Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway
| Autor: | Li Wang, Yong Li, Cao Lv, Hongping Song, Zhong Liu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Biophysics Dasatinib Antigens CD34 Apoptosis Pharmacology Protein Serine-Threonine Kinases Biochemistry 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Humans Progenitor cell Cell Self Renewal Phosphorylation Extracellular Signal-Regulated MAP Kinases neoplasms Molecular Biology Niclosamide Tumor Stem Cell Assay Anthelmintics Chemistry Intracellular Signaling Peptides and Proteins Myeloid leukemia Drug Synergism Cell Biology 030104 developmental biology Eukaryotic Initiation Factor-4E 030220 oncology & carcinogenesis Neoplastic Stem Cells Signal transduction Tyrosine kinase medicine.drug Signal Transduction |
| Zdroj: | Biochemical and biophysical research communications. 478(2) |
| ISSN: | 1090-2104 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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