Liu Zhong, Li Yong, Lv Cao, Wang Li, Song Hongping
Department of Pharmacy, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China.
Department of Obstetrics and Gynecology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, China.
Biochem Biophys Res Commun. 2016 Sep 16;478(2):893-9. doi: 10.1016/j.bbrc.2016.08.047. Epub 2016 Aug 9.
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.
慢性髓性白血病（CML）对BCR-ABL酪氨酸激酶抑制剂（TKI）反应良好，但进展至急变期（BP）后会对TKI产生耐药性。在此我们表明，一种经美国食品药品监督管理局（FDA）批准的驱虫药氯硝柳胺，通过抑制Erk/Mnk1/eIF4E信号通路，增强了BP-CML细胞对达沙替尼（第二代BCR-ABL TKI）的敏感性。氯硝柳胺在一组CML细胞系中呈剂量依赖性地抑制增殖并诱导凋亡。它还通过诱导凋亡、抑制集落形成和自我更新能力，选择性地靶向BP-CML CD34干细胞/祖细胞，同时不影响正常骨髓（NBM）细胞。此外，氯硝柳胺和达沙替尼联合使用在CML细胞系和BP-CML CD34细胞中具有协同作用。重要的是，氯硝柳胺抑制CML细胞中Erk、Mnk1和eIF4E的磷酸化。eIF4E的磷酸模拟物而非非磷酸化形式的过表达可逆转氯硝柳胺的抑制作用，这表明eIF4E抑制是氯硝柳胺在CML中发挥作用所必需的。与NBM相比，CML CD34细胞中eIF4E水平及其活性的升高可能解释了氯硝柳胺对CML与NBM的选择性毒性。我们进一步表明，达沙替尼可时间依赖性地诱导eIF4E磷酸化。eIF4E缺失与达沙替尼联合使用产生的效果与氯硝柳胺和达沙替尼联合使用相似，这表明氯硝柳胺通过靶向eIF4E增强了达沙替尼的作用。我们的研究首次证明氯硝柳胺是一种潜在药物，可克服BP-CML中对BCR-ABL TKI治疗的耐药性。我们的研究结果还提示了Erk/Mnk/eIF4E在CML治疗中的治疗价值。
