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, p-
histone 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.