当前位置： SCI文献检索 > BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS期刊下所有文献 > Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway.

Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway.

Abstract：

: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.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Liu Z,Li Y,Lv C,Wang L,Song H

doi

10.1016/j.bbrc.2016.08.047

subject

Has Abstract

pub_date

2016-09-16 00:00:00

pages

893-9

issue

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(16)31302-X

journal_volume

478

pub_type

杂志文章

在线工具

Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway.