文章：

磺酰化雌二醇类似物靶向肌动蛋白与微管细胞骨架在体外及卵内模型展现抗肿瘤特性

Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo

原文发布日期：23 August 2024

DOI: 10.3390/cancers16172941

类型: Article

开放获取: 是

英文摘要：

The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class.

摘要翻译： 

微管破坏剂2-甲氧基雌二醇（2-ME）具有抗肿瘤和抗血管生成特性，但其药代动力学特性不佳导致临床开发受阻。为此，我们通过计算机模拟设计了两种具有改良药理特性的2-ME类似物——ESE-15-one与ESE-16。本研究在体外探究了这些化合物对细胞骨架的影响，并在卵内模型中评估其抗血管生成及抗转移特性。延时荧光显微技术显示，亚致死剂量的化合物可破坏微管动态平衡。经药物处理的宫颈癌（HeLa）、转移性乳腺癌（MDA-MB-231）及人脐静脉内皮细胞（HUVECs）在2小时后出现增厚且稳定的肌动蛋白应力纤维，至24小时重排为外周放射状模式。丝切蛋白磷酸化及磷酸化埃兹蛋白/根蛋白/膜突蛋白复合物可能调控此肌动蛋白应答。这些信号通路与抗血管生成、细胞外通讯及黏附通路存在重叠。亚致死浓度的化合物可同时抑制细胞迁移与侵袭能力。通过TIMP2和磷酸化VEGF受体-2的上调，抗血管生成及细胞外基质信号通路被显著激活。采用鸡胚绒毛尿囊膜实验证实，ESE-15-one与ESE-16在体内均表现出抗肿瘤及抗转移特性。综上所述，磺酰化2-ME类似物展现出良好的抗肿瘤、抗转移及抗血管生成潜力。鉴于同类药物临床应用中出现骨髓增殖效应，后续研究将重点评估该化合物的骨髓增殖影响。

原文链接：

Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo