Preclinical testing of the Akt inhibitor triciribine in T‐cell acute lymphoblastic leukemia
Identifieur interne : 001520 ( Main/Exploration ); précédent : 001519; suivant : 001521Preclinical testing of the Akt inhibitor triciribine in T‐cell acute lymphoblastic leukemia
Auteurs : Camilla Evangelisti [Italie] ; Francesca Ricci [Italie] ; Pierluigi Tazzari [Italie] ; Francesca Chiarini [Italie] ; Michela Battistelli [Italie] ; Elisabetta Falcieri [Italie] ; Andrea Ognibene [Italie] ; Pasqualepaolo Pagliaro [Italie] ; Lucio Cocco [Italie] ; James A. Mccubrey [États-Unis] ; Alberto M. Martelli [Italie]Source :
- Journal of Cellular Physiology [ 0021-9541 ] ; 2011-03.
English descriptors
- Teeft :
- Abcg2, Abcg2 activity, Acute lymphoblastic leukemia, Akt1, Akt2, Akt3, Annexin staining, Apoptosis, Apoptotic, Apoptotic cells, Assay, Autophagy, Beckman coulter, Caspase, Cell cycle, Cell cycle progression, Cell lines, Cell viability, Cellular physiology, Chemotherapeutic, Chiarini, Chloroquine, Clinical trials, Contract grant sponsor, Ctrl, Cytometric, Cytometric analysis, Cytometry, Different experiments, Different phases, Drug combination, Evangelisti, Flow cytometric analysis, Hoechst, Immunoprecipitation, Inhibitor, Jurkat cells, Kinase, Leukemia, Lymphoblastic, Mammalian target, Martelli, Mtor, Mtorc1, Mtorc2, Mtorc2 activity, Nitrocellulose membranes, Pathway, Perifosine, Phase cells, Phosphorylated, Phosphorylation, Physiology, Separate experiments, Side population, Synergistic, Synergistic effect, Triciribine, Triciribine activity, Triciribine treatment, Untreated, Untreated cells, Viability, Western blot analysis, Whole cell lysates.
Abstract
Over the past 20 years, survival rates of T‐cell acute lymphoblastic leukemia (T‐ALL) patients have improved, mainly because of advances in polychemotherapy protocols. Despite these improvements, we still need novel and less toxic treatment strategies targeting aberrantly activated signaling networks which increase proliferation, survival, and drug resistance of T‐ALL cells. One such network is represented by the phosphatidylinositol 3‐kinase (PI3K)/Akt axis. PI3K inhibitors have displayed some promising effects in preclinical models of T‐ALL. Here, we have analyzed the therapeutic potential of the Akt inhibitor, triciribine, in T‐ALL cell lines. Triciribine caused cell cycle arrest and caspase‐dependent apoptosis. Western blots demonstrated a dose‐dependent dephosphorylation of Akt1/Akt2, and of mammalian target of rapamycin complex 1 downstream targets in response to triciribine. Triciribine induced autophagy, which could be interpreted as a defensive mechanism, because an autophagy inhibitor (chloroquine) increased triciribine‐induced apoptosis. Triciribine synergized with vincristine, a chemotherapeutic drug employed for treating T‐ALL patients, and targeted the side population of T‐ALL cell lines, which might correspond to leukemia initiating cells. Our findings indicate that Akt inhibition, either alone or in combination with chemotherapeutic drugs, may serve as an efficient treatment towards T‐ALL cells requiring upregulation of this signaling pathway for their proliferation and survival. J. Cell. Physiol. 226: 822–831, 2011. © 2010 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/jcp.22407
Affiliations:
