Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.
Identifieur interne : 000170 ( Main/Exploration ); précédent : 000169; suivant : 000171Frenolicin 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 :
- Cell chemical biology [ 2451-9448 ] ; 2019.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Antinéoplasiques (composition chimique), Antinéoplasiques (pharmacologie), Antinéoplasiques (usage thérapeutique), Complexe-1 cible mécanistique de la rapamycine (métabolisme), Espèces réactives de l'oxygène (métabolisme), Glutarédoxines (antagonistes et inhibiteurs), Glutarédoxines (métabolisme), Humains (MeSH), Interférence par ARN (MeSH), Lignée cellulaire tumorale (MeSH), Mâle (MeSH), Naphtoquinones (composition chimique), Naphtoquinones (pharmacologie), Naphtoquinones (usage thérapeutique), Peroxirédoxines (antagonistes et inhibiteurs), Peroxirédoxines (métabolisme), Petit ARN interférent (métabolisme), Phosphorylation (effets des médicaments et des substances chimiques), Protéines adaptatrices de la transduction du signal (antagonistes et inhibiteurs), Protéines adaptatrices de la transduction du signal (génétique), Protéines adaptatrices de la transduction du signal (métabolisme), Protéines du cycle cellulaire (antagonistes et inhibiteurs), Protéines du cycle cellulaire (génétique), Protéines du cycle cellulaire (métabolisme), Souris (MeSH), Souris nude (MeSH), Survie cellulaire (effets des médicaments et des substances chimiques), Transduction du signal (effets des médicaments et des substances chimiques), Transplantation hétérologue (MeSH), Tumeurs (anatomopathologie), Tumeurs (traitement médicamenteux).
- MESH :
- anatomopathologie : Tumeurs.
- antagonistes et inhibiteurs : Glutarédoxines, Peroxirédoxines, Protéines adaptatrices de la transduction du signal, Protéines du cycle cellulaire.
- composition chimique : Antinéoplasiques, Naphtoquinones.
- effets des médicaments et des substances chimiques : Phosphorylation, Survie cellulaire, Transduction du signal.
- génétique : Protéines adaptatrices de la transduction du signal, Protéines du cycle cellulaire.
- métabolisme : Complexe-1 cible mécanistique de la rapamycine, Espèces réactives de l'oxygène, Glutarédoxines, Peroxirédoxines, Petit ARN interférent, Protéines adaptatrices de la transduction du signal, Protéines du cycle cellulaire.
- pharmacologie : Antinéoplasiques, Naphtoquinones.
- traitement médicamenteux : Tumeurs.
- usage thérapeutique : Antinéoplasiques, Naphtoquinones.
- Animaux, Humains, Interférence par ARN, Lignée cellulaire tumorale, Mâle, Souris, Souris nude, Transplantation hétérologue.
English descriptors
- KwdEn :
- Adaptor Proteins, Signal Transducing (antagonists & inhibitors), Adaptor Proteins, Signal Transducing (genetics), Adaptor Proteins, Signal Transducing (metabolism), Animals (MeSH), Antineoplastic Agents (chemistry), Antineoplastic Agents (pharmacology), Antineoplastic Agents (therapeutic use), Cell Cycle Proteins (antagonists & inhibitors), Cell Cycle Proteins (genetics), Cell Cycle Proteins (metabolism), Cell Line, Tumor (MeSH), Cell Survival (drug effects), Glutaredoxins (antagonists & inhibitors), Glutaredoxins (metabolism), Humans (MeSH), Male (MeSH), Mechanistic Target of Rapamycin Complex 1 (metabolism), Mice (MeSH), Mice, Nude (MeSH), Naphthoquinones (chemistry), Naphthoquinones (pharmacology), Naphthoquinones (therapeutic use), Neoplasms (drug therapy), Neoplasms (pathology), Peroxiredoxins (antagonists & inhibitors), Peroxiredoxins (metabolism), Phosphorylation (drug effects), RNA Interference (MeSH), RNA, Small Interfering (metabolism), Reactive Oxygen Species (metabolism), Signal Transduction (drug effects), Transplantation, Heterologous (MeSH).
- MESH :
- chemical , antagonists & inhibitors : Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Glutaredoxins, Peroxiredoxins.
- chemical , chemistry : Antineoplastic Agents, Naphthoquinones.
- chemical , genetics : Adaptor Proteins, Signal Transducing, Cell Cycle Proteins.
- chemical , metabolism : Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Glutaredoxins, Mechanistic Target of Rapamycin Complex 1, Peroxiredoxins, RNA, Small Interfering, Reactive Oxygen Species.
- chemical , pharmacology : Antineoplastic Agents, Naphthoquinones.
- chemical , therapeutic use : Antineoplastic Agents, Naphthoquinones.
- drug effects : Cell Survival, Phosphorylation, Signal Transduction.
- drug therapy : Neoplasms.
- pathology : Neoplasms.
- Animals, Cell Line, Tumor, Humans, Male, Mice, Mice, Nude, RNA Interference, Transplantation, Heterologous.
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:
Links toward previous steps (curation, corpus...)
Le document en format XML
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<author><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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<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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<sourceDesc><biblStruct><analytic><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>
<wicri:noRegion>Jiangsu 210047</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cao, Yanan" sort="Cao, Yanan" uniqKey="Cao Y" first="Yanan" last="Cao">Yanan Cao</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>
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<author><name sortKey="Wang, Xiachang" sort="Wang, Xiachang" uniqKey="Wang X" first="Xiachang" last="Wang">Xiachang Wang</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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<author><name sortKey="Guo, Yubin" sort="Guo, Yubin" uniqKey="Guo Y" first="Yubin" last="Guo">Yubin Guo</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>
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<author><name sortKey="Chen, Jing" sort="Chen, Jing" uniqKey="Chen J" first="Jing" last="Chen">Jing Chen</name>
<affiliation wicri:level="2"><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>
<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="Ponomareva, Larissa V" sort="Ponomareva, Larissa V" uniqKey="Ponomareva L" first="Larissa V" last="Ponomareva">Larissa V. Ponomareva</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="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><region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Anderson, Bradley D" sort="Anderson, Bradley D" uniqKey="Anderson B" first="Bradley D" last="Anderson">Bradley D. Anderson</name>
<affiliation wicri:level="2"><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>
<wicri:regionArea>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</wicri:regionArea>
<placeName><region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author><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>
<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="Zhu, Haining" sort="Zhu, Haining" uniqKey="Zhu H" first="Haining" last="Zhu">Haining Zhu</name>
<affiliation wicri:level="2"><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>
</affiliation>
</author>
<author><name sortKey="Leggas, Markos" sort="Leggas, Markos" uniqKey="Leggas M" first="Markos" last="Leggas">Markos Leggas</name>
<affiliation wicri:level="2"><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>
<wicri:regionArea>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</wicri:regionArea>
<placeName><region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Thorson, Jon S" sort="Thorson, Jon S" uniqKey="Thorson J" first="Jon S" last="Thorson">Jon S. Thorson</name>
<affiliation wicri:level="2"><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>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>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</wicri:regionArea>
<placeName><region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="She, Qing Bai" sort="She, Qing Bai" uniqKey="She Q" first="Qing-Bai" last="She">Qing-Bai She</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. 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>
<placeName><region type="state">Kentucky</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell chemical biology</title>
<idno type="eISSN">2451-9448</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><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>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term>
<term>Cell Cycle Proteins</term>
<term>Glutaredoxins</term>
<term>Peroxiredoxins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Naphthoquinones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term>
<term>Cell Cycle Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><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>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Naphthoquinones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Naphthoquinones</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><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>
</keywords>
<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>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Phosphorylation</term>
<term>Survie cellulaire</term>
<term>Transduction du signal</term>
</keywords>
<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>
</keywords>
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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><MedlineCitation Status="MEDLINE" Owner="NLM"><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>
<AuthorList CompleteYN="Y"><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>
</Author>
<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>
</Author>
<Author ValidYN="Y"><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>
</Author>
<Author ValidYN="Y"><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>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Guo</LastName>
<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>
</Author>
<Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Jing</ForeName>
<Initials>J</Initials>
<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>
</Author>
<Author ValidYN="Y"><LastName>Horn</LastName>
<ForeName>Jamie</ForeName>
<Initials>J</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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ponomareva</LastName>
<ForeName>Larissa V</ForeName>
<Initials>LV</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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chaiswing</LastName>
<ForeName>Luksana</ForeName>
<Initials>L</Initials>
<AffiliationInfo><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>
</Author>
<Author ValidYN="Y"><LastName>Shaaban</LastName>
<ForeName>Khaled A</ForeName>
<Initials>KA</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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wei</LastName>
<ForeName>Qiou</ForeName>
<Initials>Q</Initials>
<AffiliationInfo><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>
</Author>
<Author ValidYN="Y"><LastName>Anderson</LastName>
<ForeName>Bradley D</ForeName>
<Initials>BD</Initials>
<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>
</Author>
<Author ValidYN="Y"><LastName>St Clair</LastName>
<ForeName>Daret K</ForeName>
<Initials>DK</Initials>
<AffiliationInfo><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>
</Author>
<Author ValidYN="Y"><LastName>Zhu</LastName>
<ForeName>Haining</ForeName>
<Initials>H</Initials>
<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>
</Author>
<Author ValidYN="Y"><LastName>Leggas</LastName>
<ForeName>Markos</ForeName>
<Initials>M</Initials>
<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>
</Author>
<Author ValidYN="Y"><LastName>Thorson</LastName>
<ForeName>Jon S</ForeName>
<Initials>JS</Initials>
<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>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>She</LastName>
<ForeName>Qing-Bai</ForeName>
<Initials>QB</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. Electronic address: qing-bai.she@uky.edu.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>UL1 TR000117</GrantID>
<Acronym>TR</Acronym>
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