Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma
Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma
复制标题
DOI：
10.1158/1078-0432.ccr-06-1331
复制
发表时间：
2006-11-15
影响因子：
11.5
通讯作者：
Ghobrial, Irene M.
中科院分区：
文献类型：
--
作者：
Francis, Lanie K.;Alsayed, Yazan;Ghobrial, Irene M.
目的：磷脂酰肌醇 3-激酶/AKT/哺乳动物雷帕霉素靶蛋白 (mTOR) 通路和热休克蛋白家族在多发性骨髓瘤中上调，并且都是细胞周期蛋白 D/视网膜母细胞瘤通路（多发性骨髓瘤的关键通路）的调节因子。 mTOR 和 HSP90 蛋白抑制剂在多发性骨髓瘤中表现出体外和体内单药活性。我们的目的是确定 mTOR 抑制剂雷帕霉素和 HSP90 抑制剂 17-烯丙氨基-17-去甲氧基格尔德霉素 (17-AAG) 对多发性骨髓瘤细胞的影响。 实验设计：将多发性骨髓瘤细胞系与雷帕霉素 (0.1-100 nmol/L) 和 17-AAG (100-600 nmol/L) 单独孵育，并在 结果：在这项研究中，我们发现雷帕霉素和 17-AAG 的组合可协同抑制增殖，诱导细胞凋亡和细胞周期停滞，诱导聚 (ADPribose) 聚合酶和 caspase-8/caspase-9 的裂解，以及磷脂酰肌醇 3-激酶/AKT/mTOR 和细胞周期蛋白中的信号传导失调 D1/视网膜母细胞瘤途径。此外，我们还发现 17-AAG 和雷帕霉素均可抑制血管生成和破骨细胞形成，表明这些药物不仅针对多发性骨髓瘤细胞，还针对骨髓微环境。结论：这些研究为该组合对多发性骨髓瘤患者的潜在临床评估提供了基础。
Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells.Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination.Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADPribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment.Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.