Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity.
Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity.
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发表时间：
2003-12
期刊：
影响因子：
11.2
通讯作者：
K. Bisht;C. Bradbury;D. Mattson;A. Kaushal;A. Sowers;S. Markovina;Karen L. Ortiz;Leah K Sieck;J. Isaacs;M. Brechbiel;James B. Mitchell;L. Neckers;D. Gius
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作者：
K. Bisht;C. Bradbury;D. Mattson;A. Kaushal;A. Sowers;S. Markovina;Karen L. Ortiz;Leah K Sieck;J. Isaacs;M. Brechbiel;James B. Mitchell;L. Neckers;D. Gius
安莎霉素抗生素抑制热休克蛋白（HSP）90的功能，导致几种细胞内蛋白质的选择性降解，这些蛋白质调节增殖、细胞周期调节和促生存信号级联反应等过程。HSP 90以前已被鉴定为抗癌剂（包括电离辐射（IR））的分子靶标。因此，我们假设抑制HSP 90的安莎霉素格尔德霉素及其17-烯丙基氨基-17-去甲氧基类似物（17-AAG）将增强肿瘤细胞对IR的细胞毒性的敏感性。（HeLa和SiHa）与格尔德霉素和17-AAG的组合导致细胞毒性，并且当与IR组合时，增强辐射响应，每种效应的时间范围为药物暴露后6至48小时。此外，小鼠体内模型使用17-AAG在临床上可达到的浓度产生的结果，证明了体外放射增敏研究的单一和分次照射过程。IR诱导的细胞死亡的增加似乎可归因于程序性和非程序性细胞死亡的组合。我们还测量了几种促生存和凋亡信号蛋白的总水平。Akt 1、细胞外信号调节激酶-1、Glut-1、HER-2/neu、林恩、cAMP依赖性蛋白激酶、Raf-1和血管内皮生长因子表达在17-AAG处理的细胞中下调，将这些因子鉴定为分子标记物和潜在的治疗靶点。最后，一系列的永生化和人乳头瘤病毒转化的细胞系被用来证明，17-AAG的放射增敏作用仅限于转化细胞，这表明可能的差异细胞毒性效应。这项工作表明，改变HSP 90功能诱导显着的肿瘤细胞毒性和放射增敏，这表明了潜在的治疗效用。
Ansamycin antibiotics inhibit function of the heat shock protein (HSP) 90, causing selective degradation of several intracellular proteins regulating such processes as proliferation, cell cycle regulation, and prosurvival signaling cascades. HSP90 has been identified previously as a molecular target for anticancer agents, including ionizing radiation (IR). Therefore, we hypothesized that the ansamycin geldanamycin and its 17-allylamino-17-demethoxy analog (17-AAG), which inhibit HSP90, would enhance tumor cell susceptibility to the cytotoxicity of IR. Treatment of two human cervical carcinoma cell lines (HeLa and SiHa) with geldanamycin and 17-AAG resulted in cytotoxicity and, when combined with IR, enhanced the radiation response, each effect with a temporal range from 6 to 48 h after drug exposure. In addition, mouse in vivo models using 17-AAG at clinically achievable concentrations yielded results that paralleled the in vitro radiosensitization studies of both single and fractioned courses of irradiation. The increase in IR-induced cell death appears to be attributable to a combination of both programmed and nonprogrammed cell death. We also measured total levels of several prosurvival and apoptotic signaling proteins. Akt1, extracellular signal-regulated kinase-1, Glut-1, HER-2/neu, Lyn, cAMP-dependent protein kinase, Raf-1, and vascular endothelial growth factor expression were down-regulated in 17-AAG-treated cells, identifying these factors as molecular markers and potential therapeutic targets. Finally, a series of immortalized and human papillomavirus-transformed cell lines were used to demonstrate that the radiosensitizing effects of 17-AAG were limited to transformed cells, suggesting a possible differential cytotoxic effect. This work shows that altered HSP90 function induces significant tumor cytotoxicity and radiosensitization, suggesting a potential therapeutic utility.