RapamycinFungusV1, Main, Exploration, bibRecord, 000D30

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.

Identifieur interne : 000D30 ( Main/Exploration ); précédent : 000D29; suivant : 000D31

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.

Auteurs : Stefano Iacovelli [Italie] ; Maria Rosaria Ricciardi [Italie] ; Matteo Allegretti [Italie] ; Simone Mirabilii [Italie] ; Roberto Licchetta [Italie] ; Paola Bergamo [Italie] ; Cinzia Rinaldo [Italie] ; Ann Zeuner [Italie] ; Robin Foà [Italie] ; Michele Milella [Italie] ; James A. Mccubrey [États-Unis] ; Alberto M. Martelli [Italie] ; Agostino Tafuri [Italie]

Source :

Oncotarget [ 1949-2553 ] ; 2015.

RBID : pubmed:26392332

Descripteurs français

English descriptors

KwdEn :
- Adult (MeSH), Antineoplastic Agents (pharmacology), Apoptosis (drug effects), Biomimetics (MeSH), Biphenyl Compounds (pharmacology), Blotting, Western (MeSH), Cell Cycle (drug effects), Cell Proliferation (drug effects), Child (MeSH), Drug Resistance, Neoplasm (drug effects), Drug Synergism (MeSH), Female (MeSH), Humans (MeSH), Male (MeSH), Mechanistic Target of Rapamycin Complex 1 (MeSH), Multiprotein Complexes (metabolism), Myeloid Cell Leukemia Sequence 1 Protein (metabolism), Nitrophenols (pharmacology), Peptide Fragments (pharmacology), Piperazines (pharmacology), Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy), Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism), Precursor Cell Lymphoblastic Leukemia-Lymphoma (pathology), Proto-Oncogene Proteins (pharmacology), Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors), Proto-Oncogene Proteins c-bcl-2 (metabolism), Sirolimus (analogs & derivatives), Sirolimus (pharmacology), Sulfonamides (pharmacology), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism), Tumor Cells, Cultured (MeSH).
MESH :
- chemical , analogs & derivatives : Sirolimus.
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins c-bcl-2, TOR Serine-Threonine Kinases.
- chemical , metabolism : Multiprotein Complexes, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antineoplastic Agents, Biphenyl Compounds, Nitrophenols, Peptide Fragments, Piperazines, Proto-Oncogene Proteins, Sirolimus, Sulfonamides.
- drug effects : Apoptosis, Cell Cycle, Cell Proliferation, Drug Resistance, Neoplasm.
- drug therapy : Precursor Cell Lymphoblastic Leukemia-Lymphoma.
- metabolism : Precursor Cell Lymphoblastic Leukemia-Lymphoma.
- pathology : Precursor Cell Lymphoblastic Leukemia-Lymphoma.
- Adult, Biomimetics, Blotting, Western, Child, Drug Synergism, Female, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Tumor Cells, Cultured.

Abstract

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.

DOI: 10.18632/oncotarget.5156
PubMed: 26392332
PubMed Central: PMC4741661

Affiliations:

