Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.
Clin Cancer Res
; 22(3): 621-32, 2016 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-26080839
ABSTRACT
PURPOSE:
The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in acute lymphoblastic leukemia (ALL). EXPERIMENTALDESIGN:
The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry, and immunoprecipitation.RESULTS:
Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the proapoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression.CONCLUSIONS:
Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinolinas
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Regulación Neoplásica de la Expresión Génica
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Proteínas Proto-Oncogénicas
/
Resistencia a Antineoplásicos
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Inhibidores de Proteínas Quinasas
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Proteínas Reguladoras de la Apoptosis
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Imidazoles
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Proteínas de la Membrana
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2016
Tipo del documento:
Article