Luteolin inhibits the TGF-β signaling pathway to overcome bortezomib resistance in multiple myeloma
Luteolin inhibits the TGF-β signaling pathway to overcome bortezomib resistance in multiple myeloma
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DOI：
10.1016/j.canlet.2022.216019
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发表时间：
2022-12-07
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：
Li, Zhenzhen;Wang, Haiqin;Xiao, Xiaojuan
多发性骨髓瘤（MM）是一种无法治愈的疾病，也是第二常见的血液恶性肿瘤。在过去的几年里，MM的治疗取得了进展，但大多数患者仍然复发。多发性骨髓瘤干细胞样细胞（MMSC）被认为是耐药性和最终复发的主要原因。目前，还没有足够的治疗剂被鉴定用于根除MMSC，因此，对MMSC的鉴定可以减轻患者的复发问题。在本研究中，我们发现，从不同植物，如蔬菜，草药和水果中获得的天然化合物木犀草素（LUT），有效地抑制MM细胞的增殖，并在体外和体内克服硼替佐米（BTZ）的耐药性，主要是通过降低ALDH 1（+）细胞的比例。此外，LUT处理MM细胞系和MM异种移植小鼠模型后的RNA测序显示，该化合物的作用是通过抑制转化生长因子-β信号传导介导的。同样，我们发现LUT也显著降低了原代CD 138+浆细胞中ALDH 1（+）细胞的比例。LUT可抑制BTZ诱导的ALDH 1+细胞比例增加，二者联合对骨髓瘤细胞具有协同作用。总的来说，我们的研究结果表明，LUT是一种很有前途的药物，可以单独或与BTZ联合使用，证明MMSC可以克服BTZ耐药性，因此，LUT是一种治疗MM的潜在治疗药物。
Multiple myeloma (MM) is an incurable condition and the second most common hematological malignancy. Over the past few years, there has been progress in the treatment of MM, but most patients still relapse. Multiple myeloma stem-like cells (MMSCs) are believed to be the main reason for drug resistance and eventual relapse. Currently, there are not enough therapeutic agents that have been identified for eradication of MMSCs, and thus, identification of the same may alleviate the issue of relapse in patients. In the present study, we showed that luteolin (LUT), a natural compound obtained from different plants, such as vegetables, medicinal herbs, and fruits, effectively inhibits the proliferation of MM cells and overcomes bortezomib (BTZ) resistance in them in vitro and in vivo, mainly by decreasing the proportion of ALDH1(+) cells. Furthermore, RNA sequencing after LUT treatment of MM cell lines and an MM xenograft mouse model revealed that the effects of the compound are mediated through inhibition of transforming growth factor-beta signaling. Similarly, we found that LUT also significantly reduced the proportion of ALDH1(+) cells in primary CD138+ plasma cells. In addition, LUT could overcome the BTZ treatment-induced increase in the proportion of ALDH1+ cells, and the combination of LUT and BTZ had a synergistic effect against myeloma cells. Collectively, our findings suggested that LUT is a promising agent that manifests MMSCs to overcome BTZ resistance, alone or in combination with BTZ, and thus, is a potential therapeutic drug for the treatment of MM.