Proapoptotic Activity and Chemosensitizing Effect of the Novel Akt Inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-Cell Acute Lymphoblastic Leukemia

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dc.contributor.authorFala, Federicaen_US
dc.contributor.authorBlalock, William L.en_US
dc.contributor.authorTazzari, Pier Luigien_US
dc.contributor.authorCappellini, Alessandraen_US
dc.contributor.authorChiarini, Francescaen_US
dc.contributor.authorMartinelli, Giovannien_US
dc.contributor.authorTafuri, Agostinoen_US
dc.contributor.authorMcCubrey, James A.en_US
dc.contributor.authorCocco, Lucioen_US
dc.contributor.authorMartelli, Alberto M.en_US
dc.date.accessioned2011-03-02T15:28:30Zen_US
dc.date.accessioned2011-05-17T01:40:03Z
dc.date.available2011-03-02T15:28:30Zen_US
dc.date.available2011-05-17T01:40:03Z
dc.date.issued2008-09en_US
dc.description.abstractConstitutively activated AKT kinase is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that the novel AKT inhibitor (2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2Hindazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) leads to rapid cell death of T-ALL lines and patient samples. Treatment of CEM, Jurkat, and MOLT-4 cells with nanomolar doses of the inhibitor led to AKT phosphorylation accompanied by dephosphorylation and activation of the downstream target, glycogen synthase kinase-3â. Effects were time- and dose-dependent, resulting in apoptotic cell death. Treatment of Jurkat cells with A443654 resulted in activation of caspase-2, -3, -6, -8, and -9. Apoptotic cell death was mostly dependent on caspase-2 activation, as demonstrated by preincubation with a selective pharmacological inhibitor. It is remarkable that A443654 was highly effective against the drug-resistant cell line CEMVBL100, which expresses 170-kDa P-glycoprotein. Moreover, A443654 synergized with the DNA-damaging agent etoposide in both drug-sensitive and drug-resistant cell lines when coadministered [combination index (CI) = 0.39] or when pretreated with etoposide followed by A443654 (CI = 0.689). The efficacy of A443654 was confirmed using blasts from six patients with T-ALL, all of whom displayed low levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and constitutive phosphorylation of Akt on Ser473. At 1 ìM, the inhibitor was able to induce apoptotic cell death of T-ALL blast cells, as indicated by flow cytometric analysis of samples immunostained for active (cleaved) caspase-3. Because activated AKT is seen in a large percentage of patients with T-ALL, A443654, either alone or in combination with existing drugs, may be a useful therapy for primary and drug-resistant T-ALL. Originally published Molecular Pharmacology, Vol. 74, No. 3, Sep 2008en_US
dc.identifier.citationMolecular Pharmacology; 74:3 p. 884-895en_US
dc.identifier.pmidPMC2659779en_US
dc.identifier.urihttp://hdl.handle.net/10342/3274en_US
dc.language.isoen_USen_US
dc.publisherEast Carolina Universityen_US
dc.relation.urihttp://molpharm.aspetjournals.org/content/74/3/884.longen_US
dc.rightsAuthor notified of opt-out rights by Cammie Jennings.en_US
dc.subjectT-cell acute lymphoblastic leukemiaen_US
dc.subjectAkten_US
dc.subjectA443654en_US
dc.titleProapoptotic Activity and Chemosensitizing Effect of the Novel Akt Inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-Cell Acute Lymphoblastic Leukemiaen_US
dc.typeArticleen_US

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