Chronic myeloid leukemia (CML) responds well to
BCR-ABL tyrosine kinase inhibitors (TKI), but becomes resistant to TKIs after it progresses to
blast phase (BP). Here we show that
niclosamide, a FDA-approved
anthelmintic drug, enhances the sensitivity of BP-CML cells to
dasatinib (2nd generation of BCR-ABL TKI) through inhibiting Erk/Mnk1/
eIF4E signaling pathway.
Niclosamide dose-dependently inhibits proliferation and induces apoptosis in a panel of CML cell lines. It also selectively targets BP-CML CD34 stem/progenitor cells through inducing apoptosis, inhibiting colony formation and self-renewal capacity while sparing normal bone marrow (NBM) counterparts. In addition, combination of
niclosamide and
dasatinib is synergistic in CML cell lines and BP-CML CD34 cells. Importantly,
niclosamide inhibits phosphorylation of Erk, Mnk1 and
eIF4E in CML cells. Overexpression of phosphomimetic but not nonphosphorylatable form of
eIF4E reverses the inhibitory effects of
niclosamide, suggesting that
eIF4E inhibition is required for the action of
niclosamide in CML. Compared to NBM, the increased levels of
eIF4E and its activity in CML CD34 cells might explain the selective toxicity of
niclosamide in CML versus NBM. We further show that
dasatinib time-dependently induces
eIF4E phosphorylation. The combination of
eIF4E depletion and
dasatinib results in similar effects as the combination of
niclosamide and
dasatinib, suggesting that
niclosamide enhances
dasatinib through targeting
eIF4E. Our work is the first to demonstrate that
niclosamide is a potential
drug to overcome resistance to BCR-ABL TKI treatment in BP-CML. Our findings also suggest the therapeutic value of Erk/Mnk/
eIF4E in CML treatment.