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.