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.

中文翻译：

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甲苯咪唑是有效的抗化学性T细胞急性淋巴细胞白血病细胞的抑制剂。

甲苯达唑（MBZ）是一种微管蛋白抑制性抗蠕虫药，具有低毒性，已被重新用于治疗不同类型的肿瘤。在难治性或复发性T细胞急性淋巴细胞白血病（T-ALL）中，化学耐药性非常普遍，这导致康复的机会不佳。在这项研究中，发现MBZ在纳摩尔浓度下可抑制T-ALL细胞系CCRF-CEM及其化学抗性衍生物CEM / C1的增殖并降低其活力。发现抑制作用是剂量依赖性的，不受CEM / C1细胞化学耐药性的影响。在MBZ处理的T-ALL细胞中发现了细胞周期停滞，caspase 3/7激活和微管蛋白破坏。Notch1信号通常在T-ALL细胞中异常激活，已被MBZ治疗抑制。小鼠T-ALL模型中的MBZ给药也抑制了CEM / C1细胞的生长，表明MBZ可能被开发为抗化学性T-ALL的治疗剂。还证实了Notch1和Hes1的mRNA水平在体内被MBZ抑制，这与体外观察一致。这项研究首次证明了MBZ可以在体内外抑制化学耐药性T-ALL细胞，并且MBZ处理可以抑制Notch1信号通路。