17-Allyamino-17-demethoxygeldanamycin and 17-NN-dimethyl ethylene diamine-geldanamycin have cytotoxic activity against multiple gynecologic cancer cell types
17-Allyamino-17-demethoxygeldanamycin and 17-NN-dimethyl ethylene diamine-geldanamycin have cytotoxic activity against multiple gynecologic cancer cell types
复制标题
DOI：
10.1016/j.ygyno.2004.10.009
复制
发表时间：
2005-02-01
影响因子：
4.7
通讯作者：
Lin, JY
中科院分区：
文献类型：
--
作者：
Gossett, DR;Bradley, MS;Lin, JY
目标。HSP90是一种在许多癌症中过度表达的细胞伴侣蛋白。HSP90有助于各种病人的正确折叠。其中很多是癌蛋白。HSP90已被证明在子宫内膜，卵巢中升高。和乳房枪骑兵。此外，已知HSP90可以稳定癌蛋白Akt；Akt通路的破坏在妇科恶性肿瘤中很常见。我们试图评估热休克蛋白90抑制剂在妇科肿瘤中的有效性。我们测试了两种HSP90抑制剂17-AAG和17-DMAG对妇科癌细胞系（四种子宫内膜癌、一种宫颈癌、一种卵巢癌和一种乳腺癌）的作用。我们进行了Western blots来确定处理对HSP90客户蛋白水平和PARP切割的影响。采用3-（4,5-二甲基噻唑-2-基）-2.5-二甲基溴化四唑（MTT）测定细胞活力，流式细胞术定量细胞周期分布和凋亡情况。在17-AAG或17-DMAG治疗后，我们检测到HSP90水平没有下降。其他癌蛋白的水平也随着治疗而降低：磷酸化和总Akt，以及Met。一个细胞系出现G(1)阻滞，五个细胞系出现G(2)阻滞。所有细胞均表现出不同程度的凋亡细胞死亡，通过检测PARP切割证实了这一点。不同细胞系对药物的敏感性不同，治疗后细胞凋亡20%至90%不等。我们的数据表明17-DMAG可能比17- aag更有效。HSP90抑制剂是妇科肿瘤细胞有效的细胞毒性药物。进一步的体内模型系统测试是必要的，目标是最终转化为妇科肿瘤患者的临床试验。(C) 2004爱思唯尔公司版权所有。
Objective. HSP90 is a cellular chaperone that is overexpressed in many cancers. HSP90 assists in proper folding of a variety of clients. many of which are oncoproteins. HSP90 has been shown to be elevated in endometrial, ovarian. and breast Lancer. Furthermore, HSP90 is known to stabilize the oncoprotein Akt; disruptions of the Akt pathway are common in gynecologic malignancies. We sought to evaluate the effectiveness of HSP90 inhibitors in gynecologic cancer.Methods. We tested two HSP90 inhibitors, 17-AAG and 17-DMAG, against gvnecologic cancer cell lines (four endometrial, one cervical, one ovarian, and one breast cancer line). We performed Western blots to determine effects of treatment on levels of HSP90 client proteins and PARP cleavage. 3-(4,5-Dimethylthiazol-2-yl)-2.5-diptletlyltetrazolium bromide (MTT) assays were used to assess cell viability, and flow cytometry to quantitate cell-cycle distribution and apoptosis.Results. After treatment with 17-AAG or 17-DMAG, we detected no decrease in HSP90 levels. Levels of other oncoproteins did decrease with treatment: phosphorylated and total Akt, and Met. One cell line underwent G(1) arrest, and five showed G(2) arrest. All showed some level of apoptotic cell death, which was confirmed by detection of PARP cleavage. Sensitivity to the drugs varied among cell lines, ranging from 20% to 90% apoptosis after treatment. Our data suggest that 17-DMAG may be more potent than 17-AAG.Conclusions. HSP90 inhibitors are effective cytotoxic agents in gynecologic cancer cells. Further testing in in vivo model systems is warranted, with the goal of eventual translation to clinical trials in gynecologic oncology patients. (C) 2004 Elsevier Inc. All rights reserved.