Department of Gynaecology and Obstetrics, Georg-August University, Göttingen, Germany.
Anticancer Res. 2010 Jun;30(6):2025-31.
In patients with advanced estrogen-dependent type I endometrial cancer (EC), pharmacological treatment with progestins or antiestrogens is recommended, but primary and secondary resistance are common. The aim of our study was to investigate single-agent and dual-agent therapeutic strategies in estrogen receptor-positive human EC cells.
Human EC cells Ishikawa and HEC1A were cultivated under estrogen-reduced conditions and exposed to 4-hydroxytamoxifen (OHT), fulvestrant, gefitinib, everolimus, and the AKT inhibitor perifosine. Effects of drugs were analyzed by proliferation and apoptosis assays. Additionally, we analyzed expression of aromatase, phosphatase and tensin homolog (PTEN), AKT and pAKT and G protein-coupled receptor 30 (GPR30).
Neither OHT nor fulvestrant inhibited cell growth, nor did they induce apoptosis. Gefitinib, everolimus and perifosine inhibited proliferation in all cell lines. Only perifosine induced apoptosis. In PTEN-positive HEC1A cells, combined treatment of gefitinib plus OHT showed increased antiproliferative effects. In Ishikawa cells, combined treatment of everolimus plus gefitinib had synergistic antiproliferative effects. The most effective single-agent treatment and the only drug that induced apoptosis was perifosine. Activation of AKT had no predictive value for the effects perifosine. Due to mutation of PTEN, activated AKT was highly expressed in Ishikawa cells and scarcely detectable in HEC1A cells.
Under estrogen-reduced conditions, growth of ER-positive EC cells can be reduced by inhibitors of AKT, mTOR and the erbB pathway, whereas antiestrogens have no effects. In PTEN-positive HEC1A cells, the absence of estradiol probably restores OHT-induced ER-mediated repression of nuclear co-activators and increases susceptibility to inhibitors of the erbB pathway. In PTEN-negative Ishikawa cells, OHT in combination with any drug had no effects, but inhibition of the PI3K/AKT/mTOR pathway by everolimus in combination with gefitinib showed synergistic effects.
在晚期雌激素依赖性 I 型子宫内膜癌（EC）患者中，推荐使用孕激素或抗雌激素进行药物治疗，但原发性和继发性耐药很常见。本研究旨在研究在雌激素受体阳性的人 EC 细胞中单药和双药治疗策略。
在雌激素减少的条件下培养人 EC 细胞 Ishikawa 和 HEC1A，并暴露于 4-羟基他莫昔芬（OHT）、氟维司群、吉非替尼、依维莫司和 AKT 抑制剂培非司亭。通过增殖和凋亡测定分析药物的作用。此外，我们还分析了芳香酶、磷酸酶和张力蛋白同源物（PTEN）、AKT 和 pAKT 以及 G 蛋白偶联受体 30（GPR30）的表达。
OHT 和氟维司群均不能抑制细胞生长，也不能诱导细胞凋亡。吉非替尼、依维莫司和培非司亭均能抑制所有细胞系的增殖。只有培非司亭诱导细胞凋亡。在 PTEN 阳性的 HEC1A 细胞中，吉非替尼联合 OHT 治疗显示出更强的抗增殖作用。在 Ishikawa 细胞中，依维莫司联合吉非替尼治疗具有协同的抗增殖作用。最有效的单药治疗和唯一诱导细胞凋亡的药物是培非司亭。AKT 的激活对培非司亭的作用没有预测价值。由于 PTEN 的突变，激活的 AKT 在 Ishikawa 细胞中高度表达，而在 HEC1A 细胞中几乎检测不到。
在雌激素减少的条件下，AKT、mTOR 和 erbB 通路抑制剂可降低 ER 阳性 EC 细胞的生长，而抗雌激素则无作用。在 PTEN 阳性的 HEC1A 细胞中，缺乏雌二醇可能会恢复 OHT 诱导的 ER 介导的核共激活物抑制，并增加对 erbB 通路抑制剂的敏感性。在 PTEN 阴性的 Ishikawa 细胞中，OHT 联合任何药物均无作用，但依维莫司联合吉非替尼抑制 PI3K/AKT/mTOR 通路显示出协同作用。
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