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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 <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. 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\u2010eIF4E(S209) level in a dose\u2010 and time\u2010dependent 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.<\/jats:p>","DOI":"10.1002\/jbt.22007","type":"journal-article","created":{"date-parts":[[2017,11,7]],"date-time":"2017-11-07T15:02:59Z","timestamp":1510066979000},"source":"Crossref","is-referenced-by-count":20,"title":["Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin\u2010induced eIF4E activation"],"prefix":"10.1002","volume":"32","author":[{"given":"Jun","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Hepatology Ningbo No. 2 Hospital  Ningbo 315010 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfen","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hepatology Ningbo No. 2 Hospital  Ningbo 315010 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Ningbo Medical Treatment Center Li Huili Hospital  Ningbo 315041 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1567-8485","authenticated-orcid":false,"given":"Mi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Medicine Ningbo University  Ningbo 315211 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoren","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Hepatology Ningbo No. 2 Hospital  Ningbo 315010 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1159\/000367754","volume":"5","author":"Lu L. 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