title: 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.
authors: Department of Pharmacy, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China.
authors: Zhong
authors: Z
authors: Liu
authors: Department of Pharmacy, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China.
authors: Yong
authors: Y
authors: Li
authors: Department of Pharmacy, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China.
authors: Cao
authors: C
authors: Lv
authors: Department of Obstetrics and Gynecology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China. Electronic address: 932259164@qq.com.
authors: Li
authors: L
authors: Wang
authors: Department of Pharmacy, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China. Electronic address: yjkpuai@126.com.
authors: Hongping
authors: H
authors: Song
mesh_terms: D000871:Anthelmintics / Q000494:pharmacology*; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology*; D004357:Drug Synergism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009534:Niclosamide / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
chemical_list: D000871:Anthelmintics; D018952:Antigens, CD34; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D009534:Niclosamide; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000069439:Dasatinib
keywords: Chronic myeloid leukemia; Erk/Mnk/eIF4E; Niclosamide; TKI resistance