R406 elicits anti-Warburg effect via Syk-dependent and -independent mechanisms to trigger apoptosis in glioma stem cells.
Cell Death Dis
; 10(5): 358, 2019 05 01.
Article
em En
| MEDLINE
| ID: mdl-31043589
ABSTRACT
Given that glioma stem cells (GSCs) play a critical role in the initiation and chemoresistance in glioblastoma multiforme (GBM), targeting GSCs is an attractive strategy to treat GBM. Utilizing an anti-cancer compound library, we identified R406, the active metabolite of a FDA-approved Syk inhibitor for immune thrombocytopenia (ITP), with remarkable cytotoxicity against GSCs but not normal neural stem cells. R406 significantly inhibited neurosphere formation and triggered apoptosis in GSCs. R406 induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and subsequently production of excess ROS in GSCs. R406 also diminished tumor growth and efficiently sensitized gliomas to temozolomide in GSC-initiating xenograft mouse models. Mechanistically, the anti-GSC effect of R406 was due to the disruption of Syk/PI3K signaling in Syk-positive GSCs and PI3K/Akt pathway in Syk-negative GSCs respectively. Overall, these findings not only identify R406 as a promising GSC-targeting agent but also reveal the important role of Syk and PI3K pathways in the regulation of energy metabolism in GSCs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxazinas
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Piridinas
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Neoplasias Encefálicas
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Regulação Neoplásica da Expressão Gênica
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Glioblastoma
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Inibidores de Proteínas Quinases
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Quinase Syk
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Antineoplásicos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China