Serveur d'exploration sur la glutarédoxine

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Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.

Identifieur interne : 000170 ( Main/Exploration ); précédent : 000169; suivant : 000171

Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.

Auteurs : Qing Ye [États-Unis] ; Yinan Zhang [République populaire de Chine] ; Yanan Cao [États-Unis] ; Xiachang Wang [République populaire de Chine] ; Yubin Guo [États-Unis] ; Jing Chen [États-Unis] ; Jamie Horn [États-Unis] ; Larissa V. Ponomareva [États-Unis] ; Luksana Chaiswing [États-Unis] ; Khaled A. Shaaban [États-Unis] ; Qiou Wei [États-Unis] ; Bradley D. Anderson [États-Unis] ; Daret K. St Clair [États-Unis] ; Haining Zhu [États-Unis] ; Markos Leggas [États-Unis] ; Jon S. Thorson [États-Unis] ; Qing-Bai She [États-Unis]

Source :

RBID : pubmed:30661989

Descripteurs français

English descriptors

Abstract

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.

DOI: 10.1016/j.chembiol.2018.11.013
PubMed: 30661989
PubMed Central: PMC6557261


Affiliations:


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Le document en format XML

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<name sortKey="Ye, Qing" sort="Ye, Qing" uniqKey="Ye Q" first="Qing" last="Ye">Qing Ye</name>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
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<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047, China.</nlm:affiliation>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
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<name sortKey="Wang, Xiachang" sort="Wang, Xiachang" uniqKey="Wang X" first="Xiachang" last="Wang">Xiachang Wang</name>
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<name sortKey="Guo, Yubin" sort="Guo, Yubin" uniqKey="Guo Y" first="Yubin" last="Guo">Yubin Guo</name>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="Horn, Jamie" sort="Horn, Jamie" uniqKey="Horn J" first="Jamie" last="Horn">Jamie Horn</name>
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<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Ponomareva, Larissa V" sort="Ponomareva, Larissa V" uniqKey="Ponomareva L" first="Larissa V" last="Ponomareva">Larissa V. Ponomareva</name>
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<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Chaiswing, Luksana" sort="Chaiswing, Luksana" uniqKey="Chaiswing L" first="Luksana" last="Chaiswing">Luksana Chaiswing</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Shaaban, Khaled A" sort="Shaaban, Khaled A" uniqKey="Shaaban K" first="Khaled A" last="Shaaban">Khaled A. Shaaban</name>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="Wei, Qiou" sort="Wei, Qiou" uniqKey="Wei Q" first="Qiou" last="Wei">Qiou Wei</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Anderson, Bradley D" sort="Anderson, Bradley D" uniqKey="Anderson B" first="Bradley D" last="Anderson">Bradley D. Anderson</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
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<name sortKey="St Clair, Daret K" sort="St Clair, Daret K" uniqKey="St Clair D" first="Daret K" last="St Clair">Daret K. St Clair</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
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<region type="state">Kentucky</region>
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<name sortKey="Zhu, Haining" sort="Zhu, Haining" uniqKey="Zhu H" first="Haining" last="Zhu">Haining Zhu</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
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<name sortKey="Leggas, Markos" sort="Leggas, Markos" uniqKey="Leggas M" first="Markos" last="Leggas">Markos Leggas</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<region type="state">Kentucky</region>
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<name sortKey="Thorson, Jon S" sort="Thorson, Jon S" uniqKey="Thorson J" first="Jon S" last="Thorson">Jon S. Thorson</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA. Electronic address: jsthorson@uky.edu.</nlm:affiliation>
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<name sortKey="She, Qing Bai" sort="She, Qing Bai" uniqKey="She Q" first="Qing-Bai" last="She">Qing-Bai She</name>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: qing-bai.she@uky.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
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<region type="state">Kentucky</region>
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<title xml:lang="en">Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.</title>
<author>
<name sortKey="Ye, Qing" sort="Ye, Qing" uniqKey="Ye Q" first="Qing" last="Ye">Qing Ye</name>
<affiliation wicri:level="2">
<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
<region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Zhang, Yinan" sort="Zhang, Yinan" uniqKey="Zhang Y" first="Yinan" last="Zhang">Yinan Zhang</name>
<affiliation wicri:level="1">
<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047</wicri:regionArea>
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<name sortKey="Cao, Yanan" sort="Cao, Yanan" uniqKey="Cao Y" first="Yanan" last="Cao">Yanan Cao</name>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
<region type="state">Kentucky</region>
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<name sortKey="Wang, Xiachang" sort="Wang, Xiachang" uniqKey="Wang X" first="Xiachang" last="Wang">Xiachang Wang</name>
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<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047, China.</nlm:affiliation>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047</wicri:regionArea>
<wicri:noRegion>Jiangsu 210047</wicri:noRegion>
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<name sortKey="Guo, Yubin" sort="Guo, Yubin" uniqKey="Guo Y" first="Yubin" last="Guo">Yubin Guo</name>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
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<name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
