Jian Yuan, Gao Wen, Geng Chuanying, Zhou Huixing, Leng Yun, Li Yanchen, Chen Wenming
Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.
Multiple Myeloma Research Center of Beijing, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.
Oncol Lett. 2017 Sep;14(3):3243-3248. doi: 10.3892/ol.2017.6502. Epub 2017 Jun 30.
The mechanism of the anti-myeloma effect of the immunomodulatory drug lenalidomide relies upon the binding of lenalidomide or an analogue to cereblon (CRBN) ubiquitin ligase, which inhibits it and results in the degradation of Ikaros-family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). To determine whether the traditional Chinese medicine arsenic trioxide, could potentiate sensitivity of multiple myeloma (MM) cells to lenalidomide and identify the mechanism by which this happens, the present study investigated how arsenic trioxide affected CRBN on MM cell lines and examined the anti-myeloma effect and mechanism in the combination of arsenic trioxide and lenalidomide. The present study revealed that arsenic trioxide upregulates the transcription and protein levels of CRBN, the anti-myeloma target of lenalidomide, thus potentiating the sensitivity of multiple myeloma cells to lenalidomide and enhancing the lenalidomide-dependent degradation of IKZF1 and IKZF3. The results of the present study indicate that clinical trials of this combination therapy could take place within the near future, with the aim of improving MM patient outcome.
免疫调节药物来那度胺的抗骨髓瘤作用机制依赖于来那度胺或其类似物与脑啡肽（CRBN）泛素连接酶的结合，这会抑制该酶并导致伊卡罗斯家族锌指蛋白1和3（IKZF1和IKZF3）的降解。为了确定中药三氧化二砷是否能增强多发性骨髓瘤（MM）细胞对来那度胺的敏感性并确定其发生机制，本研究调查了三氧化二砷如何影响MM细胞系上的CRBN，并研究了三氧化二砷与来那度胺联合使用时的抗骨髓瘤作用及机制。本研究表明，三氧化二砷上调了来那度胺的抗骨髓瘤靶点CRBN的转录水平和蛋白水平，从而增强了多发性骨髓瘤细胞对来那度胺的敏感性，并增强了来那度胺依赖性的IKZF1和IKZF3降解。本研究结果表明，这种联合疗法的临床试验可能在不久的将来开展，目的是改善MM患者的预后。
