Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Mol Cancer Ther. 2010 Jun;9(6):1574-82. doi: 10.1158/1535-7163.MCT-10-0104. Epub 2010 Jun 1.
Multiple myeloma remains incurable with conventional therapeutics. Thus, new treatments for this condition are clearly required. In this study we evaluated the novel NF-kappaB inhibitor LC-1 in multiple myeloma cell lines and plasma cells derived from multiple myeloma patients. LC-1 was cytotoxic to multiple myeloma cell lines H929, U266, and JJN3, and induced apoptosis in a dose-dependent manner with an overall LD(50) of 3.6 micromol/L (+/-1.8) after 48 hours in culture. Primary multiple myeloma cells, identified by CD38 and CD138 positivity, had a mean LD(50) for LC-1 of 4.9 micromol/L (+/-1.6); normal bone marrow cells were significantly less sensitive to the cytotoxic effects of LC-1 (P = 0.0002). Treatment of multiple myeloma cell lines with LC-1 resulted in decreased nuclear localization of the NF-kappaB subunit Rel A and the inhibition of NF-kappaB target genes. In addition, LC-1 showed synergy with melphalan, bortezomib, and doxorubicin (combination indices of 0.72, 0.61, and 0.78, respectively), and was more effective when cells were cultured on fibronectin. These data show that LC-1 has activity in multiple myeloma cell lines and primary multiple myeloma cells, and its ability to inhibit NF-kappaB seems important for its cytotoxic effects. Furthermore, LC-1-induced transcriptional suppression of survivin and MCL1 provides a potential explanation for its synergy with conventional agents.
多发性骨髓瘤用传统疗法仍然无法治愈。因此，显然需要新的治疗方法。在这项研究中，我们评估了新型 NF-κB 抑制剂 LC-1 在多发性骨髓瘤细胞系和多发性骨髓瘤患者来源的浆细胞中的作用。LC-1 对多发性骨髓瘤细胞系 H929、U266 和 JJN3 具有细胞毒性，并呈剂量依赖性诱导细胞凋亡，在 48 小时培养后总体 LD50 为 3.6 μmol/L（±1.8）。通过 CD38 和 CD138 阳性鉴定的原代多发性骨髓瘤细胞的 LC-1 LD50 平均值为 4.9 μmol/L（±1.6）；正常骨髓细胞对 LC-1 的细胞毒性作用明显不敏感（P=0.0002）。LC-1 处理多发性骨髓瘤细胞系导致 NF-κB 亚基 Rel A 的核定位减少和 NF-κB 靶基因的抑制。此外，LC-1 与美法仑、硼替佐米和阿霉素表现出协同作用（组合指数分别为 0.72、0.61 和 0.78），并且在细胞在纤维连接蛋白上培养时更有效。这些数据表明 LC-1 在多发性骨髓瘤细胞系和原代多发性骨髓瘤细胞中具有活性，其抑制 NF-κB 的能力对于其细胞毒性作用很重要。此外，LC-1 诱导的 survivin 和 MCL1 的转录抑制为其与传统药物的协同作用提供了潜在的解释。
