Albendazole inhibits NF-KB signaling pathway to overcome tumor stemness and bortezomib resistance in multiple myeloma
Albendazole inhibits NF-KB signaling pathway to overcome tumor stemness and bortezomib resistance in multiple myeloma
复制标题
阿苯达唑抑制核因子-KB信号通路克服多发性骨髓瘤的肿瘤干性和对硼替佐米的耐药性
DOI：
10.1016/j.canlet.2021.08.009
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发表时间：
2021-08-16
期刊：
影响因子：
9.7
通讯作者：
Xiao, Xiaojuan
中科院分区：
文献类型：
--
作者：
Yi, Hui;Liang, Long;Xiao, Xiaojuan
多发性骨髓瘤（MM）是不可治愈的，是浆细胞中第二常见的血液恶性肿瘤。多发性骨髓瘤干细胞样细胞（MMSCs）是一种罕见的MM细胞，被认为是MM患者耐药性和高复发率的主要原因。因此，开发新的策略来根除MMSCs可能有利于骨髓瘤治疗。在这项研究中，基于药物重新定位策略，我们发现阿苯达唑（ABZ），一种广谱抗寄生虫药物，在体外和体内选择性抑制多发性骨髓瘤细胞的增殖，并减少MM中醛脱氢酶（ALDH）阳性MMSCs的数量。此外，ABZ处理后MM细胞的RNA-seq显示，核因子κ B（NF-κ B）途径的抑制是ABZ抗MM的关键介质。我们证明了ABZ可以通过减少ALDH 1 + MMSC的数量来使耐硼替佐米的细胞重新敏感并克服MMSC诱导的硼替佐米耐药性。我们的研究结果为利用先前已知的抗肿瘤药物阿苯达唑治疗多发性骨髓瘤提供了临床前证据。
Multiple myeloma (MM) is incurable and the second most common hematologic malignancy in plasma cells. Multiple myeloma stem cell-like cells (MMSCs), a rare population of MM cells, are believed to be the major cause of drug resistance and high recurrence rates in patients with MM. Therefore, developing novel strategies to eradicate MMSCs may favor myeloma treatment. In this study, based on the drug repositioning strategy, we found that albendazole (ABZ), a broad-spectrum antiparasitic drug, selectively suppresses the proliferation of multiple myeloma cells in vitro and in vivo and decreases number of aldehyde dehydrogenase (ALDH)-positive MMSCs in MM. Furthermore, RNA-seq of MM cells after ABZ treatment revealed that inhibition of the nuclear factor kappa-B (NF-KB) pathway is a key mediator of ABZ against MM. Moreover, we demonstrated that ABZ can resensitize cells resistant to bortezomib and overcome MMSCs-induced bortezomib resistance by decreasing ALDH1+ MMSCs numbers. Our findings provide preclinical evidence for utilizing the previously known pharmacologically active drug albendazole for the treatment of multiple myeloma.