Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners. 1894 20

Oltipraz protects cells from chemical-induced carcinogenesis partly because of phase 2 enzyme induction. Certain oltipraz metabolites also induce phase 2 enzymes. This study investigated the cytoprotective effects of the oxidized metabolites of oltipraz against arachidonic acid (AA), a proinflammatory fatty acid that causes cellular reactive oxygen species (ROS) production and mitochondrial impairment, and the mechanistic basis of their action in HepG2 cells. Treatment with 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one (M1) or 7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]-pyrazine (M2), but not 7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine (M3) or 7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine (M4), enabled cells to protect against AA-induced apoptosis. M1 and M2 treatment protected cells from ROS produced by AA and inhibited AA-induced glutathione depletion. Moreover, both M1 and M2 effectively inhibited mitochondrial dysfunction induced by AA, although M2 alone slightly elicited it at a relatively high concentration. M1 and M2 activated AMP-activated protein kinase (AMPK), but M3 and M4 failed to do so. AMPK activation by M1 and M2 contributed to cell survival against AA through a decrease in cellular ROS production and prevention of mitochondrial dysfunction, as shown by the reversal of the metabolites' restoration of mitochondrial membrane potential by compound C treatment or overexpression of a dominant-negative mutant AMPK. Consistently, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, an AMPK activator, also had a cytoprotective and antioxidant effect against AA. Our results demonstrate that, of the major metabolites of oltipraz, M1 and M2 are capable of protecting cells from AA-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.
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PMID:Oxidized metabolites of oltipraz exert cytoprotective effects against arachidonic acid through AMP-activated protein kinase-dependent cellular antioxidant effect and mitochondrial protection. 1929 24

Hypoxia-inducible factor-1alpha (HIF-1alpha) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1alpha, and the augmented HIF-1alpha activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1alpha activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1alpha expression through an increase in ubiquitination, thereby accelerating HIF-1alpha degradation and inhibiting HIF-1alpha-dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1alpha activity. CA-S6K1 overexpression reversed HIF-1alpha inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1alpha was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-alpha to restore the ability of insulin to increase HIF-1alpha against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H(2)O(2) production, thereby preventing H(2)O(2)-enhanced HIF-1alpha expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1alpha activity and HIF-1alpha-dependent tumor growth, which may result from a decrease in HIF-1alpha stability through S6K1 inhibition in combination with an H(2)O(2)-scavenging effect.
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PMID:Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1alpha activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect. 1978 18