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
Author
Fala, Federica; Blalock, William L.; Tazzari, Pier Luigi; Cappellini, Alessandra; Chiarini, Francesca; Martinelli, Giovanni; Tafuri, Agostino; McCubrey, James A.; Cocco, Lucio; Martelli, Alberto M.
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
Subject
Date
2008-09
Citation:
APA:
Fala, Federica, & Blalock, William L., & Tazzari, Pier Luigi, & Cappellini, Alessandra, & Chiarini, Francesca, & Martinelli, Giovanni, & Tafuri, Agostino, & McCubrey, James A., & Cocco, Lucio, & Martelli, Alberto M.. (September 2008).
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.
Molecular Pharmacology,
74(3),
884-
895. Retrieved from
http://hdl.handle.net/10342/3274
MLA:
Fala, Federica, and Blalock, William L., and Tazzari, Pier Luigi, and Cappellini, Alessandra, and Chiarini, Francesca, and Martinelli, Giovanni, and Tafuri, Agostino, and McCubrey, James A., and Cocco, Lucio, and 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". Molecular Pharmacology.
74:3. (884-895),
September 2008.
December 10, 2023.
http://hdl.handle.net/10342/3274.
Chicago:
Fala, Federica and Blalock, William L. and Tazzari, Pier Luigi and Cappellini, Alessandra and Chiarini, Francesca and Martinelli, Giovanni and Tafuri, Agostino and McCubrey, James A. and Cocco, Lucio and 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," Molecular Pharmacology 74, no.
3 (September 2008),
http://hdl.handle.net/10342/3274 (accessed
December 10, 2023).
AMA:
Fala, 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. Molecular Pharmacology.
September 2008;
74(3):
884-895.
http://hdl.handle.net/10342/3274. Accessed
December 10, 2023.
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Publisher
East Carolina University