Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells
Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells
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DOI：
10.1186/bcr1790
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发表时间：
2007-01-01
影响因子：
7.4
通讯作者：
Lu, Junxuan
中科院分区：
文献类型：
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作者：
Jiang, Cheng;Guo, Junming;Lu, Junxuan
雌激素和雌激素受体(ER)介导的信号转导对人类乳腺癌的发生和发展起着至关重要的作用。通过天然产物降低ER活性是降低乳腺癌风险的一个很有前途的策略。我们最近发现，吡喃香豆素类化合物去甲肾上腺素及其异构体去甲肾上腺素(DA)具有新型的抗雄激素受体信号转导活性。因为ER和雄激素受体属于类固醇受体超家族，所以我们研究了这些化合物是否影响乳腺癌细胞中ER的表达和信号转导。方法我们用降钙素和DA处理雌激素依赖的MCF-7和非雌激素依赖的人乳腺癌细胞MB-231，检测这两种细胞的生长、凋亡以及ERα和ERβ的表达，特别是雌激素刺激的MCF-7细胞中的信号转导。结果月桂素和DA通过G(1)期阻滞和caspase介导的细胞凋亡抑制MCF-7细胞的生长。这些化合物在mRNA和蛋白水平上都降低了MCF-7细胞的ERα，并抑制了雌激素刺激的基因。Decursin和纯抗雌激素Faslodex T对MCF-7细胞具有相加的生长抑制作用。在MDA MB-231细胞中，这些化合物诱导细胞周期停滞在G(1)和G(2)期，并诱导细胞凋亡，同时伴随着ERβ表达的增加。相反，在相似的浓度下，缺乏下丘脑素和DA侧链的十字草素没有这些细胞和分子活性。结论下丘脑素和DA的侧链在其抗ER信号和抑制乳腺癌生长活性中起着关键作用。这些数据为在乳腺癌的临床前动物模型中验证地塞米松及其衍生物的化学预防和治疗效果提供了机制基础。
Introduction Estrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer. Attenuating ER activities by natural products is a promising strategy to decrease breast cancer risk. We recently discovered that the pyranocoumarin compound decursin and its isomer decursinol angelate (DA) have potent novel antiandrogen receptor signaling activities. Because the ER and the androgen receptor belong to the steroid receptor superfamily, we examined whether these compounds affected ER expression and signaling in breast cancer cells.Methods We treated estrogen-dependent MCF-7 and estrogen-independent MDA MB-231 human breast cancer cells with decursin and DA, and examined cell growth, apoptosis, and ER alpha and ER beta expression in both cell lines - and, in particular, estrogen-stimulated signaling in the MCF-7 cells. We compared these compounds with decursinol to determine their structure-activity relationship.Results Decursin and DA exerted growth inhibitory effects on MCF-7 cells through G(1) arrest and caspase-mediated apoptosis. These compounds decreased ER alpha in MCF-7 cells at both mRNA and protein levels, and suppressed estrogen-stimulated genes. Decursin and the pure antiestrogen Faslodex T exerted an additive growth inhibitory effect on MCF-7 cells. In MDA MB-231 cells, these compounds induced cell-cycle arrests in the G(1) and G(2) phases as well as inducing apoptosis, accompanied by an increased expression of ER beta. In contrast, decursinol, which lacks the side chain of decursin and DA, did not have these cellular and molecular activities at comparable concentrations.Conclusion The side chain of decursin and DA is crucial for their anti-ER signaling and breast cancer growth inhibitory activities. These data provide mechanistic rationales for validating the chemopreventive and therapeutic efficacy of decursin and its derivatives in preclinical animal models of breast cancer.