SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK
SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK
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DOI：
10.1182/blood-2008-04-151928
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发表时间：
2009-01-22
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Okawa, Yutaka;Hideshima, Teru;Anderson, Kenneth C.
热休克蛋白90（Hsp 90）作为维持客户蛋白的构象稳定性所需的分子伴侣，调节细胞增殖、存活和凋亡。在这里，我们研究了Hsp 90抑制在多发性骨髓瘤（MM）和其他血液肿瘤中的生物学意义，使用口服的新型小分子抑制剂SNX-2112，其相对于17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）具有独特的活性。SNX-2112引发生长抑制，比17-AAG更有效地对抗MM和其他恶性肿瘤。它通过半胱天冬酶-8、-9、-3和聚（ADP-核糖）聚合酶裂解诱导细胞凋亡。SNX-2112抑制精氨酸诱导的Akt和细胞外信号相关激酶（ERK）活化，并克服白细胞介素-6、胰岛素样生长因子-1和骨髓基质细胞赋予的生长优势。重要的是，SNX-2112通过废除eNOS/Akt途径抑制人脐静脉内皮细胞的管形成，并通过下调ERK/c-fos和PU显著抑制破骨细胞形成。最后，通过其前药SNX-5422递送的SNX-2112在异种移植鼠模型中抑制MM细胞生长和骨髓瘤存活。我们的研究结果表明，SNX-2112对Hsp 90的阻断不仅抑制sMM细胞的生长，而且在骨髓微环境中起作用以阻断血管生成和破骨细胞生成。总之，我们的数据为SNX-2112改善MM和其他血液恶性肿瘤患者结局的临床研究提供了框架。（血。2009; 113：846-855）
Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintaining the conformational stability of client proteins regulating cell proliferation, survival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hematologic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17-allyamino-17-demethoxy-geldanamycin (17-AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apoptosis via caspase-8, -9, -3, and poly (ADP-ribose) polymerase cleavage. SNX-2112 inhibits cytokine-inducedAkt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibitsMMcell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies. (Blood. 2009; 113:846-855)