Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib.
Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib.
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DOI：
10.1038/bcj.2012.13
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发表时间：
2012-04
影响因子：
12.8
通讯作者：
Shiotsu, Y.
中科院分区：
文献类型：
--
作者：
Ishii, T.;Seike, T.;Nakashima, T.;Juliger, S.;Maharaj, L.;Soga, S.;Akinaga, S.;Cavenagh, J.;Joel, S.;Shiotsu, Y.
热休克蛋白 90 (Hsp90) 是一个有前景的抗肿瘤治疗靶点。我们之前报道了一种新型 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。在这项研究中，我们在体外和体内检查了 KW-2478 和蛋白酶体抑制剂硼替佐米的联合作用。在体外，KW-2478 增强了 MM 细胞系和原代患者 MM 细胞中硼替佐米诱导的细胞生长抑制。 KW-2478 和硼替佐米的组合也在 MM 细胞系中诱导 caspase 激活。有趣的是，这种组合协同增强了人MM细胞和外周血单核细胞中Hsp70B（Hsp70的同源物）的表达，表明Hsp70B可以作为Hsp90和蛋白酶体抑制剂组合的替代生物标志物。在体内，KW-2478 与硼替佐米的组合在皮下接种的人骨髓瘤模型中显示出协同抗肿瘤活性，且体重没有显着下降。此外，该组合还显示出在原位骨髓瘤模型中协同减少骨髓中的肿瘤负荷。我们的结果强烈表明，KW-2478 与硼替佐米的组合可以表现出增强的针对人骨髓瘤的抗肿瘤活性。
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.
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影响因子：
6.5
作者：
Richardson PG;Badros AZ;Jagannath S;Tarantolo S;Wolf JL;Albitar M;Berman D;Messina M;Anderson KC
通讯作者：
Anderson KC
DOI：
10.1016/j.bbrc.2008.10.112
发表时间：
2008-12-26
影响因子：
3.1
作者：
Nakashima, Takayuki;Tanaka, Rieko;Hara, Mitsunobu
通讯作者：
Hara, Mitsunobu
影响因子：
11.5
作者：
Nakashima, Takayuki;Ishii, Toshihiko;Shiotsu, Yukimasa
通讯作者：
Shiotsu, Yukimasa
影响因子：
--
作者：
Neznanov N;Komarov AP;Neznanova L;Stanhope-Baker P;Gudkov AV
通讯作者：
Gudkov AV
影响因子：
11.4
作者：
Kastritis, E.;Zervas, K.;Dimopoulos, M. A.
通讯作者：
Dimopoulos, M. A.