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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

William L. Blalock (Creator)

Alessandra Cappelini (Creator)

Francesca Chiarini (Creator)

Lucio Cocco (Creator)

Federica Fala (Creator)

Alberto M. Martelli (Creator)

Giovanni Martinelli (Creator)

James A. McCubrey (Creator)

Agostino Tafuri (Creator)

Pier Luigi Tazzari (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

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-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 2008

Additional Information

Publication

Other

Molecular Pharmacology. 74:3(September 2008) p. 884-895.

Language: English

Date: 2011

Keywords

T-cell acute lymphoblastic leukemia, Akt, A443654

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