RapamycinFungusV1, Main, Exploration, bibRecord, 000E60

Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.

Identifieur interne : 000E60 ( Main/Exploration ); précédent : 000E59; suivant : 000E61

Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.

Auteurs : Mihajlo Bosnjak [Serbie] ; Biljana Ristic [Serbie] ; Katarina Arsikin [Serbie] ; Aleksandar Mircic [Serbie] ; Violeta Suzin-Zivkovic [Serbie] ; Vladimir Perovic [Serbie] ; Andrija Bogdanovic [Serbie] ; Verica Paunovic [Serbie] ; Ivanka Markovic [Serbie] ; Vladimir Bumbasirevic [Serbie] ; Vladimir Trajkovic [Serbie] ; Ljubica Harhaji-Trajkovic [Serbie]

Source :

PloS one [ 1932-6203 ] ; 2014.

RBID : pubmed:24714637

Descripteurs français

KwdFr :
- AMP-Activated Protein Kinases (métabolisme), Agranulocytes (métabolisme), Antimétabolites antinéoplasiques (pharmacologie), Apoptose (effets des médicaments et des substances chimiques), Apoptose (génétique), Autophagie (effets des médicaments et des substances chimiques), Autophagie (génétique), Cytarabine (pharmacologie), Extracellular Signal-Regulated MAP Kinases (métabolisme), Humains (MeSH), Interférence par ARN (MeSH), Leucémies (génétique), Leucémies (métabolisme), Leucémies (traitement médicamenteux), Lignée cellulaire tumorale (MeSH), Protéines proto-oncogènes c-akt (métabolisme), Régulation de l'expression des gènes dans la leucémie (MeSH), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (effets des médicaments et des substances chimiques).
MESH :
- antagonistes et inhibiteurs : Sérine-thréonine kinases TOR.
- effets des médicaments et des substances chimiques : Apoptose, Autophagie, Transduction du signal.
- génétique : Apoptose, Autophagie, Leucémies.
- métabolisme : AMP-Activated Protein Kinases, Agranulocytes, Extracellular Signal-Regulated MAP Kinases, Leucémies, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Antimétabolites antinéoplasiques, Cytarabine.
- traitement médicamenteux : Leucémies.
- Humains, Interférence par ARN, Lignée cellulaire tumorale, Régulation de l'expression des gènes dans la leucémie.

English descriptors

KwdEn :
- AMP-Activated Protein Kinases (metabolism), Antimetabolites, Antineoplastic (pharmacology), Apoptosis (drug effects), Apoptosis (genetics), Autophagy (drug effects), Autophagy (genetics), Cell Line, Tumor (MeSH), Cytarabine (pharmacology), Extracellular Signal-Regulated MAP Kinases (metabolism), Gene Expression Regulation, Leukemic (MeSH), Humans (MeSH), Leukemia (drug therapy), Leukemia (genetics), Leukemia (metabolism), Leukocytes, Mononuclear (metabolism), Proto-Oncogene Proteins c-akt (metabolism), RNA Interference (MeSH), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism).
MESH :
- chemical , antagonists & inhibitors : TOR Serine-Threonine Kinases.
- chemical , metabolism : AMP-Activated Protein Kinases, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antimetabolites, Antineoplastic, Cytarabine.
- drug effects : Apoptosis, Autophagy, Signal Transduction.
- drug therapy : Leukemia.
- genetics : Apoptosis, Autophagy, Leukemia.
- metabolism : Leukemia, Leukocytes, Mononuclear.
- Cell Line, Tumor, Gene Expression Regulation, Leukemic, Humans, RNA Interference.

Abstract

The present study investigated the role of autophagy, a cellular self-digestion process, in the cytotoxicity of antileukemic drug cytarabine towards human leukemic cell lines (REH, HL-60, MOLT-4) and peripheral blood mononuclear cells from leukemic patients. The induction of autophagy was confirmed by acridine orange staining of intracellular acidic vesicles, electron microscopy visualization of autophagic vacuoles, as well as by the increase in autophagic proteolysis and autophagic flux, demonstrated by immunoblot analysis of p62 downregulation and LC3-I conversion to autophagosome-associated LC3-II in the presence of proteolysis inhibitors, respectively. Moreover, the expression of autophagy-related genes Atg4, Atg5 and Atg7 was stimulated by cytarabine in REH cells. Cytarabine reduced the phosphorylation of the major negative regulator of autophagy, mammalian target of rapamycin (mTOR), and its downstream target p70S6 kinase in REH cells, which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase. Cytarabine had no effect on the activation of mTOR inhibitor AMP-activated protein kinase. Leucine, an mTOR activator, reduced both cytarabine-induced autophagy and cytotoxicity. Accordingly, pharmacological downregulation of autophagy with bafilomycin A1 and chloroquine, or RNA interference-mediated knockdown of LC3β or p62, markedly increased oxidative stress, mitochondrial depolarization, caspase activation and subsequent DNA fragmentation and apoptotic death in cytarabine-treated REH cells. Cytarabine also induced mTOR-dependent cytoprotective autophagy in HL-60 and MOLT-4 leukemic cell lines, as well as primary leukemic cells, but not normal leukocytes. These data suggest that the therapeutic efficiency of cytarabine in leukemic patients could be increased by the inhibition of the mTOR-dependent autophagic response.

DOI: 10.1371/journal.pone.0094374
PubMed: 24714637
PubMed Central: PMC3979773

Affiliations:

Serbie

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000E68
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Le document en format XML

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<author><name sortKey="Paunovic, Verica" sort="Paunovic, Verica" uniqKey="Paunovic V" first="Verica" last="Paunovic">Verica Paunovic</name>
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<author><name sortKey="Markovic, Ivanka" sort="Markovic, Ivanka" uniqKey="Markovic I" first="Ivanka" last="Markovic">Ivanka Markovic</name>
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<country xml:lang="fr">Serbie</country>
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<author><name sortKey="Bumbasirevic, Vladimir" sort="Bumbasirevic, Vladimir" uniqKey="Bumbasirevic V" first="Vladimir" last="Bumbasirevic">Vladimir Bumbasirevic</name>
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<author><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name>
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<term>Antimetabolites, Antineoplastic (pharmacology)</term>
<term>Apoptosis (drug effects)</term>
<term>Apoptosis (genetics)</term>
<term>Autophagy (drug effects)</term>
<term>Autophagy (genetics)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cytarabine (pharmacology)</term>
<term>Extracellular Signal-Regulated MAP Kinases (metabolism)</term>
<term>Gene Expression Regulation, Leukemic (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Leukemia (drug therapy)</term>
<term>Leukemia (genetics)</term>
<term>Leukemia (metabolism)</term>
<term>Leukocytes, Mononuclear (metabolism)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>RNA Interference (MeSH)</term>
<term>Signal Transduction (drug effects)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>AMP-Activated Protein Kinases (métabolisme)</term>
<term>Agranulocytes (métabolisme)</term>
<term>Antimétabolites antinéoplasiques (pharmacologie)</term>
<term>Apoptose (effets des médicaments et des substances chimiques)</term>
<term>Apoptose (génétique)</term>
<term>Autophagie (effets des médicaments et des substances chimiques)</term>
<term>Autophagie (génétique)</term>
<term>Cytarabine (pharmacologie)</term>
<term>Extracellular Signal-Regulated MAP Kinases (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Interférence par ARN (MeSH)</term>
<term>Leucémies (génétique)</term>
<term>Leucémies (métabolisme)</term>
<term>Leucémies (traitement médicamenteux)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Régulation de l'expression des gènes dans la leucémie (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>AMP-Activated Protein Kinases</term>
<term>Extracellular Signal-Regulated MAP Kinases</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimetabolites, Antineoplastic</term>
<term>Cytarabine</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Autophagy</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Leukemia</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Apoptose</term>
<term>Autophagie</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Apoptosis</term>
<term>Autophagy</term>
<term>Leukemia</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Apoptose</term>
<term>Autophagie</term>
<term>Leucémies</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Leukemia</term>
<term>Leukocytes, Mononuclear</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>AMP-Activated Protein Kinases</term>
<term>Agranulocytes</term>
<term>Extracellular Signal-Regulated MAP Kinases</term>
<term>Leucémies</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antimétabolites antinéoplasiques</term>
<term>Cytarabine</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Leucémies</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term>
<term>Gene Expression Regulation, Leukemic</term>
<term>Humans</term>
<term>RNA Interference</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Humains</term>
<term>Interférence par ARN</term>
<term>Lignée cellulaire tumorale</term>
<term>Régulation de l'expression des gènes dans la leucémie</term>
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<front><div type="abstract" xml:lang="en">The present study investigated the role of autophagy, a cellular self-digestion process, in the cytotoxicity of antileukemic drug cytarabine towards human leukemic cell lines (REH, HL-60, MOLT-4) and peripheral blood mononuclear cells from leukemic patients. The induction of autophagy was confirmed by acridine orange staining of intracellular acidic vesicles, electron microscopy visualization of autophagic vacuoles, as well as by the increase in autophagic proteolysis and autophagic flux, demonstrated by immunoblot analysis of p62 downregulation and LC3-I conversion to autophagosome-associated LC3-II in the presence of proteolysis inhibitors, respectively. Moreover, the expression of autophagy-related genes Atg4, Atg5 and Atg7 was stimulated by cytarabine in REH cells. Cytarabine reduced the phosphorylation of the major negative regulator of autophagy, mammalian target of rapamycin (mTOR), and its downstream target p70S6 kinase in REH cells, which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase. Cytarabine had no effect on the activation of mTOR inhibitor AMP-activated protein kinase. Leucine, an mTOR activator, reduced both cytarabine-induced autophagy and cytotoxicity. Accordingly, pharmacological downregulation of autophagy with bafilomycin A1 and chloroquine, or RNA interference-mediated knockdown of LC3β or p62, markedly increased oxidative stress, mitochondrial depolarization, caspase activation and subsequent DNA fragmentation and apoptotic death in cytarabine-treated REH cells. Cytarabine also induced mTOR-dependent cytoprotective autophagy in HL-60 and MOLT-4 leukemic cell lines, as well as primary leukemic cells, but not normal leukocytes. These data suggest that the therapeutic efficiency of cytarabine in leukemic patients could be increased by the inhibition of the mTOR-dependent autophagic response. </div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24714637</PMID>
<DateCompleted><Year>2014</Year>
<Month>12</Month>
<Day>03</Day>
</DateCompleted>
<DateRevised><Year>2018</Year>
<Month>11</Month>
<Day>13</Day>
</DateRevised>
<Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1932-6203</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>9</Volume>
<Issue>4</Issue>
<PubDate><Year>2014</Year>
</PubDate>
</JournalIssue>
<Title>PloS one</Title>
<ISOAbbreviation>PLoS One</ISOAbbreviation>
</Journal>
<ArticleTitle>Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.</ArticleTitle>
<Pagination><MedlinePgn>e94374</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pone.0094374</ELocationID>
