Premium
Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation
Author(s) -
Tan Jun,
Ye Jingfen,
Song Meijun,
Zhou Mi,
Hu Yaoren
Publication year - 2018
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.22007
Subject(s) - eif4e , doxorubicin , ribavirin , hepatocellular carcinoma , cancer research , protein kinase b , pi3k/akt/mtor pathway , pharmacology , phosphorylation , apoptosis , chemistry , chemotherapy , biology , medicine , translation (biology) , immunology , messenger rna , biochemistry , hepatitis c virus , virus , gene
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.