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

Federica Falà, William L. Blalock, Pier Luigi Tazzari, Alessandra Cappellini, Francesca Chiarini, Giovanni Martinelli, Agostino Tafuri, James A. McCubrey, Lucio Cocco, Alberto M. Martelli

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Abstract

Constitutively 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-2H-indazol-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-3β. 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 μM, the inhibitor was able to induce apoptotic cell death of T-ALL blast cells, as indicated by flow cytometric analysis of samples immuno-stained 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.

Original languageEnglish
Pages (from-to)884-895
Number of pages12
JournalMolecular Pharmacology
Volume74
Issue number3
DOIs
Publication statusPublished - Sep 2008

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Amines
Cell Death
Caspase 2
Etoposide
Caspase 3
Pharmaceutical Preparations
Phosphorylation
Glycogen Synthase Kinase 3
Cell Line
Chromosomes, Human, Pair 10
Jurkat Cells
P-Glycoprotein
Phosphoric Monoester Hydrolases
Phosphotransferases
Pharmacology
Drug Therapy
DNA
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Falà, Federica; Blalock, William L.; Tazzari, Pier Luigi; Cappellini, Alessandra; Chiarini, Francesca; Martinelli, Giovanni; Tafuri, Agostino; McCubrey, James A.; Cocco, Lucio; Martelli, Alberto M.

In: Molecular Pharmacology, Vol. 74, No. 3, 09.2008, p. 884-895.

Research output: Contribution to journalArticle

Falà, Federica ; Blalock, William L. ; Tazzari, Pier Luigi ; Cappellini, Alessandra ; Chiarini, Francesca ; Martinelli, Giovanni ; Tafuri, Agostino ; McCubrey, James A. ; Cocco, Lucio ; Martelli, Alberto M. / 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. In: Molecular Pharmacology. 2008 ; Vol. 74, No. 3. pp. 884-895.
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AU - Chiarini, Francesca

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