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
| العنوان: | 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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| المؤلفون: | Alberto M. Martelli, William L. Blalock, Lucio Cocco, Federica Fala, Pier Luigi Tazzari, Giovanni Martinelli, Alessandra Cappellini, James A. McCubrey, Francesca Chiarini, Agostino Tafuri |
| المساهمون: | Falà F, Blalock WL, Tazzari PL, Cappellini A, Chiarini F, Martinelli G, Tafuri A, McCubrey JA, Cocco L, Martelli AM |
| المصدر: | Molecular Pharmacology. 74:884-895 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Indazoles, Indoles, T cell, Apoptosis, Jurkat cells, Article, Glycogen Synthase Kinase 3, Phosphoserine, Cell Line, Tumor, medicine, Humans, Leukemia-Lymphoma, Adult T-Cell, PTEN, Phosphorylation, Protein kinase B, Etoposide, Cell Proliferation, Pharmacology, Glycogen Synthase Kinase 3 beta, Dose-Response Relationship, Drug, biology, Cell growth, Drug Synergism, Enzyme Activation, Phosphothreonine, medicine.anatomical_structure, Drug Resistance, Neoplasm, Caspases, biology.protein, Cancer research, Molecular Medicine, Drug Screening Assays, Antitumor, Proto-Oncogene Proteins c-akt, medicine.drug |
| الوصف: | 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-3beta. 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 CEM-VBL100, 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 microM, 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. |
| وصف الملف: | STAMPA |
| تدمد: | 1521-0111 0026-895X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd190d0684fcdaac7a62d9e6cd2108cdTest https://doi.org/10.1124/mol.108.047639Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cd190d0684fcdaac7a62d9e6cd2108cd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
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