Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model
Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model
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DOI：
10.1158/0008-5472.can-12-0658
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发表时间：
2012-10-15
期刊：
影响因子：
11.2
通讯作者：
Panaretakis, Theocharis
中科院分区：
文献类型：
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作者：
Kharaziha, Pedram;De Raeve, Hendrik;Panaretakis, Theocharis
多发性骨髓瘤（MM）是一种B细胞恶性肿瘤，其特征在于骨髓内克隆性浆母细胞/浆细胞的扩增，其依赖于多种信号级联，包括酪氨酸激酶激活途径，以增殖和逃避细胞死亡。尽管出现了新的治疗策略，但多发性骨髓瘤目前仍无法治愈。因此，通过使用多酪氨酸激酶抑制剂（TKI）索拉非尼靶向几个信号级联的新方法似乎是多发性骨髓瘤的有希望的治疗方法。在这里，我们发现索拉非尼以半胱天冬酶依赖和非依赖的方式诱导多发性骨髓瘤细胞系和富含CD 138（+）的原发性多发性骨髓瘤患者样本中的细胞死亡。此外，索拉非尼在5 T33 MM小鼠模型中具有强的抗肿瘤和抗血管生成活性，导致总生存期增加。多发性骨髓瘤细胞在索拉非尼的作用下发生自噬，抑制这种细胞保护途径增强了这种TKI的疗效。多发性骨髓瘤中的存活因子Mcl-1在蛋白水平上被索拉非尼下调，允许执行细胞死亡，因为该蛋白的异位过表达保护多发性骨髓瘤细胞。索拉非尼同时靶向Mcl-1和拮抗剂ABT 737同时靶向Bcl-2/Bcl-xL可提高索拉非尼在多发性骨髓瘤细胞系和骨髓基质细胞存在下富含CD 138（+）的原代细胞中的疗效。总之，我们的数据支持使用索拉非尼作为一种新的治疗方式对人类多发性骨髓瘤，其疗效可能会加强与ABT 737组合。Cancer Res; 72（20）; 5348-62. (C)2012年AACR。
Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, multiple myeloma remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multi-tyrosine kinase inhibitor (TKI), sorafenib, seem a promising treatment approach for multiple myeloma. Here, we show that sorafenib induces cell death in multiple myeloma cell lines and in CD138(+)-enriched primary multiple myeloma patient samples in a caspase-dependent and -independent manner. Furthermore, sorafenib has a strong antitumoral and -angiogenic activity in the 5T33MM mouse model leading to increased overall survival. Multiple myeloma cells undergo autophagy in response to sorafenib, and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in multiple myeloma, is downregulated at the protein level by sorafenib allowing for the execution of cell death, as ectopic overexpression of this protein protects multiple myeloma cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in multiple myeloma cell lines and CD138(+)-enriched primary cells in the presence of bone marrow stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human multiple myeloma, and its efficacy may be potentiated in combination with ABT737. Cancer Res; 72(20); 5348-62. (C) 2012 AACR.