Multiple myeloma (MM) is characterised by the proliferation and accumulation of malignant plasma cells in the bone marrow. Despite the progress in treatment over the last few years, MM remains incurable and the majority of patients relapse. MM stem‐like cells (MMSCs) have been considered as the main reason for drug resistance and eventual relapse. Currently, therapeutic agents are not enough to eradicate MMSCs, and finding effective strategies to eradicate MMSCs may improve the outcome of patients. Here we showed that lycorine, a natural compound from the Amaryllidaceae species, effectively inhibits the proliferation of myeloma cells from cell lines or patients, mainly through decreasing ALDH1⁺ cells. Mechanistically, lycorine decreases the MMSC population through inhibition of the Wnt/β‐catenin pathway by reducing the β‐catenin protein level. Moreover, lycorine could overcome the increasing proportion of ALDH1⁺ cells caused by bortezomib (BTZ) treatment, and a combination BTZ and lycorine have a synergistic effect on anti‐myeloma cells. Furthermore, we found a similar reduction of MMSC characteristics by lycorine in BTZ‐resistant MM cells and primary CD138⁺ plasma cells. Collectively, our findings indicate lycorine as a promising agent to target MMSCs to overcome the drug resistance of BTZ, and that, alone or in combination with BTZ, lycorine is a potential therapeutic strategy for MM treatments.

中文翻译：

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肾上腺素通过抑制Wnt /β-catenin途径靶向多发性骨髓瘤干细胞样细胞。

多发性骨髓瘤（MM）的特征是骨髓中恶性浆细胞的增殖和积累。尽管最近几年治疗取得了进展，但MM仍然无法治愈，大多数患者复发。MM干细胞样细胞（MMSC）被认为是耐药性和最终复发的主要原因。当前，治疗剂不足以根除MMSC，并且寻找根除MMSC的有效策略可以改善患者的预后。在这里，我们证明了赖草碱（一种来自石蒜科植物的天然化合物）主要通过降低ALDH1 ^+来有效抑制细胞系或患者的骨髓瘤细胞的增殖。细胞。从机理上讲，赖氨酸通过降低β-catenin蛋白水平，通过抑制Wnt /β-catenin途径而降低了MMSC的数量。此外，lycorine可以克服由硼替佐米（BTZ）治疗引起的ALDH1 ⁺细胞比例的增加，并且BTZ和lycorine的组合对抗骨髓瘤细胞具有协同作用。此外，我们发现耐BTZ的MM细胞和原代CD138 ⁺浆细胞中的赖氨酸会降低MMSC特性。总体而言，我们的研究结果表明，番红花碱是靶向MMSC克服BTZ耐药性的有前途的药物，而单独或与BTZ结合使用，番荔枝碱是MM治疗的潜在治疗策略。