Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin-induced eIF4E activation.
J Biochem Mol Toxicol
; 32(1)2018 Jan.
Article
em En
| MEDLINE
| ID: mdl-29112301
ABSTRACT
Activation of eukaryotic translation initiation factor 4E (eIF4E) is a cellular survival mechanism in response to chemotherapy in cancers. In this work, we demonstrate that targeting eIF4E by ribavirin sensitizes hepatocellular carcinoma (HCC) cell response to doxorubicin. Ribavirin inhibits growth and survival of HCC cells, and to a greater extent than in normal liver cells. Its combination with doxorubicin achieves greater efficacy than single drug in vitro and in vivo. Ribavirin suppresses phosphorylation of molecules involved in Akt/mTOR/eIF4E pathway. Overexpression of the phosphomimetic form (S209D) but not the nonphosphorylatable form (S209A) eIF4E significantly reverses the inhibitory effects of ribavirin. Interestingly, doxorubicin significantly increases p-eIF4E(S209) level in a dose- and time-dependent manner, suggesting that doxorubicin induces eIF4E activation in HCC cells. In addition, eIF4E activation induced by doxorubicin in HCC cells is inhibited by ribavirin. Our work demonstrates the greater efficacy of ribavirin and doxorubicin combination and its underlying mechanisms.
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MEDLINE
Assunto principal:
Ribavirina
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Protocolos de Quimioterapia Combinada Antineoplásica
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Doxorrubicina
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Carcinoma Hepatocelular
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Fator de Iniciação 4E em Eucariotos
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Neoplasias Hepáticas
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article