<Abstract><AbstractText>The present study investigated the role of autophagy, a cellular self-digestion process, in the cytotoxicity of antileukemic drug cytarabine towards human leukemic cell lines (REH, HL-60, MOLT-4) and peripheral blood mononuclear cells from leukemic patients. The induction of autophagy was confirmed by acridine orange staining of intracellular acidic vesicles, electron microscopy visualization of autophagic vacuoles, as well as by the increase in autophagic proteolysis and autophagic flux, demonstrated by immunoblot analysis of p62 downregulation and LC3-I conversion to autophagosome-associated LC3-II in the presence of proteolysis inhibitors, respectively. Moreover, the expression of autophagy-related genes Atg4, Atg5 and Atg7 was stimulated by cytarabine in REH cells. Cytarabine reduced the phosphorylation of the major negative regulator of autophagy, mammalian target of rapamycin (mTOR), and its downstream target p70S6 kinase in REH cells, which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase. Cytarabine had no effect on the activation of mTOR inhibitor AMP-activated protein kinase. Leucine, an mTOR activator, reduced both cytarabine-induced autophagy and cytotoxicity. Accordingly, pharmacological downregulation of autophagy with bafilomycin A1 and chloroquine, or RNA interference-mediated knockdown of LC3β or p62, markedly increased oxidative stress, mitochondrial depolarization, caspase activation and subsequent DNA fragmentation and apoptotic death in cytarabine-treated REH cells. Cytarabine also induced mTOR-dependent cytoprotective autophagy in HL-60 and MOLT-4 leukemic cell lines, as well as primary leukemic cells, but not normal leukocytes. These data suggest that the therapeutic efficiency of cytarabine in leukemic patients could be increased by the inhibition of the mTOR-dependent autophagic response. </AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bosnjak</LastName>
<ForeName>Mihajlo</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ristic</LastName>
<ForeName>Biljana</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Arsikin</LastName>
<ForeName>Katarina</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mircic</LastName>
<ForeName>Aleksandar</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Suzin-Zivkovic</LastName>
<ForeName>Violeta</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Perovic</LastName>
<ForeName>Vladimir</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bogdanovic</LastName>
<ForeName>Andrija</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Clinic of Hematology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Paunovic</LastName>
<ForeName>Verica</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Markovic</LastName>
<ForeName>Ivanka</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bumbasirevic</LastName>
<ForeName>Vladimir</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Trajkovic</LastName>
<ForeName>Vladimir</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Harhaji-Trajkovic</LastName>
<ForeName>Ljubica</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Institute for Biological Research, University of Belgrade, Belgrade, Serbia.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2014</Year>
<Month>04</Month>
<Day>08</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>PLoS One</MedlineTA>
<NlmUniqueID>101285081</NlmUniqueID>
<ISSNLinking>1932-6203</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000964">Antimetabolites, Antineoplastic</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>04079A1RDZ</RegistryNumber>
<NameOfSubstance UI="D003561">Cytarabine</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber>
<NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.24</RegistryNumber>
<NameOfSubstance UI="D048049">Extracellular Signal-Regulated MAP Kinases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.31</RegistryNumber>
<NameOfSubstance UI="D055372">AMP-Activated Protein Kinases</NameOfSubstance>
</Chemical>
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<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D055372" MajorTopicYN="N">AMP-Activated Protein Kinases</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000964" MajorTopicYN="N">Antimetabolites, Antineoplastic</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017209" MajorTopicYN="N">Apoptosis</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
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<MeshHeading><DescriptorName UI="D048049" MajorTopicYN="N">Extracellular Signal-Regulated MAP Kinases</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015973" MajorTopicYN="N">Gene Expression Regulation, Leukemic</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007938" MajorTopicYN="N">Leukemia</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007963" MajorTopicYN="N">Leukocytes, Mononuclear</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D034622" MajorTopicYN="N">RNA Interference</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
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<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2013</Year>
<Month>10</Month>
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<Month>03</Month>
<Day>14</Day>
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<affiliations><list><country><li>Serbie</li>
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<name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name>
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<name sortKey="Mircic, Aleksandar" sort="Mircic, Aleksandar" uniqKey="Mircic A" first="Aleksandar" last="Mircic">Aleksandar Mircic</name>
<name sortKey="Paunovic, Verica" sort="Paunovic, Verica" uniqKey="Paunovic V" first="Verica" last="Paunovic">Verica Paunovic</name>
<name sortKey="Perovic, Vladimir" sort="Perovic, Vladimir" uniqKey="Perovic V" first="Vladimir" last="Perovic">Vladimir Perovic</name>
<name sortKey="Ristic, Biljana" sort="Ristic, Biljana" uniqKey="Ristic B" first="Biljana" last="Ristic">Biljana Ristic</name>
<name sortKey="Suzin Zivkovic, Violeta" sort="Suzin Zivkovic, Violeta" uniqKey="Suzin Zivkovic V" first="Violeta" last="Suzin-Zivkovic">Violeta Suzin-Zivkovic</name>
<name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name>
</country>
</tree>
</affiliations>
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   |texte=   Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.
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Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.

Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death.

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