Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
Research, Development and Innovation Centre, Tampere University Hospital, 33520 Tampere, Finland.
Cells. 2022 May 7;11(9):1574. doi: 10.3390/cells11091574.
Mesenchymal stem/stromal cells (MSCs) are self-renewing and multipotent progenitors, which constitute the main cellular compartment of the bone marrow stroma. Because MSCs have an important role in the pathogenesis of multiple myeloma, it is essential to know if novel drugs target MSCs. Melflufen is a novel anticancer peptide-drug conjugate compound for patients with relapsed refractory multiple myeloma. Here, we studied the cytotoxicity of melflufen, melphalan and doxorubicin in healthy human bone marrow-derived MSCs (BMSCs) and how these drugs affect BMSC proliferation. We established co-cultures of BMSCs with MM.1S myeloma cells to see if BMSCs increase or decrease the cytotoxicity of melflufen, melphalan, bortezomib and doxorubicin. We evaluated how the drugs affect BMSC differentiation into adipocytes and osteoblasts and the BMSC-supported formation of vascular networks. Our results showed that BMSCs were more sensitive to melflufen than to melphalan. The cytotoxicity of melflufen in myeloma cells was not affected by the co-culture with BMSCs, as was the case for melphalan, bortezomib and doxorubicin. Adipogenesis, osteogenesis and BMSC-mediated angiogenesis were all affected by melflufen. Melphalan and doxorubicin affected BMSC differentiation in similar ways. The effects on adipogenesis and osteogenesis were not solely because of effects on proliferation, seen from the differential expression of differentiation markers normalized by cell number. Overall, our results indicate that melflufen has a significant impact on BMSCs, which could possibly affect therapy outcome.
间充质干细胞（MSCs）是自我更新和多能祖细胞，构成骨髓基质的主要细胞区室。由于 MSCs 在多发性骨髓瘤的发病机制中具有重要作用，因此了解新型药物是否靶向 MSCs 至关重要。美法仑是一种新型的抗癌肽-药物偶联物，用于治疗复发性难治性多发性骨髓瘤患者。在这里，我们研究了美法仑、美法仑和阿霉素对健康人骨髓来源的间充质干细胞（BMSCs）的细胞毒性，以及这些药物如何影响 BMSC 的增殖。我们建立了 BMSCs 与 MM.1S 骨髓瘤细胞的共培养物，以观察 BMSCs 是否增加或减少美法仑、美法仑、硼替佐米和阿霉素的细胞毒性。我们评估了药物如何影响 BMSC 分化为脂肪细胞和成骨细胞以及 BMSC 支持的血管网络形成。结果表明，BMSCs 对美法仑比美法仑更敏感。骨髓瘤细胞中美法仑的细胞毒性不受与 BMSCs 共培养的影响，美法仑、硼替佐米和阿霉素也是如此。脂肪生成、成骨和 BMSC 介导的血管生成均受美法仑影响。美法仑和阿霉素以相似的方式影响 BMSC 分化。脂肪生成和成骨的影响不仅是由于对增殖的影响，从细胞数量归一化的分化标志物的差异表达可以看出。总的来说，我们的结果表明美法仑对 BMSCs 有显著影响，这可能会影响治疗效果。
