文献类型：期刊文献

英文题名：Mebendazole is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells

作者：Wang, Xiaolei[1,2];Lou, Kaiyan[1,2];Song, Xiaodong[3];Ma, Huijuan[1,2];Zhou, Xinyi[1,2];Xu, Huan[1,2];Wang, Wei[1,2,4,5]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Dept Pharmaceut Sci, Shanghai 200237, Peoples R China;[3]Fudan Univ, Hua Shan Hosp North, Med Lab Dept, Shanghai 201907, Peoples R China;[4]Univ Arizona, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA;[5]Univ Arizona, BIO5 Inst, Tucson, AZ 85721 USA

年份：2020

卷号：396

外文期刊名：TOXICOLOGY AND APPLIED PHARMACOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000529799700009)】；

基金：This work was funded by National Natural Science Foundation of China [grant No. 21906057 to H.X., grant No. 21738002 to W.W., grant No. 21577037 to K.L.] and Shanghai Science and Technology Committee through the Shanghai Sailing Program [grant No. 19YF1412500 to H.X.].

语种：英文

外文关键词：Mebendazole; T cell acute lymphoblastic leukemia; Notch1; Drug repurposing; Apoptosis; Chemoresistance

摘要：Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo, and the Notch1 signaling pathway was suppressed by MBZ treatment.