exerts a deleterious effect on mitochondria and promotes reactive oxygen species (ROS) production. This study investigated whether AA alone or in combination with iron (catalyst of autooxidation) causes ROS-mediated mitochondrial impairment, and if so, whether oltipraz and synthetic 1,2-dithiole-3-thiones protect mitochondria and cells against excess ROS produced by AA + iron. Oltipraz treatment effectively inhibited mitochondrial permeability transition promoted by AA + iron in HepG2 cells, thereby protecting cells from ROS-induced apoptosis. Oltipraz was found to attenuate apoptosis induced by rotenone (complex I inhibitor), but not that by antimycin A (complex III inhibitor), suggesting that the inhibition of AA-induced apoptosis by oltipraz might be associated with the electron transport system. AMPK activation by oltipraz contributed to cell survival, which was supported by the reversal of oltipraz's restoration of mitochondrial membrane potential by concomitant treatment of compound C. By the same token, an AMPK activator inhibited AA + iron-induced mitochondrial permeability transition with an increase in cell viability. Moreover, new 1,2-dithiole-3-thiones with the capability of AMPK activation protected cells from mitochondrial permeability transition and ROS overproduction induced by AA + iron. Our results demonstrate that oltipraz and new 1,2-dithiole-3-thiones are capable of protecting cells from AA + iron-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.

Footnotes

  • This work was supported by the Korea Science and Engineering Foundation (KOSEF) funded by the government (MEST) [Grant R11-2007-107-01001-0].

  • ABBREVIATIONS: TNFα, tumor necrosis factor-α; ROS, reactive oxygen species; AMPK, AMP-activated protein kinase; AA, arachidonic acid; ACC, acetyl-CoA carboxylase; PARP, poly(ADP-ribose)polymerase; NTA, nitrilotriacetic acid; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; Rh123, rhodamine 123; PI, propidium iodide; DCFH-DA, 2′, 7′-dichlorofluorescin diacetate; PEG-SOD, polyethylene glycol-superoxide dismutase; NAC, N-acetyl-l-cysteine; MMP, mitochondrial membrane potential; S6K1, p70 ribosomal S6 kinase-1; GSK3β, glycogen synthase kinase-3β; MEM, minimal essential medium; PBS, phosphate-buffered saline; ER, endoplasmic reticulum; CHOP, CCAAT enhancer-binding protein homologous protein; Grp78, glucose-regulated protein 78; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.

    • Received August 5, 2008.
    • Accepted October 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (1)
Molecular Pharmacology
Vol. 75, Issue 1
1 Jan 2009
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Research ArticleArticle

Inhibition of Arachidonic Acid and Iron-Induced Mitochondrial Dysfunction and Apoptosis by Oltipraz and Novel 1,2-Dithiole-3-thione Congeners

Sang Mi Shin and Sang Geon Kim
Molecular Pharmacology January 1, 2009, 75 (1) 242-253; DOI: https://doi.org/10.1124/mol.108.051128

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Research ArticleArticle

Inhibition of Arachidonic Acid and Iron-Induced Mitochondrial Dysfunction and Apoptosis by Oltipraz and Novel 1,2-Dithiole-3-thione Congeners

Sang Mi Shin and Sang Geon Kim
Molecular Pharmacology January 1, 2009, 75 (1) 242-253; DOI: https://doi.org/10.1124/mol.108.051128
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