| [PMID]: | 27776559 |
| [Au] Autor: | Lonetti A; Cappellini A; Bertaina A; Locatelli F; Pession A; Buontempo F; Evangelisti C; Evangelisti C; Orsini E; Zambonin L; Neri LM; Martelli AM; Chiarini F |
| [Ad] Endereço: | Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. |
| [Ti] Título: | Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway. |
| [So] Source: | J Hematol Oncol;9(1):114, 2016 10 24. |
| [Is] ISSN: | 1756-8722 |
| [Cp] País de publicação: | England |
| [La] Idioma: | eng |
| [Ab] Resumo: | BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. METHODS: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. RESULTS: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. CONCLUSIONS: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients. |
| [Mh] Termos MeSH primário: |
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/antagonistas & inibidores
|
| [Mh] Termos MeSH secundário: |
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade
Apoptose/efeitos dos fármacos
Arabinonucleosídeos/uso terapêutico
Arabinonucleosídeos/toxicidade
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico
Sobrevivência Celular/efeitos dos fármacos
Sinergismo Farmacológico
Seres Humanos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações
Proteínas Proto-Oncogênicas c-akt
Piridonas/uso terapêutico
Pirimidinonas/uso terapêutico
Sulfonamidas/uso terapêutico
Triazinas/uso terapêutico
Células Tumorais Cultivadas
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Arabinonucleosides); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Pyridones); 0 (Pyrimidinones); 0 (Sulfonamides); 0 (Triazines); 0 (ZSTK474); 33E86K87QN (trametinib); 60158CV180 (nelarabine); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); N54AIC43PW (venetoclax) |
| [Em] Mês de entrada: | 1712 |
| [Cu] Atualização por classe: | 171206 |
[Lr] Data última revisão:
| 171206 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 161026 |
| [St] Status: | MEDLINE |
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