Synergistic Cytotoxicity of Lenalidomide and Dexamethasone in Mantle Cell Lymphoma via Cereblon-dependent Targeting of the IL-6/STAT3/PI3K Axis
Synergistic Cytotoxicity of Lenalidomide and Dexamethasone in Mantle Cell Lymphoma via Cereblon-dependent Targeting of the IL-6/STAT3/PI3K Axis
复制标题
来那度胺和地塞米松通过 Cereblon 依赖性 IL-6/STAT3/PI3K 轴靶向治疗套细胞淋巴瘤的协同细胞毒性
DOI：
10.1016/j.ebiom.2017.04.037
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发表时间：
2017-06-01
期刊：
影响因子：
11.1
通讯作者：
Xie, Yanhui
中科院分区：
文献类型：
--
作者：
Ma, Jiexian;Wu, Kefei;Xie, Yanhui
在我们的中心，复发性套细胞淋巴瘤（MCL）可以通过连续低剂量来那度胺和短期高剂量地塞米松（LD方案）组成的维持治疗来治疗，该方案获得了良好的反应（更长的总生存期和无进展生存期）和低毒性。Cereblon可能是来那度胺和地塞米松的靶向药物，通过抑制白细胞介素-6/信号转导和转录激活因子3（IL-6/STAT 3）、磷脂酰肌醇3-激酶（PI 3 K）/AKT和AKT 2/叉头盒O3（FOXO 3A）/BCL 2样11（BIM）通路，在MCL中产生协同细胞毒性。这两种药物协同抑制相同的途径，但通过不同的网站。Cereblon在大多数MCL组织中表达（阳性率91.3%）。此外，cereblon表达与LD方案敏感性正相关：长期来那度胺暴露下调cereblon，并在体外诱导对来那度胺、地塞米松、阿糖胞苷、顺铂和甲氨蝶呤的多药耐药。去除来那度胺使来那度胺耐药MCL细胞对来那度胺和地塞米松重新敏感。我们的研究表明，LD方案与其他方案轮换将改善MCL维持治疗。(C)2017由Elsevier B. V.出版
At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the inter-leukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy. (C) 2017 Published by Elsevier B.V.