Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells.
Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells.
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DOI：
10.1016/j.bbrc.2014.06.130
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发表时间：
2014-08-08
影响因子：
3.1
通讯作者：
Winfield, Leyte L.
中科院分区：
文献类型：
--
作者：
Payton-Stewart, Florastina;Tilghman, Syreeta L.;Williams, LaKeisha G.;Winfield, Leyte L.
雌激素受体(ERα和ERβ)是核受体超家族的成员。它们调节雌激素反应基因的转录，并介导许多与雌激素相关的疾病(如生育、骨质疏松症、癌症等)。因此，ER对于开发对激素敏感的人类乳腺癌的治疗和诊断工具具有潜在的有用的靶点。在这项工作中，两个基于苯并咪唑的磺胺类药物最初设计用于抑制前列腺癌的增殖，已通过细胞活力分析评估了它们对雌激素依赖和独立细胞系(MCF-7和MDA-MB 231)生长的调节能力。这些分子抑制了MCF-7细胞的生长，但对MDA-MB 231细胞的生长影响不同。虽然这两个分子都以剂量依赖的方式降低雌激素反应元件(ERE)的转录活性，但在MDA-MB-231细胞中相反的活性似乎表明，这两个分子可能通过交替的ER介导的途径发挥作用。此外，甲基类似物在ER基因表达阵列面板中对ERβ受体显示出适度的选择性。然而，napthyl类似物降低了基因表达。这些分子被对接在ERα拮抗剂和ERβ激动剂晶体结构的配体结合区域，以评估分子与受体相互作用的潜力。计算分析补充了转录活性和基因表达分析的结果，表明这些分子上调ERβ的活性，而下调ERα的活性。
Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulphonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel. However, the napthyl analog diminished gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules upregulate ERβ activity while down regulating that of ERα.
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影响因子：
4.3
作者：
Bocca, Claudia;Bozzo, Francesca;Miglietta, Antonella
通讯作者：
Miglietta, Antonella
影响因子：
3.5
作者：
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通讯作者：
Shirazi, Amir Nasrolahi
影响因子：
56.9
作者：
EVANS, RM
通讯作者：
EVANS, RM
影响因子：
--
作者：
Matthews, Jason;Gustafsson, Jan-Ake
通讯作者：
Gustafsson, Jan-Ake
DOI：
10.3109/14756366.2012.729828
发表时间：
2013-12-01
影响因子：
5.6
作者：
Rahim, Aisyah Saad Abdul;Salhimi, Salizawati Muhamad;Mat, Ishak B.
通讯作者：
Mat, Ishak B.