Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Más filtros

Bases de datos
Tipo del documento
Intervalo de año de publicación
1.
Biochem Pharmacol ; 155: 213-223, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30006194

RESUMEN

Choline kinase alpha 1 (ChoKα1) has recently become an interesting therapeutic target since its overexpression has been associated to tumorigenesis in many cancers. Nevertheless, little is known regarding hematological malignancies. In this manuscript, we investigated the effect of a novel and selective ChoKα inhibitor EB-3D in T acute lymphoblastic leukemia (T-ALL). The effect of EB-3D was evaluated in a panel of T-leukemia cell lines and ex-vivo primary cultures derived from pediatric T-ALL patients. We also evaluated in detail, using Reverse Phase Protein Array (RPPA), protein phosphorylation level changes in T-ALL cells upon treatment. The drug exhibits a potent antiproliferative activity in a panel of T-leukemia cell lines and primary cultures of pediatric patients. Moreover, the drug strongly induces apoptosis and more importantly it enhanced T-leukemia cell sensitivity to chemotherapeutic agents, such as dexamethasone and l-asparaginase. In addition, the compound induces an early activation of AMPK, the main regulator of cellular energy homeostasis, by its phosphorylation at residue T712 of catalytic subunit α, and thus repressing mTORC1 pathway, as shown by mTOR S2448 dephosphorylation. The inhibition of mTOR in turn affects the activity of several known downstream targets, such as 4E-BP1, p70S6K, S6 Ribosomal Protein and GSK3 that ultimately may lead to a reduction of protein synthesis and cell death. Taken together, our findings suggest that targeting ChoKα may be an interesting option for treating T-ALL and that EB-3D could represent a valuable therapeutic tool.


Asunto(s)
Colina Quinasa/antagonistas & inhibidores , Colina Quinasa/biosíntesis , Inhibidores Enzimáticos/farmacología , Leucemia de Células T/metabolismo , Proteínas Quinasas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Células Jurkat , Leucemia de Células T/patología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA