文章：

Hsp90抑制剂KW-2478与硼替佐米联合抗多发性骨髓瘤活性研究

Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib

原文发布日期：2012-04-27

DOI: 10.1038/bcj.2012.13

类型: Original Article

开放获取: 是

英文摘要：

Heat shock protein 90 (Hsp90) is a promising target for anti-tumor therapy. We previously reported the anti-tumor activity of a novel Hsp90 inhibitor, KW-2478, in multiple myeloma (MM) as a single agent. In this study, we examined the combinational effect of KW-2478 and bortezomib, a proteasome inhibitor, in vitro and in vivo. In vitro, KW-2478 enhanced bortezomib-induced cell growth inhibition, both in MM cell lines and primary patient MM cells. The combination of KW-2478 and bortezomib also induced caspase activation in MM cell lines. Interestingly, the combination synergistically enhanced the expression of Hsp70B, a homolog of Hsp70, in human MM cells and peripheral blood mononuclear cells, indicating Hsp70B could be a surrogate biomarker for the combination of Hsp90 and proteasome inhibitors. In vivo, the combination of KW-2478 with bortezomib showed synergistic anti-tumor activity without significant body weight loss in a subcutaneously inoculated human myeloma model. Furthermore, the combination also showed synergistic reduction of tumor burden in bone marrow in an orthotopic myeloma model. Our results strongly suggest that combination of KW-2478 with bortezomib could exhibit enhanced anti-tumor activity against human myeloma.

摘要翻译： 

热休克蛋白90（Hsp90）是抗肿瘤治疗中一个颇具前景的靶点。我们先前报道过新型Hsp90抑制剂KW-2478作为单一药物在多发性骨髓瘤（MM）中的抗肿瘤活性。本研究通过体外和体内实验检测了KW-2478与蛋白酶体抑制剂硼替佐米的联合效应。在体外实验中，无论是在MM细胞系还是原代患者MM细胞中，KW-2478均能增强硼替佐米诱导的细胞生长抑制作用。两者联合还可在MM细胞系中诱导caspase活化。值得注意的是，该联合用药能协同增强人MM细胞及外周血单核细胞中Hsp70同源蛋白Hsp70B的表达，表明Hsp70B可能成为Hsp90抑制剂与蛋白酶体抑制剂联合治疗的替代生物标志物。在皮下接种的人骨髓瘤模型体内实验中，KW-2478与硼替佐米联合显示出协同抗肿瘤活性，且未引起显著体重下降。此外，在原位骨髓瘤模型中，该联合方案还能协同降低骨髓中的肿瘤负荷。我们的研究结果充分表明，KW-2478与硼替佐米联用可对人骨髓瘤产生增强的抗肿瘤活性。

原文链接：

Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib