Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: An orally bioavailable heat shock protein 90 modulator
Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: An orally bioavailable heat shock protein 90 modulator
复制标题
DOI：
10.1158/1078-0432.ccr-03-0795
复制
发表时间：
2004-07-15
影响因子：
11.5
通讯作者：
Giavazzi, R
中科院分区：
文献类型：
--
作者：
Kaur, G;Belotti, D;Giavazzi, R
目的：本研究的目的是研究 17-(二甲氨基乙基氨基)-17-去甲氧基格尔德霉素 (17-DMAG；NSC707545)（一种水溶性苯醌安沙霉素）的抗血管生成特性。 实验设计：评估 17-DMAG 在体内的活性，以抑制皮下成纤维细胞生长因子 (FGF)-2 诱导的血管生成。将基质胶植入小鼠体内。体外，在FGF-2中测试17-DMAG对内皮细胞（人脐静脉内皮细胞；HUVEC）的活性；血管内皮生长因子 (VEGF) 诱导的增殖和凋亡、运动和细胞外基质侵袭；以及基质胶中毛细管样结构的排列。通过蛋白质印迹法检测 FGF-2 和 VEGF 刺激的 HUVEC 中热休克蛋白 (Hsp)90 和客户蛋白的蛋白水平。结果：每日口服 17-DMAG 以剂量依赖性方式影响 Matrigel 中的血管生成反应。基质胶植入物中的血红蛋白含量被显着抑制，组织学分析证实CD31(+)内皮细胞以及脐带和含红细胞血管中组织的结构减少。在体外，该化合物以剂量依赖性方式抑制 HUVEC 的迁移和细胞外基质侵袭性及其在基质胶中形成毛细血管样结构的能力。 17-DMAG 治疗还抑制 FGF-2 和 VEGF 诱导的 HUVEC 增殖并导致细胞凋亡。因此，Hsp90 直接客户蛋白（pAkt 和 c-Raf-1）或其下游底物（包括 pERK）的表达也受到影响。 17-DMAG 持续增加 Hsp70 的表达。在整个研究中，17-烯丙氨基-17-去甲氧基格尔德霉素（17-AAG；NSC3-30507）获得了类似的结果，该化合物目前正在进行临床试验。结论：我们表明，Hsp90 靶向药物 17-DMAG 和 17-AAG 抑制血管生成。体外对内皮细胞功能的强烈影响表明 17-DMAG/17-AAG 的抗血管生成活性也可能是由于对内皮细胞的直接影响。 17-DMAG 的口服生物利用度可能有利于研究该化合物在抗血管生成和抗增殖终点临床试验中的潜力。
Purpose: The purpose of this study was to investigate the antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; NSC707545), a water-soluble benzoquinone ansamycin.Experimental Design: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c. implanted Matrigel in mice. In vitro, the activity of 17-DMAG on endothelial cells (human umbilical vein endothelial cells; HUVEC) was tested in FGF-2; and vascular endothelial growth factor (VEGF)induced proliferation and apoptosis, motility, and extracellular matrix invasion; and on the alignment of capillary like structures in Matrigel. The protein level of heat shock protein (Hsp)90 and client proteins was examined by Western blot in FGF-2 and VEGF-stimulated HUVEC.Results: Daily oral administration of 17-DMAG affected the angiogenic response in Matrigel in a dose-dependent manner. The hemoglobin content in the Matrigel implants was significantly inhibited, and the histological analysis confirmed a decrease of CD31(+) endothelial cells and of structures organized in cord and erythrocyte-containing vessels. In vitro, the compound inhibited dose-dependently the migration and the extracellular matrix-invasiveness of HUVEC and their capacity to form capillary like structures in Matrigel. 17-DMAG treatment also inhibited FGF-2 and VEGF-induced HUVEC proliferation and resulted in apoptosis. Accordingly, the expression of Hsp90 direct client proteins (pAkt and c-Raf-1) or their downstream substrates including pERK was also affected. 17-DMAG consistently increased the expression of Hsp70. Throughout the study similar results were obtained with 17-allylamino-17-demethoxygeldanamycin (17-AAG; NSC3-30507), the analog compound currently undergoing clinical trials.Conclusions: We show that the Hsp90 targeting agents 17-DMAG and 17-AAG inhibit angiogenesis. The strong effects on endothelial cell functions, in vitro, indicate that the antiangiogenic activity of 17-DMAG/17-AAG could also be due to a direct effect on endothelial cells. The oral bioavailability of 17-DMAG might be of advantage in investigating the potential of this compound in clinical trials with antiangiogenic as well as antiproliferative endpoints.