The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress.
Identifieur interne : 000114 ( Main/Exploration ); précédent : 000113; suivant : 000115The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress.
Auteurs : Xiaoyuan Ren [Suède] ; Sebastin M. Santhosh [Suède] ; Lucia Coppo [Suède] ; Fernando T. Ogata [Suède] ; Jun Lu [République populaire de Chine] ; Arne Holmgren [Suède]Source :
- Free radical biology & medicine [ 1873-4596 ] ; 2019.
Descripteurs français
- KwdFr :
- Acide ascorbique (pharmacologie), Association médicamenteuse (MeSH), Cellules cancéreuses en culture (MeSH), Espèces réactives de l'oxygène (métabolisme), Glutarédoxines (génétique), Glutarédoxines (métabolisme), Glutathion (métabolisme), Humains (MeSH), Mort cellulaire (MeSH), Ménadione (pharmacologie), Récepteurs nucléaires orphelins (génétique), Récepteurs nucléaires orphelins (métabolisme), Régulation de l'expression des gènes tumoraux (effets des médicaments et des substances chimiques), Réplication de l'ADN (effets des médicaments et des substances chimiques), Stress oxydatif (effets des médicaments et des substances chimiques), Thiorédoxines (génétique), Thiorédoxines (métabolisme), Tumeurs (anatomopathologie), Tumeurs (métabolisme), Tumeurs (traitement médicamenteux), Vitamines (pharmacologie).
- MESH :
- anatomopathologie : Tumeurs.
- effets des médicaments et des substances chimiques : Régulation de l'expression des gènes tumoraux, Réplication de l'ADN, Stress oxydatif.
- génétique : Glutarédoxines, Récepteurs nucléaires orphelins, Thiorédoxines.
- métabolisme : Espèces réactives de l'oxygène, Glutarédoxines, Glutathion, Récepteurs nucléaires orphelins, Thiorédoxines, Tumeurs.
- pharmacologie : Acide ascorbique, Ménadione, Vitamines.
- traitement médicamenteux : Tumeurs.
- Association médicamenteuse, Cellules cancéreuses en culture, Humains, Mort cellulaire.
English descriptors
- KwdEn :
- Ascorbic Acid (pharmacology), Cell Death (MeSH), DNA Replication (drug effects), Drug Combinations (MeSH), Gene Expression Regulation, Neoplastic (drug effects), Glutaredoxins (genetics), Glutaredoxins (metabolism), Glutathione (metabolism), Humans (MeSH), Neoplasms (drug therapy), Neoplasms (metabolism), Neoplasms (pathology), Orphan Nuclear Receptors (genetics), Orphan Nuclear Receptors (metabolism), Oxidative Stress (drug effects), Reactive Oxygen Species (metabolism), Thioredoxins (genetics), Thioredoxins (metabolism), Tumor Cells, Cultured (MeSH), Vitamin K 3 (pharmacology), Vitamins (pharmacology).
- MESH :
- chemical , genetics : Glutaredoxins, Orphan Nuclear Receptors, Thioredoxins.
- chemical , metabolism : Glutaredoxins, Glutathione, Orphan Nuclear Receptors, Reactive Oxygen Species, Thioredoxins.
- chemical , pharmacology : Ascorbic Acid, Vitamin K 3, Vitamins.
- drug effects : DNA Replication, Gene Expression Regulation, Neoplastic, Oxidative Stress.
- drug therapy : Neoplasms.
- metabolism : Neoplasms.
- pathology : Neoplasms.
- Cell Death, Drug Combinations, Humans, Tumor Cells, Cultured.
Abstract
The combination of ascorbate and menadione (VC:VK3 = 100:1) is an investigational treatment for cancer under clinical trials. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, can be taken up by cells via glucose transporters, over-expressed in many cancer cells. It has been known that the combination of VC/VK3 kills cancer cells by inducing hydrogen peroxide (H2O2) via a redox cycling reaction. However, the mechanism has not been fully understood yet. Intracellularly, DHA is reduced to ascorbate by NADPH via GSH and glutaredoxin as well as by thioredoxin (Trx) and the selenoenzyme thioredoxin reductase (TrxR). These two systems are also critical as electron donors for ribonucleotide reductase (RNR), which produces deoxyribonucleotides de novo for DNA replication and DNA repair and is highly expressed in tumor cells. We found that RNR was highly sensitive to VC/VK3 in vitro with similar effects as observed with H2O2. In cancer cells, VC/VK3 inhibited RNR mainly by targeting its R2 subunit. More importantly, both the Trx and GSH systems were oxidized by the combination, which resulted in the loss of GSH, increased protein glutathionylation, and highly oxidized Trx1. The mechanism of cell death induced by VC/VK3 was also elucidated. We found that VC/VK3 inhibited glutathione peroxidase activity and led to an elevated level of lipid peroxidation, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway. Therefore, the combination not only induced replicative stress by inhibiting RNR, but also oxidative stress by targeting anti-oxidant systems and triggered AIF-mediated cancer cell death.
DOI: 10.1016/j.freeradbiomed.2019.01.037
PubMed: 30703479
Affiliations:
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Santhosh</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Coppo, Lucia" sort="Coppo, Lucia" uniqKey="Coppo L" first="Lucia" last="Coppo">Lucia Coppo</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Ogata, Fernando T" sort="Ogata, Fernando T" uniqKey="Ogata F" first="Fernando T" last="Ogata">Fernando T. Ogata</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Lu, Jun" sort="Lu, Jun" uniqKey="Lu J" first="Jun" last="Lu">Jun Lu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden; School of Pharmaceutical Sciences, Southwest University, 400715, Chongqing, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden; School of Pharmaceutical Sciences, Southwest University, 400715, Chongqing</wicri:regionArea><wicri:noRegion>Chongqing</wicri:noRegion></affiliation></author><author><name sortKey="Holmgren, Arne" sort="Holmgren, Arne" uniqKey="Holmgren A" first="Arne" last="Holmgren">Arne Holmgren</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden. Electronic address: arne.holmgren@ki.se.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></analytic><series><title level="j">Free radical biology & medicine</title><idno type="eISSN">1873-4596</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Ascorbic Acid (pharmacology)</term><term>Cell Death (MeSH)</term><term>DNA Replication (drug effects)</term><term>Drug Combinations (MeSH)</term><term>Gene Expression Regulation, Neoplastic (drug effects)</term><term>Glutaredoxins (genetics)</term><term>Glutaredoxins (metabolism)</term><term>Glutathione (metabolism)</term><term>Humans (MeSH)</term><term>Neoplasms (drug therapy)</term><term>Neoplasms (metabolism)</term><term>Neoplasms (pathology)</term><term>Orphan Nuclear Receptors (genetics)</term><term>Orphan Nuclear Receptors (metabolism)</term><term>Oxidative Stress (drug effects)</term><term>Reactive Oxygen Species (metabolism)</term><term>Thioredoxins (genetics)</term><term>Thioredoxins (metabolism)</term><term>Tumor Cells, Cultured (MeSH)</term><term>Vitamin K 3 (pharmacology)</term><term>Vitamins (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acide ascorbique (pharmacologie)</term><term>Association médicamenteuse (MeSH)</term><term>Cellules cancéreuses en culture (MeSH)</term><term>Espèces réactives de l'oxygène (métabolisme)</term><term>Glutarédoxines (génétique)</term><term>Glutarédoxines (métabolisme)</term><term>Glutathion (métabolisme)</term><term>Humains (MeSH)</term><term>Mort cellulaire (MeSH)</term><term>Ménadione (pharmacologie)</term><term>Récepteurs nucléaires orphelins (génétique)</term><term>Récepteurs nucléaires orphelins (métabolisme)</term><term>Régulation de l'expression des gènes tumoraux (effets des médicaments et des substances chimiques)</term><term>Réplication de l'ADN (effets des médicaments et des substances chimiques)</term><term>Stress oxydatif (effets des médicaments et des substances chimiques)</term><term>Thiorédoxines (génétique)</term><term>Thiorédoxines (métabolisme)</term><term>Tumeurs (anatomopathologie)</term><term>Tumeurs (métabolisme)</term><term>Tumeurs (traitement médicamenteux)</term><term>Vitamines (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Glutaredoxins</term><term>Orphan Nuclear Receptors</term><term>Thioredoxins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glutaredoxins</term><term>Glutathione</term><term>Orphan Nuclear Receptors</term><term>Reactive Oxygen Species</term><term>Thioredoxins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Ascorbic Acid</term><term>Vitamin K 3</term><term>Vitamins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>DNA Replication</term><term>Gene Expression Regulation, Neoplastic</term><term>Oxidative Stress</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>Régulation de l'expression des gènes tumoraux</term><term>Réplication de l'ADN</term><term>Stress oxydatif</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glutarédoxines</term><term>Récepteurs nucléaires orphelins</term><term>Thiorédoxines</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Espèces réactives de l'oxygène</term><term>Glutarédoxines</term><term>Glutathion</term><term>Récepteurs nucléaires orphelins</term><term>Thiorédoxines</term><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Acide ascorbique</term><term>Ménadione</term><term>Vitamines</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Death</term><term>Drug Combinations</term><term>Humans</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Association médicamenteuse</term><term>Cellules cancéreuses en culture</term><term>Humains</term><term>Mort cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The combination of ascorbate and menadione (VC:VK3 = 100:1) is an investigational treatment for cancer under clinical trials. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, can be taken up by cells via glucose transporters, over-expressed in many cancer cells. It has been known that the combination of VC/VK3 kills cancer cells by inducing hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) via a redox cycling reaction. However, the mechanism has not been fully understood yet. Intracellularly, DHA is reduced to ascorbate by NADPH via GSH and glutaredoxin as well as by thioredoxin (Trx) and the selenoenzyme thioredoxin reductase (TrxR). These two systems are also critical as electron donors for ribonucleotide reductase (RNR), which produces deoxyribonucleotides de novo for DNA replication and DNA repair and is highly expressed in tumor cells. We found that RNR was highly sensitive to VC/VK3 in vitro with similar effects as observed with H<sub>2</sub>O<sub>2</sub>. In cancer cells, VC/VK3 inhibited RNR mainly by targeting its R2 subunit. More importantly, both the Trx and GSH systems were oxidized by the combination, which resulted in the loss of GSH, increased protein glutathionylation, and highly oxidized Trx1. The mechanism of cell death induced by VC/VK3 was also elucidated. We found that VC/VK3 inhibited glutathione peroxidase activity and led to an elevated level of lipid peroxidation, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway. Therefore, the combination not only induced replicative stress by inhibiting RNR, but also oxidative stress by targeting anti-oxidant systems and triggered AIF-mediated cancer cell death.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30703479</PMID><DateCompleted><Year>2020</Year><Month>04</Month><Day>21</Day></DateCompleted><DateRevised><Year>2020</Year><Month>04</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1873-4596</ISSN><JournalIssue CitedMedium="Internet"><Volume>134</Volume><PubDate><Year>2019</Year><Month>04</Month></PubDate></JournalIssue><Title>Free radical biology & medicine</Title><ISOAbbreviation>Free Radic Biol Med</ISOAbbreviation></Journal><ArticleTitle>The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress.</ArticleTitle><Pagination><MedlinePgn>350-358</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0891-5849(18)32479-1</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.freeradbiomed.2019.01.037</ELocationID><Abstract><AbstractText>The combination of ascorbate and menadione (VC:VK3 = 100:1) is an investigational treatment for cancer under clinical trials. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, can be taken up by cells via glucose transporters, over-expressed in many cancer cells. It has been known that the combination of VC/VK3 kills cancer cells by inducing hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) via a redox cycling reaction. However, the mechanism has not been fully understood yet. Intracellularly, DHA is reduced to ascorbate by NADPH via GSH and glutaredoxin as well as by thioredoxin (Trx) and the selenoenzyme thioredoxin reductase (TrxR). These two systems are also critical as electron donors for ribonucleotide reductase (RNR), which produces deoxyribonucleotides de novo for DNA replication and DNA repair and is highly expressed in tumor cells. We found that RNR was highly sensitive to VC/VK3 in vitro with similar effects as observed with H<sub>2</sub>O<sub>2</sub>. In cancer cells, VC/VK3 inhibited RNR mainly by targeting its R2 subunit. More importantly, both the Trx and GSH systems were oxidized by the combination, which resulted in the loss of GSH, increased protein glutathionylation, and highly oxidized Trx1. The mechanism of cell death induced by VC/VK3 was also elucidated. We found that VC/VK3 inhibited glutathione peroxidase activity and led to an elevated level of lipid peroxidation, which triggered apoptosis-inducing factor (AIF) mediated cell death pathway. Therefore, the combination not only induced replicative stress by inhibiting RNR, but also oxidative stress by targeting anti-oxidant systems and triggered AIF-mediated cancer cell death.</AbstractText><CopyrightInformation>Copyright © 2019. Published by Elsevier Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ren</LastName><ForeName>Xiaoyuan</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Santhosh</LastName><ForeName>Sebastin M</ForeName><Initials>SM</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coppo</LastName><ForeName>Lucia</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ogata</LastName><ForeName>Fernando T</ForeName><Initials>FT</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Jun</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden; School of Pharmaceutical Sciences, Southwest University, 400715, Chongqing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Holmgren</LastName><ForeName>Arne</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden. Electronic address: arne.holmgren@ki.se.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>01</Month><Day>28</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Free Radic Biol Med</MedlineTA><NlmUniqueID>8709159</NlmUniqueID><ISSNLinking>0891-5849</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004338">Drug Combinations</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C516005">GLRX protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D054477">Glutaredoxins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C403073">NR2E3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D057093">Orphan Nuclear Receptors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D017382">Reactive Oxygen Species</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C491203">TXN protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014815">Vitamins</NameOfSubstance></Chemical><Chemical><RegistryNumber>52500-60-4</RegistryNumber><NameOfSubstance UI="D013879">Thioredoxins</NameOfSubstance></Chemical><Chemical><RegistryNumber>723JX6CXY5</RegistryNumber><NameOfSubstance UI="D024483">Vitamin K 3</NameOfSubstance></Chemical><Chemical><RegistryNumber>GAN16C9B8O</RegistryNumber><NameOfSubstance UI="D005978">Glutathione</NameOfSubstance></Chemical><Chemical><RegistryNumber>PQ6CK8PD0R</RegistryNumber><NameOfSubstance UI="D001205">Ascorbic Acid</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001205" MajorTopicYN="N">Ascorbic Acid</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016923" MajorTopicYN="N">Cell Death</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004261" MajorTopicYN="N">DNA Replication</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004338" MajorTopicYN="N">Drug Combinations</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015972" MajorTopicYN="N">Gene Expression Regulation, Neoplastic</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D054477" MajorTopicYN="N">Glutaredoxins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005978" MajorTopicYN="N">Glutathione</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009369" MajorTopicYN="N">Neoplasms</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D057093" MajorTopicYN="N">Orphan Nuclear Receptors</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018384" MajorTopicYN="N">Oxidative Stress</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017382" MajorTopicYN="N">Reactive Oxygen Species</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013879" MajorTopicYN="N">Thioredoxins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014407" MajorTopicYN="N">Tumor Cells, Cultured</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D024483" MajorTopicYN="N">Vitamin K 3</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014815" MajorTopicYN="N">Vitamins</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Ascorbate</Keyword><Keyword MajorTopicYN="Y">Cell death</Keyword><Keyword MajorTopicYN="Y">DNA synthesis</Keyword><Keyword MajorTopicYN="Y">Glutaredoxin</Keyword><Keyword MajorTopicYN="Y">Glutathione</Keyword><Keyword MajorTopicYN="Y">Menadione</Keyword><Keyword MajorTopicYN="Y">Thioredoxin</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>11</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>01</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>01</Month><Day>26</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>2</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>4</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>2</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30703479</ArticleId><ArticleId IdType="pii">S0891-5849(18)32479-1</ArticleId><ArticleId IdType="doi">10.1016/j.freeradbiomed.2019.01.037</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>République populaire de Chine</li><li>Suède</li></country><region><li>Svealand</li></region><settlement><li>Stockholm</li></settlement></list><tree><country name="Suède"><region name="Svealand"><name sortKey="Ren, Xiaoyuan" sort="Ren, Xiaoyuan" uniqKey="Ren X" first="Xiaoyuan" last="Ren">Xiaoyuan Ren</name></region><name sortKey="Coppo, Lucia" sort="Coppo, Lucia" uniqKey="Coppo L" first="Lucia" last="Coppo">Lucia Coppo</name><name sortKey="Holmgren, Arne" sort="Holmgren, Arne" uniqKey="Holmgren A" first="Arne" last="Holmgren">Arne Holmgren</name><name sortKey="Ogata, Fernando T" sort="Ogata, Fernando T" uniqKey="Ogata F" first="Fernando T" last="Ogata">Fernando T. Ogata</name><name sortKey="Santhosh, Sebastin M" sort="Santhosh, Sebastin M" uniqKey="Santhosh S" first="Sebastin M" last="Santhosh">Sebastin M. Santhosh</name></country><country name="République populaire de Chine"><noRegion><name sortKey="Lu, Jun" sort="Lu, Jun" uniqKey="Lu J" first="Jun" last="Lu">Jun Lu</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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