Although cancer patients initially respond well to chemotherapy, they eventually develop resistance and relapse. In this work, we demonstrate that eIF4E-targeting therapy is a potential sensitizing strategy for overcoming chemoresistance and progression in cancer. We show that ribavirin, an anti-viral drug and pharmacological eIF4E inhibitor, effectively inhibits proliferation and decreases viability of paclitaxel-resistant cervical cancer and 5-FU-resistant colon cancer cells while is less toxic to human fibroblast cells. Importantly, oral administration of ribavirin significantly inhibits paclitaxel-resistant colon and 5-FU-resistant cervical cancer growth in xenograft mouse cancer model without causing significant toxicity in mice. Consistently, combination of ribavirin with paclitaxel or 5-FU sensitizes colon and cervical cancer cells to chemotherapeutic agents treatment in vitro and in vivo. We further confirm that the mechanism of the action of ribavirin in chemoresistant cancer cells is through suppressing eIF4E function. In addition, specific eIF4E knockdown via two independent siRNA mimics the effects of ribavirin in chemoresistant colon and cervical cancer cells. Cell cycle analysis indicate that ribavirin enhances the anti-proliferative effect of 5-FU by additionally arresting cells at G2/M phase via increasing cyclin B1, phistone H3(Ser10) and Mad2 levels. Our work demonstrates that eIF4E inhibition using inhibitor or siRNA, either as single agent or in combination, could sensitize chemoresistant cancer cells to paclitaxel or 5-FU treatment and thereby improving the efficacy of chemodrug. Our findings demonstrate the therapeutic value of inhibiting eIF4E, particularly in chemoresistant cancers. Our findings also suggest ribavirin as a promising sensitizing drug for cancer treatment. (C) 2018 Elsevier Inc. All rights reserved.