The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity.
Identifieur interne : 000904 ( Main/Exploration ); précédent : 000903; suivant : 000905The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity.
Auteurs : Yu Yu [Australie] ; Yohan Suryo Rahmanto ; Clare L. Hawkins ; Des R. RichardsonSource :
- Molecular pharmacology [ 1521-0111 ] ; 2011.
Descripteurs français
- KwdFr :
- Agents chélateurs du fer (pharmacologie), Glutathion (métabolisme), Glutathione reductase (métabolisme), Humains (MeSH), Lignée cellulaire tumorale (MeSH), Pyridines (pharmacologie), Ribonucleotide reductases (métabolisme), Spectroscopie de résonance de spin électronique (MeSH), Technique de Western (MeSH), Thiols (métabolisme), Thiosemicarbazones (pharmacologie).
- MESH :
English descriptors
- KwdEn :
- Blotting, Western (MeSH), Cell Line, Tumor (MeSH), Electron Spin Resonance Spectroscopy (MeSH), Glutathione (metabolism), Glutathione Reductase (metabolism), Humans (MeSH), Iron Chelating Agents (pharmacology), Pyridines (pharmacology), Ribonucleotide Reductases (metabolism), Sulfhydryl Compounds (metabolism), Thiosemicarbazones (pharmacology).
- MESH :
- chemical , metabolism : Glutathione, Glutathione Reductase, Ribonucleotide Reductases, Sulfhydryl Compounds.
- chemical , pharmacology : Iron Chelating Agents, Pyridines, Thiosemicarbazones.
- Blotting, Western, Cell Line, Tumor, Electron Spin Resonance Spectroscopy, Humans.
Abstract
Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the iron-containing enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only N-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (p < 0.001) elevated oxidized trimeric thioredoxin levels to 213 ± 5% (n = 3) of the control. This was most likely due to a significant (p < 0.01) decrease in thioredoxin reductase activity to 65 ± 6% (n = 4) of the control. We were surprised to find that the non-redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 ± 9%; n = 3) and inhibited thioredoxin reductase activity (62 ± 5%; n = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p < 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/NADP(total) ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems.
DOI: 10.1124/mol.111.071324
PubMed: 21389104
Affiliations:
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Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity.</title><author><name sortKey="Yu, Yu" sort="Yu, Yu" uniqKey="Yu Y" first="Yu" last="Yu">Yu Yu</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Blackburn Building, University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Pathology, Blackburn Building, University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Suryo Rahmanto, Yohan" sort="Suryo Rahmanto, Yohan" uniqKey="Suryo Rahmanto Y" first="Yohan" last="Suryo Rahmanto">Yohan Suryo Rahmanto</name></author><author><name sortKey="Hawkins, Clare L" sort="Hawkins, Clare L" uniqKey="Hawkins C" first="Clare L" last="Hawkins">Clare L. Hawkins</name></author><author><name sortKey="Richardson, Des R" sort="Richardson, Des R" uniqKey="Richardson D" first="Des R" last="Richardson">Des R. Richardson</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2011">2011</date><idno type="RBID">pubmed:21389104</idno><idno type="pmid">21389104</idno><idno type="doi">10.1124/mol.111.071324</idno><idno type="wicri:Area/Main/Corpus">000936</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000936</idno><idno type="wicri:Area/Main/Curation">000936</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000936</idno><idno type="wicri:Area/Main/Exploration">000936</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity.</title><author><name sortKey="Yu, Yu" sort="Yu, Yu" uniqKey="Yu Y" first="Yu" last="Yu">Yu Yu</name><affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Blackburn Building, University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Pathology, Blackburn Building, University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Suryo Rahmanto, Yohan" sort="Suryo Rahmanto, Yohan" uniqKey="Suryo Rahmanto Y" first="Yohan" last="Suryo Rahmanto">Yohan Suryo Rahmanto</name></author><author><name sortKey="Hawkins, Clare L" sort="Hawkins, Clare L" uniqKey="Hawkins C" first="Clare L" last="Hawkins">Clare L. Hawkins</name></author><author><name sortKey="Richardson, Des R" sort="Richardson, Des R" uniqKey="Richardson D" first="Des R" last="Richardson">Des R. Richardson</name></author></analytic><series><title level="j">Molecular pharmacology</title><idno type="eISSN">1521-0111</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Blotting, Western (MeSH)</term><term>Cell Line, Tumor (MeSH)</term><term>Electron Spin Resonance Spectroscopy (MeSH)</term><term>Glutathione (metabolism)</term><term>Glutathione Reductase (metabolism)</term><term>Humans (MeSH)</term><term>Iron Chelating Agents (pharmacology)</term><term>Pyridines (pharmacology)</term><term>Ribonucleotide Reductases (metabolism)</term><term>Sulfhydryl Compounds (metabolism)</term><term>Thiosemicarbazones (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents chélateurs du fer (pharmacologie)</term><term>Glutathion (métabolisme)</term><term>Glutathione reductase (métabolisme)</term><term>Humains (MeSH)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Pyridines (pharmacologie)</term><term>Ribonucleotide reductases (métabolisme)</term><term>Spectroscopie de résonance de spin électronique (MeSH)</term><term>Technique de Western (MeSH)</term><term>Thiols (métabolisme)</term><term>Thiosemicarbazones (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glutathione</term><term>Glutathione Reductase</term><term>Ribonucleotide Reductases</term><term>Sulfhydryl Compounds</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Iron Chelating Agents</term><term>Pyridines</term><term>Thiosemicarbazones</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glutathion</term><term>Glutathione reductase</term><term>Ribonucleotide reductases</term><term>Thiols</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents chélateurs du fer</term><term>Pyridines</term><term>Thiosemicarbazones</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Blotting, Western</term><term>Cell Line, Tumor</term><term>Electron Spin Resonance Spectroscopy</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Spectroscopie de résonance de spin électronique</term><term>Technique de Western</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the iron-containing enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only N-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (p < 0.001) elevated oxidized trimeric thioredoxin levels to 213 ± 5% (n = 3) of the control. This was most likely due to a significant (p < 0.01) decrease in thioredoxin reductase activity to 65 ± 6% (n = 4) of the control. We were surprised to find that the non-redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 ± 9%; n = 3) and inhibited thioredoxin reductase activity (62 ± 5%; n = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p < 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/NADP(total) ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21389104</PMID><DateCompleted><Year>2011</Year><Month>08</Month><Day>01</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1521-0111</ISSN><JournalIssue CitedMedium="Internet"><Volume>79</Volume><Issue>6</Issue><PubDate><Year>2011</Year><Month>Jun</Month></PubDate></JournalIssue><Title>Molecular pharmacology</Title><ISOAbbreviation>Mol Pharmacol</ISOAbbreviation></Journal><ArticleTitle>The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity.</ArticleTitle><Pagination><MedlinePgn>921-31</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1124/mol.111.071324</ELocationID><Abstract><AbstractText>Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the iron-containing enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only N-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (p < 0.001) elevated oxidized trimeric thioredoxin levels to 213 ± 5% (n = 3) of the control. This was most likely due to a significant (p < 0.01) decrease in thioredoxin reductase activity to 65 ± 6% (n = 4) of the control. We were surprised to find that the non-redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 ± 9%; n = 3) and inhibited thioredoxin reductase activity (62 ± 5%; n = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p < 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/NADP(total) ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yu</LastName><ForeName>Yu</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Pathology, Blackburn Building, University of Sydney, Sydney, New South Wales, 2006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Suryo Rahmanto</LastName><ForeName>Yohan</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Hawkins</LastName><ForeName>Clare L</ForeName><Initials>CL</Initials></Author><Author ValidYN="Y"><LastName>Richardson</LastName><ForeName>Des R</ForeName><Initials>DR</Initials></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>2011</Year><Month>03</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Pharmacol</MedlineTA><NlmUniqueID>0035623</NlmUniqueID><ISSNLinking>0026-895X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C559854">2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007502">Iron Chelating Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011725">Pyridines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013438">Sulfhydryl Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013882">Thiosemicarbazones</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C539263">di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.17.4.-</RegistryNumber><NameOfSubstance UI="D012264">Ribonucleotide Reductases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.8.1.7</RegistryNumber><NameOfSubstance UI="D005980">Glutathione Reductase</NameOfSubstance></Chemical><Chemical><RegistryNumber>GAN16C9B8O</RegistryNumber><NameOfSubstance UI="D005978">Glutathione</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D015153" MajorTopicYN="N">Blotting, Western</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004578" MajorTopicYN="N">Electron Spin Resonance Spectroscopy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005978" MajorTopicYN="N">Glutathione</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005980" MajorTopicYN="N">Glutathione Reductase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007502" MajorTopicYN="N">Iron Chelating Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011725" MajorTopicYN="N">Pyridines</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012264" MajorTopicYN="N">Ribonucleotide Reductases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013438" MajorTopicYN="N">Sulfhydryl Compounds</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013882" MajorTopicYN="N">Thiosemicarbazones</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>3</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>3</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2011</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21389104</ArticleId><ArticleId IdType="pii">mol.111.071324</ArticleId><ArticleId IdType="doi">10.1124/mol.111.071324</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Australie</li></country><region><li>Nouvelle-Galles du Sud</li></region><settlement><li>Sydney</li></settlement><orgName><li>Université de Sydney</li></orgName></list><tree><noCountry><name sortKey="Hawkins, Clare L" sort="Hawkins, Clare L" uniqKey="Hawkins C" first="Clare L" last="Hawkins">Clare L. Hawkins</name><name sortKey="Richardson, Des R" sort="Richardson, Des R" uniqKey="Richardson D" first="Des R" last="Richardson">Des R. Richardson</name><name sortKey="Suryo Rahmanto, Yohan" sort="Suryo Rahmanto, Yohan" uniqKey="Suryo Rahmanto Y" first="Yohan" last="Suryo Rahmanto">Yohan Suryo Rahmanto</name></noCountry><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Yu, Yu" sort="Yu, Yu" uniqKey="Yu Y" first="Yu" last="Yu">Yu Yu</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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