RapamycinFungusV1, Main, Exploration, bibRecord, 000F27

Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.

Identifieur interne : 000F27 ( Main/Exploration ); précédent : 000F26; suivant : 000F28

Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.

Auteurs : Carolina Simioni [Italie] ; Alice Cani [Italie] ; Alberto M. Martelli [Italie] ; Giorgio Zauli [Italie] ; Giovanna Tabellini [Italie] ; James Mccubrey [États-Unis] ; Silvano Capitani [Italie] ; Luca M. Neri [Italie]

Source :

Oncotarget [ 1949-2553 ] ; 2014.

RBID : pubmed:25296981

Descripteurs français

English descriptors

KwdEn :
- Apoptosis (drug effects), Autophagy (drug effects), Cell Cycle Checkpoints (drug effects), Cell Line, Tumor (MeSH), Cell Proliferation (drug effects), Drug Synergism (MeSH), Enzyme Activation (drug effects), Everolimus (MeSH), Heterocyclic Compounds, 3-Ring (pharmacology), Humans (MeSH), Mechanistic Target of Rapamycin Complex 1 (MeSH), Multiprotein Complexes (antagonists & inhibitors), Multiprotein Complexes (metabolism), Naphthyridines (pharmacology), Phosphatidylinositol 3-Kinases (metabolism), Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy), Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism), Precursor Cell Lymphoblastic Leukemia-Lymphoma (pathology), Protein Kinase Inhibitors (pharmacology), Proto-Oncogene Proteins c-akt (antagonists & inhibitors), Proto-Oncogene Proteins c-akt (metabolism), Signal Transduction (drug effects), Sirolimus (analogs & derivatives), Sirolimus (pharmacology), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism).
MESH :
- chemical , analogs & derivatives : Sirolimus.
- chemical , antagonists & inhibitors : Multiprotein Complexes, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , metabolism : Multiprotein Complexes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Heterocyclic Compounds, 3-Ring, Naphthyridines, Protein Kinase Inhibitors, Sirolimus.
- chemical : Everolimus, Mechanistic Target of Rapamycin Complex 1.
- drug effects : Apoptosis, Autophagy, Cell Cycle Checkpoints, Cell Proliferation, Enzyme Activation, Signal Transduction.
- drug therapy : Precursor Cell Lymphoblastic Leukemia-Lymphoma.
- metabolism : Precursor Cell Lymphoblastic Leukemia-Lymphoma.
- pathology : Precursor Cell Lymphoblastic Leukemia-Lymphoma.
- Cell Line, Tumor, Drug Synergism, Humans.

Abstract

The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC₅₀ in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G₀/G₁ phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients.

DOI: 10.18632/oncotarget.2490
PubMed: 25296981
PubMed Central: PMC4259403

Affiliations:

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Le document en format XML

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<term>Autophagy (drug effects)</term>
<term>Cell Cycle Checkpoints (drug effects)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Drug Synergism (MeSH)</term>
<term>Enzyme Activation (drug effects)</term>
<term>Everolimus (MeSH)</term>
<term>Heterocyclic Compounds, 3-Ring (pharmacology)</term>
<term>Humans (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term>
<term>Multiprotein Complexes (antagonists & inhibitors)</term>
<term>Multiprotein Complexes (metabolism)</term>
<term>Naphthyridines (pharmacology)</term>
<term>Phosphatidylinositol 3-Kinases (metabolism)</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>Protein Kinase Inhibitors (pharmacology)</term>
<term>Proto-Oncogene Proteins c-akt (antagonists & inhibitors)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>Signal Transduction (drug effects)</term>
<term>Sirolimus (analogs & derivatives)</term>
<term>Sirolimus (pharmacology)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
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<term>Autophagie (effets des médicaments et des substances chimiques)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexes multiprotéiques (antagonistes et inhibiteurs)</term>
<term>Complexes multiprotéiques (métabolisme)</term>
<term>Composés hétérocycliques 3 noyaux (pharmacologie)</term>
<term>Humains (MeSH)</term>
<term>Inhibiteurs de protéines kinases (pharmacologie)</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>Lignée cellulaire tumorale (MeSH)</term>
<term>Naphtyridines (pharmacologie)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
<term>Points de contrôle du cycle cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Sirolimus (analogues et dérivés)</term>
<term>Sirolimus (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>Transduction du signal (effets des médicaments et des substances chimiques)</term>
<term>Évérolimus (MeSH)</term>
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<term>Proto-Oncogene Proteins c-akt</term>
<term>TOR Serine-Threonine Kinases</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Multiprotein Complexes</term>
<term>Phosphatidylinositol 3-Kinases</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>TOR Serine-Threonine Kinases</term>
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<term>Naphthyridines</term>
<term>Protein Kinase Inhibitors</term>
<term>Sirolimus</term>
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<keywords scheme="MESH" type="chemical" xml:lang="en"><term>Everolimus</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
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<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>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Complexes multiprotéiques</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Autophagy</term>
<term>Cell Cycle Checkpoints</term>
<term>Cell Proliferation</term>
<term>Enzyme Activation</term>
<term>Signal Transduction</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>Activation enzymatique</term>
<term>Apoptose</term>
<term>Autophagie</term>
<term>Points de contrôle du cycle cellulaire</term>
<term>Prolifération cellulaire</term>
<term>Transduction du signal</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>Phosphatidylinositol 3-kinases</term>
<term>Protéines proto-oncogènes c-akt</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>Composés hétérocycliques 3 noyaux</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Naphtyridines</term>
<term>Sirolimus</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>Cell Line, Tumor</term>
<term>Drug Synergism</term>
<term>Humans</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Synergie des médicaments</term>
<term>Évérolimus</term>
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<front><div type="abstract" xml:lang="en">The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC₅₀ in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G₀/G₁ phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients.</div>
</front>
</TEI>
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<DateCompleted><Year>2015</Year>
<Month>08</Month>
<Day>04</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>5</Volume>
<Issue>20</Issue>
<PubDate><Year>2014</Year>
<Month>Oct</Month>
<Day>30</Day>
</PubDate>
</JournalIssue>
<Title>Oncotarget</Title>
<ISOAbbreviation>Oncotarget</ISOAbbreviation>
</Journal>
<ArticleTitle>Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.</ArticleTitle>
<Pagination><MedlinePgn>10034-47</MedlinePgn>
</Pagination>
<Abstract><AbstractText>The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC₅₀ in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G₀/G₁ phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Simioni</LastName>
<ForeName>Carolina</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cani</LastName>
<ForeName>Alice</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Martelli</LastName>
<ForeName>Alberto M</ForeName>
<Initials>AM</Initials>
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   |texte=   Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.
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	Serveur d'exploration sur la rapamycine et les champignons
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Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.

Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.

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