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

to stream Main, to step Corpus: 000B79
to stream Main, to step Curation: 000B79

Le document en format XML

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<author><name sortKey="Iacovelli, Stefano" sort="Iacovelli, Stefano" uniqKey="Iacovelli S" first="Stefano" last="Iacovelli">Stefano Iacovelli</name>
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<wicri:regionArea>Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC</wicri:regionArea>
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<author><name sortKey="Martelli, Alberto M" sort="Martelli, Alberto M" uniqKey="Martelli A" first="Alberto M" last="Martelli">Alberto M. Martelli</name>
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<wicri:regionArea>Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna</wicri:regionArea>
<wicri:noRegion>Bologna</wicri:noRegion>
</affiliation>
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<author><name sortKey="Ricciardi, Maria Rosaria" sort="Ricciardi, Maria Rosaria" uniqKey="Ricciardi M" first="Maria Rosaria" last="Ricciardi">Maria Rosaria Ricciardi</name>
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<author><name sortKey="Allegretti, Matteo" sort="Allegretti, Matteo" uniqKey="Allegretti M" first="Matteo" last="Allegretti">Matteo Allegretti</name>
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<author><name sortKey="Rinaldo, Cinzia" sort="Rinaldo, Cinzia" uniqKey="Rinaldo C" first="Cinzia" last="Rinaldo">Cinzia Rinaldo</name>
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<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
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</affiliation>
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<author><name sortKey="Zeuner, Ann" sort="Zeuner, Ann" uniqKey="Zeuner A" first="Ann" last="Zeuner">Ann Zeuner</name>
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<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome</wicri:regionArea>
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<region nuts="2">Latium</region>
</placeName>
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<author><name sortKey="Foa, Robin" sort="Foa, Robin" uniqKey="Foa R" first="Robin" last="Foà">Robin Foà</name>
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<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome</wicri:regionArea>
<wicri:noRegion>Sapienza University of Rome</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Milella, Michele" sort="Milella, Michele" uniqKey="Milella M" first="Michele" last="Milella">Michele Milella</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Medical Oncology, Regina Elena National Cancer Institute, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
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<author><name sortKey="Mccubrey, James A" sort="Mccubrey, James A" uniqKey="Mccubrey J" first="James A" last="Mccubrey">James A. Mccubrey</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC</wicri:regionArea>
<placeName><region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Martelli, Alberto M" sort="Martelli, Alberto M" uniqKey="Martelli A" first="Alberto M" last="Martelli">Alberto M. Martelli</name>
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<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna</wicri:regionArea>
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</affiliation>
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<author><name sortKey="Tafuri, Agostino" sort="Tafuri, Agostino" uniqKey="Tafuri A" first="Agostino" last="Tafuri">Agostino Tafuri</name>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult (MeSH)</term>
<term>Antineoplastic Agents (pharmacology)</term>
<term>Apoptosis (drug effects)</term>
<term>Biomimetics (MeSH)</term>
<term>Biphenyl Compounds (pharmacology)</term>
<term>Blotting, Western (MeSH)</term>
<term>Cell Cycle (drug effects)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Child (MeSH)</term>
<term>Drug Resistance, Neoplasm (drug effects)</term>
<term>Drug Synergism (MeSH)</term>
<term>Female (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Male (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term>
<term>Multiprotein Complexes (metabolism)</term>
<term>Myeloid Cell Leukemia Sequence 1 Protein (metabolism)</term>
<term>Nitrophenols (pharmacology)</term>
<term>Peptide Fragments (pharmacology)</term>
<term>Piperazines (pharmacology)</term>
<term>Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)</term>
<term>Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism)</term>
<term>Precursor Cell Lymphoblastic Leukemia-Lymphoma (pathology)</term>
<term>Proto-Oncogene Proteins (pharmacology)</term>
<term>Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)</term>
<term>Proto-Oncogene Proteins c-bcl-2 (metabolism)</term>
<term>Sirolimus (analogs & derivatives)</term>
<term>Sirolimus (pharmacology)</term>
<term>Sulfonamides (pharmacology)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
<term>Tumor Cells, Cultured (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Adulte (MeSH)</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Apoptose (effets des médicaments et des substances chimiques)</term>
<term>Biomimétique (MeSH)</term>
<term>Cellules cancéreuses en culture (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexes multiprotéiques (métabolisme)</term>
<term>Cycle cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Dérivés du biphényle (pharmacologie)</term>
<term>Enfant (MeSH)</term>
<term>Femelle (MeSH)</term>
<term>Fragments peptidiques (pharmacologie)</term>
<term>Humains (MeSH)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs B et T (anatomopathologie)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs B et T (métabolisme)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs B et T (traitement médicamenteux)</term>
<term>Mâle (MeSH)</term>
<term>Nitrophénols (pharmacologie)</term>
<term>Pipérazines (pharmacologie)</term>
<term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Protéine Mcl-1 (métabolisme)</term>
<term>Protéines proto-oncogènes (pharmacologie)</term>
<term>Protéines proto-oncogènes c-bcl-2 (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-bcl-2 (métabolisme)</term>
<term>Résistance aux médicaments antinéoplasiques (effets des médicaments et des substances chimiques)</term>
<term>Sirolimus (analogues et dérivés)</term>
<term>Sirolimus (pharmacologie)</term>
<term>Sulfonamides (pharmacologie)</term>
<term>Synergie des médicaments (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Technique de Western (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Sirolimus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins c-bcl-2</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Multiprotein Complexes</term>
<term>Myeloid Cell Leukemia Sequence 1 Protein</term>
<term>Proto-Oncogene Proteins c-bcl-2</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Biphenyl Compounds</term>
<term>Nitrophenols</term>
<term>Peptide Fragments</term>
<term>Piperazines</term>
<term>Proto-Oncogene Proteins</term>
<term>Sirolimus</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Sirolimus</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Leucémie-lymphome lymphoblastique à précurseurs B et T</term>
