Guerra-Rodríguez Miguel, López-Rojas Priscila, Amesty Ángel, Aranda-Tavío Haidée, Brito-Casillas Yeray, Estévez-Braun Ana, Fernández-Pérez Leandro, Guerra Borja, Recio Carlota
Farmacología Molecular y Traslacional (BIOPharm), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria (ULPGC), Paseo Blas Cabrera Felipe Físico s/n, 35016 Las Palmas de Gran Canaria, Spain.
Departamento de Química Orgánica, Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, Spain.
Cancers (Basel). 2022 Oct 22;14(21):5174. doi: 10.3390/cancers14215174.
Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds and inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds and caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment.
他莫昔芬可提高激素受体阳性乳腺癌患者的总生存率。然而，尽管它对雌激素受体α（ERα）发挥拮抗作用，但它也可作为部分激动剂，导致雌激素敏感组织中的肿瘤生长。在本研究中，通过基于ERα和表型的筛选试验合成并评估了高度功能化的5-羟基-2-吡咯烷-2-酮。化合物 和 抑制乳腺癌细胞中17β-雌二醇（E2）刺激的ERα介导的荧光素酶报告基因转录，而不抑制雄激素或糖皮质激素受体介导的转录活性。化合物 通过部分拮抗作用调节E2刺激的ERα介导的转录，而化合物 则引起快速和非竞争性抑制。对二维和三维细胞生长的监测证实了这两种化合物对ER阳性乳腺癌细胞具有强大的抗肿瘤作用。此外，化合物 和 导致ER阳性乳腺癌细胞在亚G1期和G0/G1期发生凋亡并阻断细胞周期。有趣的是，化合物 抑制了子宫中ERα的功能活性，这通过抑制E2刺激的雌激素和孕激素受体转录以及碱性磷酸酶活性得以证明。化合物 与ERα的结合亲和力相对较低。然而，其抗雌激素作用与ERα的多聚泛素化增加和蛋白表达降低有关。临床相关的是，与化合物 联合治疗可能会增强4-羟基他莫昔芬对ER阳性乳腺癌细胞的抗肿瘤疗效。计算机辅助药物代谢动力学预测表明，这些化合物具有良好的类药性，这与其潜在的抗肿瘤作用以及缺乏雌激素活性一起，为深入研究ER阳性乳腺癌治疗提供了药理学机会。
