7-Deoxynarciclasine shows promising antitumor efficacy by targeting Akt against hepatocellular carcinoma.
Int J Cancer
; 145(12): 3334-3346, 2019 12 15.
Article
em En
| MEDLINE
| ID: mdl-31081930
ABSTRACT
Akt is a promising therapeutic target for cancer treatment. In our study, we have identified that 7-deoxynarciclasine (7-DONCS) is a potential inhibitor of Akt, which results in the repression of multiple oncogenic processes in hepatocellular carcinoma (HCC). We have found that 7-DONCS suppresses the growth of HCC by inducing the apoptotic and autophagic capacities, as well as by inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo. Pretreatment of cells with specific autophagy inhibitor (Bafilomycin A1) or knockdown of endogenous LC3B by siRNA strongly enhences 7DONCSregulated apoptosis and EMT. Consequently, we have found that 7-DONCS selectively inhibits phospho-Akt (Ser473), and subsequent molecular docking reveals that 7-DONCS directly binds to the C-terminal domain of Akt. Overexpressing Akt significantly blocks these effects via 7-DONCS in HCC cells. Furthermore, 7-DONCS, by targeting Akt, exhibits a promising therapeutic effect in orthotopic hepatocellular tumors. Finally, higher p-Akt expression is associated with poor prognosis, and higher level of Akt was positively correlated with the enrichment of both apoptosis and autophagy downregulation, and EMT upregulation in HCC patients. These studies suggest that 7-DONCS serves as an attractive drug candidate by targeting Akt for future HCC therapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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Proteínas Proto-Oncogênicas c-akt
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Isoquinolinas
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Neoplasias Hepáticas
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Int J Cancer
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China