</keywords>
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<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Cell Cycle</term>
<term>Cell Proliferation</term>
<term>Drug Resistance, Neoplasm</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Apoptose</term>
<term>Cycle cellulaire</term>
<term>Prolifération cellulaire</term>
<term>Résistance aux médicaments antinéoplasiques</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs B et T</term>
<term>Protéine Mcl-1</term>
<term>Protéines proto-oncogènes c-bcl-2</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Dérivés du biphényle</term>
<term>Fragments peptidiques</term>
<term>Nitrophénols</term>
<term>Pipérazines</term>
<term>Protéines proto-oncogènes</term>
<term>Sirolimus</term>
<term>Sulfonamides</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Leucémie-lymphome lymphoblastique à précurseurs B et T</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adult</term>
<term>Biomimetics</term>
<term>Blotting, Western</term>
<term>Child</term>
<term>Drug Synergism</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Tumor Cells, Cultured</term>
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<term>Biomimétique</term>
<term>Cellules cancéreuses en culture</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Enfant</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Synergie des médicaments</term>
<term>Technique de Western</term>
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<front><div type="abstract" xml:lang="en">Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL. </div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26392332</PMID>
<DateCompleted><Year>2016</Year>
<Month>08</Month>
<Day>18</Day>
</DateCompleted>
<DateRevised><Year>2018</Year>
<Month>11</Month>
<Day>13</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>6</Volume>
<Issue>31</Issue>
<PubDate><Year>2015</Year>
<Month>Oct</Month>
<Day>13</Day>
</PubDate>
</JournalIssue>
<Title>Oncotarget</Title>
<ISOAbbreviation>Oncotarget</ISOAbbreviation>
</Journal>
<ArticleTitle>Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.</ArticleTitle>
<Pagination><MedlinePgn>32089-103</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.5156</ELocationID>
<Abstract><AbstractText>Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL. </AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Iacovelli</LastName>
<ForeName>Stefano</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ricciardi</LastName>
<ForeName>Maria Rosaria</ForeName>
<Initials>MR</Initials>
<AffiliationInfo><Affiliation>Hematology, "Sant'Andrea" Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Allegretti</LastName>
<ForeName>Matteo</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mirabilii</LastName>
<ForeName>Simone</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Licchetta</LastName>
<ForeName>Roberto</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Hematology, "Sant'Andrea" Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bergamo</LastName>
<ForeName>Paola</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rinaldo</LastName>
<ForeName>Cinzia</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zeuner</LastName>
<ForeName>Ann</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Foà</LastName>
<ForeName>Robin</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Milella</LastName>
<ForeName>Michele</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>McCubrey</LastName>
<ForeName>James A</ForeName>
<Initials>JA</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Martelli</LastName>
<ForeName>Alberto M</ForeName>
<Initials>AM</Initials>
<AffiliationInfo><Affiliation>Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tafuri</LastName>
<ForeName>Agostino</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Hematology, "Sant'Andrea" Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy.</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>
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<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Oncotarget</MedlineTA>
<NlmUniqueID>101532965</NlmUniqueID>
<ISSNLinking>1949-2553</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C501332">ABT-737</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance>
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<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C474007">Bax protein (53-86)</NameOfSubstance>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName>
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<MeshHeading><DescriptorName UI="D001713" MajorTopicYN="N">Biphenyl Compounds</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015153" MajorTopicYN="N">Blotting, Western</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002453" MajorTopicYN="N">Cell Cycle</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
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<MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002648" MajorTopicYN="N">Child</DescriptorName>
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<MeshHeading><DescriptorName UI="D019008" MajorTopicYN="N">Drug Resistance, Neoplasm</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
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<MeshHeading><DescriptorName UI="D004357" MajorTopicYN="Y">Drug Synergism</DescriptorName>
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<MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
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<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D046912" MajorTopicYN="N">Multiprotein Complexes</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D064549" MajorTopicYN="N">Myeloid Cell Leukemia Sequence 1 Protein</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009596" MajorTopicYN="N">Nitrophenols</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010446" MajorTopicYN="N">Peptide Fragments</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010879" MajorTopicYN="N">Piperazines</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D054198" MajorTopicYN="N">Precursor Cell Lymphoblastic Leukemia-Lymphoma</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="D011518" MajorTopicYN="N">Proto-Oncogene Proteins</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D019253" MajorTopicYN="N">Proto-Oncogene Proteins c-bcl-2</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D020123" MajorTopicYN="N">Sirolimus</DescriptorName>
<QualifierName UI="Q000031" MajorTopicYN="N">analogs & derivatives</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013449" MajorTopicYN="N">Sulfonamides</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D014407" MajorTopicYN="N">Tumor Cells, Cultured</DescriptorName>
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<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">BH3 mimetic resistance</Keyword>
<Keyword MajorTopicYN="N">Mcl-1</Keyword>
<Keyword MajorTopicYN="N">acute lymphoblastic leukemia</Keyword>
<Keyword MajorTopicYN="N">mTOR inhibition</Keyword>
<Keyword MajorTopicYN="N">targeted therapies</Keyword>
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Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.

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