<region type="state">Kentucky</region>
</placeName>
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<author>
<name sortKey="Horn, Jamie" sort="Horn, Jamie" uniqKey="Horn J" first="Jamie" last="Horn">Jamie Horn</name>
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<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
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<region type="state">Kentucky</region>
</placeName>
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<author>
<name sortKey="Ponomareva, Larissa V" sort="Ponomareva, Larissa V" uniqKey="Ponomareva L" first="Larissa V" last="Ponomareva">Larissa V. Ponomareva</name>
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<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
<region type="state">Kentucky</region>
</placeName>
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<author>
<name sortKey="Chaiswing, Luksana" sort="Chaiswing, Luksana" uniqKey="Chaiswing L" first="Luksana" last="Chaiswing">Luksana Chaiswing</name>
<affiliation wicri:level="2">
<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
<region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Shaaban, Khaled A" sort="Shaaban, Khaled A" uniqKey="Shaaban K" first="Khaled A" last="Shaaban">Khaled A. Shaaban</name>
<affiliation wicri:level="2">
<nlm:affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
<region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Wei, Qiou" sort="Wei, Qiou" uniqKey="Wei Q" first="Qiou" last="Wei">Qiou Wei</name>
<affiliation wicri:level="2">
<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536</wicri:regionArea>
<placeName>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Zhu, Haining" sort="Zhu, Haining" uniqKey="Zhu H" first="Haining" last="Zhu">Haining Zhu</name>
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<nlm:affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
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<name sortKey="Leggas, Markos" sort="Leggas, Markos" uniqKey="Leggas M" first="Markos" last="Leggas">Markos Leggas</name>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="She, Qing Bai" sort="She, Qing Bai" uniqKey="She Q" first="Qing-Bai" last="She">Qing-Bai She</name>
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<nlm:affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: qing-bai.she@uky.edu.</nlm:affiliation>
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<title level="j">Cell chemical biology</title>
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<term>Adaptor Proteins, Signal Transducing (antagonists & inhibitors)</term>
<term>Adaptor Proteins, Signal Transducing (genetics)</term>
<term>Adaptor Proteins, Signal Transducing (metabolism)</term>
<term>Animals (MeSH)</term>
<term>Antineoplastic Agents (chemistry)</term>
<term>Antineoplastic Agents (pharmacology)</term>
<term>Antineoplastic Agents (therapeutic use)</term>
<term>Cell Cycle Proteins (antagonists & inhibitors)</term>
<term>Cell Cycle Proteins (genetics)</term>
<term>Cell Cycle Proteins (metabolism)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cell Survival (drug effects)</term>
<term>Glutaredoxins (antagonists & inhibitors)</term>
<term>Glutaredoxins (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Male (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Mice, Nude (MeSH)</term>
<term>Naphthoquinones (chemistry)</term>
<term>Naphthoquinones (pharmacology)</term>
<term>Naphthoquinones (therapeutic use)</term>
<term>Neoplasms (drug therapy)</term>
<term>Neoplasms (pathology)</term>
<term>Peroxiredoxins (antagonists & inhibitors)</term>
<term>Peroxiredoxins (metabolism)</term>
<term>Phosphorylation (drug effects)</term>
<term>RNA Interference (MeSH)</term>
<term>RNA, Small Interfering (metabolism)</term>
<term>Reactive Oxygen Species (metabolism)</term>
<term>Signal Transduction (drug effects)</term>
<term>Transplantation, Heterologous (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Animaux (MeSH)</term>
<term>Antinéoplasiques (composition chimique)</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Antinéoplasiques (usage thérapeutique)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Espèces réactives de l'oxygène (métabolisme)</term>
<term>Glutarédoxines (antagonistes et inhibiteurs)</term>
<term>Glutarédoxines (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Interférence par ARN (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Mâle (MeSH)</term>
<term>Naphtoquinones (composition chimique)</term>
<term>Naphtoquinones (pharmacologie)</term>
<term>Naphtoquinones (usage thérapeutique)</term>
<term>Peroxirédoxines (antagonistes et inhibiteurs)</term>
<term>Peroxirédoxines (métabolisme)</term>
<term>Petit ARN interférent (métabolisme)</term>
<term>Phosphorylation (effets des médicaments et des substances chimiques)</term>
<term>Protéines adaptatrices de la transduction du signal (antagonistes et inhibiteurs)</term>
<term>Protéines adaptatrices de la transduction du signal (génétique)</term>
<term>Protéines adaptatrices de la transduction du signal (métabolisme)</term>
<term>Protéines du cycle cellulaire (antagonistes et inhibiteurs)</term>
<term>Protéines du cycle cellulaire (génétique)</term>
<term>Protéines du cycle cellulaire (métabolisme)</term>
<term>Souris (MeSH)</term>
<term>Souris nude (MeSH)</term>
<term>Survie cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
<term>Transplantation hétérologue (MeSH)</term>
<term>Tumeurs (anatomopathologie)</term>
<term>Tumeurs (traitement médicamenteux)</term>
</keywords>
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<term>Adaptor Proteins, Signal Transducing</term>
<term>Cell Cycle Proteins</term>
<term>Glutaredoxins</term>
<term>Peroxiredoxins</term>
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<term>Antineoplastic Agents</term>
<term>Naphthoquinones</term>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Adaptor Proteins, Signal Transducing</term>
<term>Cell Cycle Proteins</term>
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<term>Adaptor Proteins, Signal Transducing</term>
<term>Cell Cycle Proteins</term>
<term>Glutaredoxins</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Peroxiredoxins</term>
<term>RNA, Small Interfering</term>
<term>Reactive Oxygen Species</term>
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<term>Antineoplastic Agents</term>
<term>Naphthoquinones</term>
</keywords>
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<term>Antineoplastic Agents</term>
<term>Naphthoquinones</term>
</keywords>
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<term>Tumeurs</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Glutarédoxines</term>
<term>Peroxirédoxines</term>
<term>Protéines adaptatrices de la transduction du signal</term>
<term>Protéines du cycle cellulaire</term>
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<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr">
<term>Antinéoplasiques</term>
<term>Naphtoquinones</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Cell Survival</term>
<term>Phosphorylation</term>
<term>Signal Transduction</term>
</keywords>
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<term>Neoplasms</term>
</keywords>
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<term>Phosphorylation</term>
<term>Survie cellulaire</term>
<term>Transduction du signal</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Protéines adaptatrices de la transduction du signal</term>
<term>Protéines du cycle cellulaire</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Espèces réactives de l'oxygène</term>
<term>Glutarédoxines</term>
<term>Peroxirédoxines</term>
<term>Petit ARN interférent</term>
<term>Protéines adaptatrices de la transduction du signal</term>
<term>Protéines du cycle cellulaire</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Antinéoplasiques</term>
<term>Naphtoquinones</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Tumeurs</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr">
<term>Antinéoplasiques</term>
<term>Naphtoquinones</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Nude</term>
<term>RNA Interference</term>
<term>Transplantation, Heterologous</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Humains</term>
<term>Interférence par ARN</term>
<term>Lignée cellulaire tumorale</term>
<term>Mâle</term>
<term>Souris</term>
<term>Souris nude</term>
<term>Transplantation hétérologue</term>
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<front>
<div type="abstract" xml:lang="en">Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.</div>
</front>
</TEI>
<pubmed>
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<PMID Version="1">30661989</PMID>
<DateCompleted>
<Year>2019</Year>
<Month>12</Month>
<Day>30</Day>
</DateCompleted>
<DateRevised>
<Year>2020</Year>
<Month>03</Month>
<Day>21</Day>
</DateRevised>
<Article PubModel="Print-Electronic">
<Journal>
<ISSN IssnType="Electronic">2451-9448</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>26</Volume>
<Issue>3</Issue>
<PubDate>
<Year>2019</Year>
<Month>03</Month>
<Day>21</Day>
</PubDate>
</JournalIssue>
<Title>Cell chemical biology</Title>
<ISOAbbreviation>Cell Chem Biol</ISOAbbreviation>
</Journal>
<ArticleTitle>Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.</ArticleTitle>
<Pagination>
<MedlinePgn>366-377.e12</MedlinePgn>
</Pagination>
<ELocationID EIdType="pii" ValidYN="Y">S2451-9456(18)30435-5</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.chembiol.2018.11.013</ELocationID>
<Abstract>
<AbstractText>Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.</AbstractText>
<CopyrightInformation>Published by Elsevier Ltd.</CopyrightInformation>
</Abstract>
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<Author ValidYN="Y">
<LastName>Ye</LastName>
<ForeName>Qing</ForeName>
<Initials>Q</Initials>
<AffiliationInfo>
<Affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y">
<LastName>Zhang</LastName>
<ForeName>Yinan</ForeName>
<Initials>Y</Initials>
<AffiliationInfo>
<Affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047, China.</Affiliation>
</AffiliationInfo>
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<LastName>Cao</LastName>
<ForeName>Yanan</ForeName>
<Initials>Y</Initials>
<AffiliationInfo>
<Affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<LastName>Wang</LastName>
<ForeName>Xiachang</ForeName>
<Initials>X</Initials>
<AffiliationInfo>
<Affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047, China.</Affiliation>
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<ForeName>Yubin</ForeName>
<Initials>Y</Initials>
<AffiliationInfo>
<Affiliation>Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<ForeName>Jing</ForeName>
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</AffiliationInfo>
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<LastName>Horn</LastName>
<ForeName>Jamie</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<AffiliationInfo>
<Affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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</AffiliationInfo>
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<Affiliation>Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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</AffiliationInfo>
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<Author ValidYN="Y">
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<AffiliationInfo>
<Affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<Affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<LastName>Zhu</LastName>
<ForeName>Haining</ForeName>
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<AffiliationInfo>
<Affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
</AffiliationInfo>
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<AffiliationInfo>
<Affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.</Affiliation>
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<AffiliationInfo>
<Affiliation>Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA. Electronic address: jsthorson@uky.edu.</Affiliation>
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<Country>United States</Country>
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