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Orsola‐Malpighi, Bologna</wicri:regionArea><wicri:noRegion>Bologna</wicri:noRegion></affiliation></author><author><name sortKey="Cocco, Lucio" sort="Cocco, Lucio" uniqKey="Cocco L" first="Lucio" last="Cocco">Lucio Cocco</name><affiliation wicri:level="4"><country xml:lang="fr">Italie</country><wicri:regionArea>Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Cell Signalling Laboratory, Università di Bologna, Bologna</wicri:regionArea><orgName type="university">Université de Bologne</orgName><placeName><settlement type="city">Bologne</settlement><region nuts="2" type="region">Émilie-Romagne</region></placeName></affiliation></author><author><name sortKey="Mccubrey, James A" sort="Mccubrey, James A" uniqKey="Mccubrey J" first="James A." last="Mccubrey">James A. Mccubrey</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville</wicri:cityArea></affiliation></author><author><name sortKey="Martelli, Alberto M" sort="Martelli, Alberto M" uniqKey="Martelli A" first="Alberto M." last="Martelli">Alberto M. Martelli</name><affiliation wicri:level="4"><country xml:lang="fr">Italie</country><wicri:regionArea>Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Cell Signalling Laboratory, Università di Bologna, Bologna</wicri:regionArea><orgName type="university">Université de Bologne</orgName><placeName><settlement type="city">Bologne</settlement><region nuts="2" type="region">Émilie-Romagne</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>IGM‐CNR, c/o I.O.R., Bologna</wicri:regionArea><wicri:noRegion>Bologna</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Italie</country><wicri:regionArea>Correspondence address: Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Cell Signalling Laboratory, Università di Bologna, Bologna</wicri:regionArea><orgName type="university">Université de Bologne</orgName><placeName><settlement type="city">Bologne</settlement><region nuts="2" type="region">Émilie-Romagne</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Cellular Physiology</title><title level="j" type="alt">JOURNAL OF CELLULAR PHYSIOLOGY</title><idno type="ISSN">0021-9541</idno><idno type="eISSN">1097-4652</idno><imprint><biblScope unit="vol">226</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="822">822</biblScope><biblScope unit="page" to="831">831</biblScope><biblScope unit="page-count">10</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-03">2011-03</date></imprint><idno type="ISSN">0021-9541</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0021-9541</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Abcg2</term><term>Abcg2 activity</term><term>Acute lymphoblastic leukemia</term><term>Akt1</term><term>Akt2</term><term>Akt3</term><term>Annexin staining</term><term>Apoptosis</term><term>Apoptotic</term><term>Apoptotic cells</term><term>Assay</term><term>Autophagy</term><term>Beckman coulter</term><term>Caspase</term><term>Cell cycle</term><term>Cell cycle progression</term><term>Cell lines</term><term>Cell viability</term><term>Cellular physiology</term><term>Chemotherapeutic</term><term>Chiarini</term><term>Chloroquine</term><term>Clinical trials</term><term>Contract grant sponsor</term><term>Ctrl</term><term>Cytometric</term><term>Cytometric analysis</term><term>Cytometry</term><term>Different experiments</term><term>Different phases</term><term>Drug combination</term><term>Evangelisti</term><term>Flow cytometric analysis</term><term>Hoechst</term><term>Immunoprecipitation</term><term>Inhibitor</term><term>Jurkat cells</term><term>Kinase</term><term>Leukemia</term><term>Lymphoblastic</term><term>Mammalian target</term><term>Martelli</term><term>Mtor</term><term>Mtorc1</term><term>Mtorc2</term><term>Mtorc2 activity</term><term>Nitrocellulose membranes</term><term>Pathway</term><term>Perifosine</term><term>Phase cells</term><term>Phosphorylated</term><term>Phosphorylation</term><term>Physiology</term><term>Separate experiments</term><term>Side population</term><term>Synergistic</term><term>Synergistic effect</term><term>Triciribine</term><term>Triciribine activity</term><term>Triciribine treatment</term><term>Untreated</term><term>Untreated cells</term><term>Viability</term><term>Western blot analysis</term><term>Whole cell lysates</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Over the past 20 years, survival rates of T‐cell acute lymphoblastic leukemia (T‐ALL) patients have improved, mainly because of advances in polychemotherapy protocols. Despite these improvements, we still need novel and less toxic treatment strategies targeting aberrantly activated signaling networks which increase proliferation, survival, and drug resistance of T‐ALL cells. One such network is represented by the phosphatidylinositol 3‐kinase (PI3K)/Akt axis. PI3K inhibitors have displayed some promising effects in preclinical models of T‐ALL. Here, we have analyzed the therapeutic potential of the Akt inhibitor, triciribine, in T‐ALL cell lines. Triciribine caused cell cycle arrest and caspase‐dependent apoptosis. Western blots demonstrated a dose‐dependent dephosphorylation of Akt1/Akt2, and of mammalian target of rapamycin complex 1 downstream targets in response to triciribine. Triciribine induced autophagy, which could be interpreted as a defensive mechanism, because an autophagy inhibitor (chloroquine) increased triciribine‐induced apoptosis. Triciribine synergized with vincristine, a chemotherapeutic drug employed for treating T‐ALL patients, and targeted the side population of T‐ALL cell lines, which might correspond to leukemia initiating cells. Our findings indicate that Akt inhibition, either alone or in combination with chemotherapeutic drugs, may serve as an efficient treatment towards T‐ALL cells requiring upregulation of this signaling pathway for their proliferation and survival. J. Cell. Physiol. 226: 822–831, 2011. © 2010 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Italie</li><li>États-Unis</li></country><region><li>Caroline du Nord</li><li>Émilie-Romagne</li></region><settlement><li>Bologne</li></settlement><orgName><li>Université de Bologne</li></orgName></list><tree><country name="Italie"><region name="Émilie-Romagne"><name sortKey="Evangelisti, Camilla" sort="Evangelisti, Camilla" uniqKey="Evangelisti C" first="Camilla" last="Evangelisti">Camilla Evangelisti</name></region><name sortKey="Battistelli, Michela" sort="Battistelli, Michela" uniqKey="Battistelli M" first="Michela" last="Battistelli">Michela Battistelli</name><name sortKey="Chiarini, Francesca" sort="Chiarini, Francesca" uniqKey="Chiarini F" first="Francesca" last="Chiarini">Francesca Chiarini</name><name sortKey="Cocco, Lucio" sort="Cocco, Lucio" uniqKey="Cocco L" first="Lucio" last="Cocco">Lucio Cocco</name><name sortKey="Falcieri, Elisabetta" sort="Falcieri, Elisabetta" uniqKey="Falcieri E" first="Elisabetta" last="Falcieri">Elisabetta Falcieri</name><name sortKey="Martelli, Alberto M" sort="Martelli, Alberto M" uniqKey="Martelli A" first="Alberto M." last="Martelli">Alberto M. Martelli</name><name sortKey="Martelli, Alberto M" sort="Martelli, Alberto M" uniqKey="Martelli A" first="Alberto M." last="Martelli">Alberto M. Martelli</name><name sortKey="Martelli, Alberto M" sort="Martelli, Alberto M" uniqKey="Martelli A" first="Alberto M." last="Martelli">Alberto M. Martelli</name><name sortKey="Ognibene, Andrea" sort="Ognibene, Andrea" uniqKey="Ognibene A" first="Andrea" last="Ognibene">Andrea Ognibene</name><name sortKey="Pagliaro, Pasqualepaolo" sort="Pagliaro, Pasqualepaolo" uniqKey="Pagliaro P" first="Pasqualepaolo" last="Pagliaro">Pasqualepaolo Pagliaro</name><name sortKey="Ricci, Francesca" sort="Ricci, Francesca" uniqKey="Ricci F" first="Francesca" last="Ricci">Francesca Ricci</name><name sortKey="Tazzari, Pierluigi" sort="Tazzari, Pierluigi" uniqKey="Tazzari P" first="Pierluigi" last="Tazzari">Pierluigi Tazzari</name></country><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Mccubrey, James A" sort="Mccubrey, James A" uniqKey="Mccubrey J" first="James A." last="Mccubrey">James A. Mccubrey</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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