白藜芦醇甲氧基类似物在恶性 MCF-7 而非非肿瘤性 MCF-10A 乳腺上皮细胞系中的抗肿瘤特性。

Anti-tumor properties of methoxylated analogues of resveratrol in malignant MCF-7 but not in non-tumorigenic MCF-10A mammary epithelial cell lines.

机构信息

Institute for Risk Assessment Sciences, Toxicology Department, Utrecht University, Yalelaan 104, 3584 CM, Utrecht, the Netherlands.

出版信息

Toxicology. 2019 Jun 15;422:35-43. doi: 10.1016/j.tox.2019.04.009. Epub 2019 Apr 18.

DOI:10.1016/j.tox.2019.04.009

PMID:31004704

Abstract

Resveratrol is a plant-derived polyphenol that is known for its anti-inflammatory and anti-tumorigenic properties in in vitro and in vivo models. Recent studies show that some resveratrol analogues might be more potent anti-tumor agents, which may partly be attributed to their ability to activate the aryl hydrocarbon receptor (AHR). Here, the anti-tumorigenic properties of resveratrol and structural analogues oxyresveratrol, pinostilbene, pterostilbene and tetramethoxystilbene (TMS) were studied in vitro, using in the malignant human MCF-7 breast cancer cell line and non-tumorigenic breast epithelial cell line MCF-10A. Cell viability and migration assays showed that methoxylated analogues of resveratrol are more potent anti-tumorigenic compounds than resveratrol and its hydroxylated analogue oxyresveratrol, with 2,3',4,5'-tetramethoxy-trans-stilbene (TMS) being the most potent compound. TMS decreased MCF-7 tumor cell viability with 50% at 3.6 μM and inhibited migration with 37.5 ± 14.8% at 3 μM. In addition, TMS activated the AHR more potently (EC50 in a reporter gene assay 2.0 μM) and induced AHR-mediated induction of cytochrome P450 1A1 (CYP1A1) activity (EC50 value of 0.7 μM) more than resveratrol and the other analogues tested. Cell cycle analysis showed that TMS induced a shift in cell cycle status from the G1 to the G2/M phase causing a cell cycle arrest in the MCF-7 cells, while no effect of TMS was observed in the non-tumorigenic MCF-10A mammary epithelial cell line. Gene expression analysis showed that 3 μM TMS increased gene expression of CYP1A1 (289-fold), CYP1B1 (5-fold) and Nqo1 (2-fold), and decreased gene expression of IL-8 (3-fold) in MCF-7 cells. In MCF-10A cells, 10 μM TMS also increased gene expression of CYP1A1 (5-fold) and CYP1B1 (2-fold), but decreased gene expression of Nqo1 (1.4-fold) in contrast to MCF-7 cells. TMS displays more potent anti-tumorigenic properties and activates the AHR more effectively than resveratrol. In addition, this is the first study to show that TMS, but not resveratrol, selectively inhibits the cell cycle of breast tumor cells and not the non-tumorigenic cells. Our study provides more insight in the anti-tumor properties of the methoxylated analogues of resveratrol in breast cells in vitro.

摘要

白藜芦醇是一种植物来源的多酚，已知具有抗炎和抗肿瘤特性，在体外和体内模型中均有研究。最近的研究表明，一些白藜芦醇类似物可能是更有效的抗肿瘤药物，这可能部分归因于它们激活芳烃受体（AHR）的能力。在这里，研究了白藜芦醇及其结构类似物氧白藜芦醇、松柏醇、紫檀芪和四甲氧基二苯乙烯（TMS）在恶性人 MCF-7 乳腺癌细胞系和非肿瘤性乳腺上皮细胞系 MCF-10A 中的抗肿瘤特性。细胞活力和迁移实验表明，白藜芦醇的甲氧基类似物比白藜芦醇及其羟基类似物氧白藜芦醇更有效，2,3',4,5'-四甲氧基反式-二苯乙烯（TMS）是最有效的化合物。TMS 以 3.6μM 时 50%的浓度降低 MCF-7 肿瘤细胞活力，以 3μM 时 37.5±14.8%的浓度抑制迁移。此外，TMS 更有效地激活 AHR（在报告基因测定中的 EC50 为 2.0μM），并诱导 AHR 介导的细胞色素 P450 1A1（CYP1A1）活性诱导（EC50 值为 0.7μM），比测试的其他类似物更强。细胞周期分析表明，TMS 诱导 MCF-7 细胞的细胞周期状态从 G1 期向 G2/M 期转变，导致细胞周期停滞，而在非肿瘤性 MCF-10A 乳腺上皮细胞系中未观察到 TMS 的作用。基因表达分析表明，3μM TMS 增加了 CYP1A1（289 倍）、CYP1B1（5 倍）和 Nqo1（2 倍）的基因表达，并降低了 MCF-7 细胞中 IL-8（3 倍）的基因表达。在 MCF-10A 细胞中，10μM TMS 还增加了 CYP1A1（5 倍）和 CYP1B1（2 倍）的基因表达，但与 MCF-7 细胞相比，Nqo1（1.4 倍）的基因表达降低。TMS 比白藜芦醇具有更强的抗肿瘤特性和更有效地激活 AHR。此外，这是第一项表明 TMS（而不是白藜芦醇）选择性抑制乳腺癌细胞而不是非肿瘤细胞的细胞周期的研究。我们的研究为白藜芦醇甲氧基类似物在体外乳腺癌细胞中的抗肿瘤特性提供了更多的见解。