Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma.
Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma.
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DOI：
10.18632/oncotarget.1706
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Yeh CN
中科院分区：
文献类型：
--
作者：
Chen MH;Chiang KC;Cheng CT;Huang SC;Chen YY;Chen TW;Yeh TS;Jan YY;Wang HM;Weng JJ;Chang PM;Liu CY;Li CP;Chao Y;Chen MH;Huang CY;Yeh CN
在常见癌症中，PI 3 K/Akt/mTOR通路被过度激活，热休克蛋白（HSP）90过表达。我们假设靶向这两种途径可以杀死肝内胆管癌（CCA）细胞。采用免疫组织化学方法检测78例肝内胆管癌组织中HSP 90和PTEN蛋白的表达。CCA细胞系和硫代乙酰胺（TAA）诱导的CCA动物模型用NVP-AUY 922（HSP 90抑制剂）和NVP-BEZ 235（PI 3 K/mTOR抑制剂）单独或组合处理。HSP 90过表达和PTEN缺失均为肝内胆管癌患者的不良预后因素。HSP 90抑制剂NVP-AUY 922和PI 3 K/mTOR抑制剂NVP-BEZ 235的组合在诱导CCA细胞中的细胞死亡方面是协同的。NVP-AUY 922和NVP-BEZ 235的组合在CCA大鼠动物模型中引起肿瘤消退。这一组合不仅抑制了PI 3 K/Akt/mTOR通路，而且还诱导了ROS，这可能加剧了ER应激的恶性循环。我们的数据表明CCA治疗同时靶向PI 3 K/mTOR和HSP通路。
The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.
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NVP-AUY922：一种小分子 HSP90 抑制剂，在临床前乳腺癌模型中具有有效的抗肿瘤活性。
DOI：
10.1186/bcr1996
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
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作者：
Jensen MR;Schoepfer J;Radimerski T;Massey A;Guy CT;Brueggen J;Quadt C;Buckler A;Cozens R;Drysdale MJ;Garcia-Echeverria C;Chène P
通讯作者：
Chène P
影响因子：
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作者：
Markman B;Dienstmann R;Tabernero J
通讯作者：
Tabernero J
影响因子：
7.3
作者：
Marsh, Victoria;Davies, Emma J.;Clarke, Alan R.
通讯作者：
Clarke, Alan R.
DOI：
10.1158/1078-0432.ccr-11-1000
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Neckers L;Workman P
通讯作者：
Workman P
影响因子：
--
作者：
Neznanov N;Komarov AP;Neznanova L;Stanhope-Baker P;Gudkov AV
通讯作者：
Gudkov AV