Anethole Dithiolethione Regulates Oxidant-Induced Tyrosine Kinase Activation in Endothelial Cells

Ben-Mahdi, Meriem Hind; Gozin, Alexia; Driss, Fathi; Andrieu, Valérie; Christen, Marie‐Odile; Pasquier, Claude

doi:10.1089/ars.2000.2.4-789

Cited by 12 publications

(8 citation statements)

References 33 publications

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“…The specific effect of OP2113 on a unique site of mitochondrial ROS/H 2 O 2 production is not only surprising but raises interesting questions about the mechanism of action of OP2113 on mitochondria. These results exclude the hypothesis that the therapeutic effects of OP2113 arise from a mere radical scavenger property as previously reported [28–30]. Indeed, we show in this study that OP2113 does not trap all the ROS produced by mitochondrial respiratory chain, independently of their site of production.…”

Section: Resultssupporting

confidence: 76%

“…Anetholtrithion also exhibits chemoprotective effects against cancer and various kinds of toxicity caused by some drugs and xenobiotics [27]. These chemoprotective effects appear to be mainly due to its antioxidant properties [28–30]. The most typical indications for which anetholtrithion is currently used include increasing salivary secretion in patients experiencing dry mouth.…”

Section: Introductionmentioning

confidence: 99%

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An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

et al. 2019

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Findings Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H 2 O 2 ) production by acting as a specific inhibitor of ROS production at the I Q site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity. Conclusion / Significance This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H 2 O 2 . OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer's diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.

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Section: Resultssupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

et al. 2019

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“…Some dithioles have known effects on endothelial cells or antiangiogenic activities (Ben-Mahdi et al, 2000;Ruggeri et al, 2002). These compounds also protect against tetrachloride and acetaminophen hepatotoxicity, possibly owing to their antioxidant properties modulating cellular glutathione, which provides cytoprotection against oxidative stress (Kensler et al, 1992;Kwak et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Isenberg

Jia

Field

et al. 2007

British J Pharmacology

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Background and purpose: Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated antiangiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. Experimental approach: Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos. Key results: Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser 78 phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H 2 S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. Conclusions and implication: S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.

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“…Adhesion to the matrix was measured with a Calcein-AM assay as previously described [ 20 ]. Following exposure to the different treatments, HUVECs monolayers were thoroughly washed to remove nonadherent cells.…”

Section: Methodsmentioning

confidence: 99%

Xanthine Oxidase‐Derived ROS Display a Biphasic Effect on Endothelial Cells Adhesion and FAK Phosphorylation

Ben-Mahdi

Dang

Gougerot‐Pocidalo

et al. 2016

Oxidative Medicine and Cellular Longevity

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In pathological situations such as ischemia-reperfusion and acute respiratory distress syndrome, reactive oxygen species (ROS) are produced by different systems which are involved in endothelial cells injury, ultimately leading to severe organ dysfunctions. The aim of this work was to study the effect of ROS produced by hypoxanthine-xanthine oxidase (Hx-XO) on the adhesion of human umbilical vein endothelial cells (HUVEC) and on the signaling pathways involved. Results show that Hx-XO-derived ROS induced an increase in HUVEC adhesion in the early stages of the process (less than 30 min), followed by a decrease in adhesion in the later stages of the process. Interestingly, Hx-XO-derived ROS induced the same biphasic effect on the phosphorylation of the focal adhesion kinase (FAK), a nonreceptor tyrosine kinase critical for cell adhesion, but not on ERK1/2 phosphorylation. The biphasic effect was not seen with ERK1/2 where a decrease in phosphorylation only was observed. Wortmannin, a PI3-kinase inhibitor, inhibited ROS-induced cell adhesion and FAK phosphorylation. Orthovanadate, a protein tyrosine phosphatase inhibitor, and Resveratrol (Resv), an antioxidant agent, protected FAK and ERK1/2 from dephosphorylation and HUVEC from ROS-induced loss of adhesion. This study shows that ROS could have both stimulatory and inhibitory effects on HUVEC adhesion and FAK phosphorylation and suggests that PI3-kinase and tyrosine phosphatase control these effects.

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Anethole Dithiolethione Regulates Oxidant-Induced Tyrosine Kinase Activation in Endothelial Cells

Cited by 12 publications

References 33 publications

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Xanthine Oxidase‐Derived ROS Display a Biphasic Effect on Endothelial Cells Adhesion and FAK Phosphorylation

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