Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells
Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells
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DOI：
10.1158/0008-5472.can-04-2740
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Fine, HA
中科院分区：
文献类型：
--
作者：
Hui, AM;Wei, Z;Fine, HA
他莫昔芬是选择性雌激素受体调节剂（SERM）家族的成员，广泛用于治疗表达乳腺癌的雌激素受体（ER）。以前已经显示，高剂量的他莫昔芬对神经胶质瘤细胞具有细胞毒性活性，但是该作用是药物特异性还是代表Serm的一般特性。在这项研究中，我们证明了他莫昔芬和CC-8490是一种具有SERM活性的新型苯甲酸酯，以剂量和时间依赖性的方式诱导神经胶质瘤细胞凋亡。此外，他莫昔芬和CC-8490的给药可抑制体内肿瘤的生长，并扩展神经胶质瘤异种移植模型中的动物存活。检查的八个神经瘤细胞系都没有表达ER-α或-beta，这表明了他莫昔芬和CC-8490诱导的胶质瘤细胞凋亡的机制与ER信号通路无关。互补的DNA微阵列表达谱分析使我们能够鉴定由他莫昔芬和CC-8490特别调节的基因集，而不是由其他凋亡刺激（包括核因子（NF）-KAPPAB）具有其靶基因IEX-3，SOD2，IL6，IL6和IL6和IL6和IL6和IL6和IL6，IL6和IL6，IL6和IL6，IL6和IL6，IL6和IL6，IL6和IL6，和ILS-kappab。 IL8。我们证明，NF-kappab激活的抑制显着增强了SERM诱导的凋亡，这表明NF-kappab在保护神经胶质瘤细胞免受Serm诱导的细胞毒性症中的作用。这些发现首次表明，他莫昔芬以外的其他Serm可以在体外和体内诱导神经胶质瘤细胞凋亡，并且Serm对治疗恶性神经胶质瘤的临床疗效可以通过同时抑制NF-kappab途径来增强恶性神经胶质瘤。
Tamoxifen, a member of the selective estrogen receptor modulator (SERM) family, is widely used in the treatment of estrogen receptor (ER)-expressing breast cancer. It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells, but whether this effect is drug specific or represents a general property of SERMs is unknown. In this study, we demonstrate that tamoxifen and CC-8490, a novel benzopyranone with SERM activity, induce glioma cell apoptosis in a dose- and time-dependent manner. Moreover, administration of tamoxifen and CC-8490 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models. None of the eight glioma cell lines examined express either ER-alpha or -beta, suggesting the mechanism for tamoxifen- and CC-8490-induced glioma cell apoptosis is independent of the ER signaling pathway. Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and CC-8490, and not by other apoptotic stimuli, including nuclear factor (NF)-kappaB with its target genes IEX-3, SOD2, IL6, and IL8. We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis, suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity. These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway.