EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #73002_C
mTOR通路抑制剂；抑制mTOR
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总览
AZD8055是一种有效、选择性强的 ATP 竞争性哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，IC₅₀值为0.8 nM （Chresta等）。针对所有PI3K同工酶，对mTOR具有约1000倍的选择性，且在高达 10 µM 的浓度下对 260 种激酶的测试中未显示出活性（Chresta 等）。
癌症研究
·在体外可抑制 A549 和 H838 小细胞肺癌细胞系的增殖，并在口服给药后抑制多种人类肿瘤异种移植模型的小鼠肿瘤生长（Chresta 等）。
·可抑制细胞增殖、促进细胞死亡，并减少他莫昔芬耐药（TamR）和雌激素剥夺耐药（MCF7-X）乳腺癌细胞系的迁移能力（Jordan 等）。
·诱导人喉癌细胞系（Hep-2）凋亡并抑制增殖（Zhao等）。
·联合ABT-737使用时，通过抑制髓系白血病细胞分化蛋白的表达，协同诱导横纹肌肉瘤（RMS）中的细胞凋亡(MCL1；Preuss等)。
·可抑制 HeLa（人宫颈癌细胞系）的增殖和糖酵解，诱导细胞凋亡（Li等人）。
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症
CAS 编号
1009298-09-2
化学式
C₂₅H₃₁N₅O₄
纯度
≥98%
通路
mTOR
靶点
mTOR
产品说明书及文档
请在《产品说明书》中查找相关支持信息和使用说明，或浏览下方更多实验方案。
相关材料与文献
技术资料 (2)
文献 (5)
Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro. Breast cancer research : BCR 2014
Abstract
INTRODUCTION: Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells. METHODS: In vitro models of tamoxifen (TamR) or oestrogen deprivation resistance (MCF7-X) were treated with RAD001 or AZD8055 alone or combined with anti-hormone fulvestrant. Endpoints included growth, cell proliferation (Ki67), viability and migration, with PI3K/AKT/mTOR signalling impact monitored by Western blotting. Potential ER cross-talk was investigated by immunocytochemistry and RT-PCR. RESULTS: RAD001 was a poor growth inhibitor of MCF7-derived TamR and MCF7-X cells (IC50 ≥1 μM), rapidly inhibiting mTORC1 but not mTORC2/AKT signalling. In contrast AZD8055, which rapidly inhibited both mTORC1 and mTORC2/AKT activity, was a highly effective (P textless0.001) growth inhibitor of TamR (IC50 18 nM) and MCF7-X (IC50 24 nM), and of a further T47D-derived tamoxifen resistant model T47D-tamR (IC50 19 nM). AZD8055 significantly (P textless0.05) inhibited resistant cell proliferation, increased cell death and reduced migration. Furthermore, dual treatment of TamR or MCF7-X cells with AZD8055 plus fulvestrant provided superior control of resistant growth versus either agent alone (P textless0.05). Co-treating with AZD8055 alongside tamoxifen (P textless0.01) or oestrogen deprivation (P textless0.05) also effectively inhibited endocrine responsive MCF-7 cells. Although AZD8055 inhibited oestrogen receptor (ER) ser167 phosphorylation in TamR and MCF7-X, it had no effect on ER ser118 activity or expression of several ER-regulated genes, suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER. CONCLUSIONS: This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance.
mTOR inhibitor AZD8055 inhibits proliferation and induces apoptosis in laryngeal carcinoma. International journal of clinical and experimental medicine 2014
Abstract
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, against all class I phosphatidylinositol3-kinase (PI3K) and other members of the PI3K-like kinase family. The study was to determine the effect of AZD8055 on proliferation and apoptosis on Hep-2, a human laryngeal cancer cell line and to investigate the underlying mechanism(s) of action. Hep-2 cells were treated with AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Rhodamine 123 and TUNEL staining were used to determine mitochondrial membrane potential and cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Protein expressions were examined by western blotting. Treatment with AZD8055 inhibited proliferation and induced apoptosis in Hep-2 cells in a dose- and time-dependent manner. During the prolonged treatment with AZD8055, AZD8055 inhibits the mammalian target of rapamycin mTOR. Further experiments showed which signaling cascade p-4EBP1 and substrate EIF4E as well as downstream proteins were down regulated. Furthermore, our study showed that the expression profiles of various BH3-only proteins including Bid, Bad, and Bim, apoptosis regulatory protein cleaved caspase3 was up regulated in a time-dependent manner in Hep-2 cells treated with AZD8055. Thus, in vitro, AZD8055 potently inhibits proliferation and induces apoptosis in head and neck squamous cell carcinoma.
The mTOR inhibitor AZD8055 inhibits proliferation and glycolysis in cervical cancer cells. Oncology letters 2013
Abstract
The aim of the present study was to determine the effect of AZD8055 on proliferation, apoptosis and glycolysis in the human cervical cancer cell line HeLa and to investigate the underlying mechanism(s) of action. HeLa human cervical cancer cells were treated with 10 nM AZD8055 for 24, 48 or 72 h. MTT was used to determine cell proliferation. Annexin V/propidium iodide staining was used to determine cell apoptosis analyzed by fluorescence-activated cell sorting (FACS). Glycolytic activity was determined by measuring the activity of the key enzyme lactate dehydrogenase (LDH) and lactate production. RNA and protein expression were examined by qRT-PCR and western blotting, respectively. Treatment with AZD8055 inhibited proliferation and glycolysis, and induced apoptosis in HeLa cells in a time-dependent manner. During the prolonged treatment with AZD8055, the phosphorylation of mammalian target of rapamycin (mTOR) C1 substrates p70S6K and phosphorylation of the mTORC2 substrate Akt were deregulated, suggesting that the activity of mTOR was downregulated. Furthermore, our study showed that the expression of miR-143 was upregulated in a time-dependent manner in HeLa cells treated with AZD8055. In summary, the present study reveals a novel antitumor mechanism of AZD8055 in HeLa human cervical cancer cells.
更多信息
| 种属 | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 1009298-09-2 |
| Chemical Formula | C₂₅H₃₁N₅O₄ |
| 纯度 | ≥ 98% |
| Target | mTOR |
| Pathway | mTOR |
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