PO.CH01.05 · 化学
发现红厚壳（Spondias mombin）黄酮类化合物芦丁作为一种新型DNA甲基转移酶1抑制剂及治疗西非血统患者三阴性乳腺癌的潜在药物
Discovery of Spondias mombin flavonoid rutin as a novel DNA methyltransferase 1 inhibitor and potential agent to treat triple negative breast cancer in patients of West African ancestry
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
西非（WA）血统女性即便被诊断为雌激素受体（ER）阳性亚型，其乳腺癌预后仍不成比例地较差。近期染色质可及性分析揭示了DNA甲基转移酶1（DNMT1）存在血统特异性上调，WA患者中升高的DNMT1水平与更差的生存相关。鉴于Spondias mombin在WA人群中用于乳腺癌的传统用途，以及黄酮类化合物已知的表观遗传活性，我们研究了其主要黄酮类化合物芦丁的治疗潜力，并试图阐明其可能的抗癌作用机制。采用分子对接和分子力学/广义玻恩表面积（MM/GBSA）结合能计算，对17个乳腺癌相关分子靶点进行了筛选。利用2D/3D相互作用图谱、氢键分析和稳定性指标对芦丁的结合相互作用进行了详细分析。芦丁对17个乳腺癌靶点中的10个显示出强潜在结合亲和力，其中与DNMT1的相互作用最为有利，超过了与HER2、mTOR、AKT1和EGFR的相互作用。对接分析在DNMT1催化口袋内鉴定出多个稳定的氢键相互作用，提示对酶活性的直接抑制。芦丁还与增殖（CDK4、Cyclin D1）、血管生成（VEGF-A）和DNA修复（BRCA1/2）的关键调控因子结合，表明其具有多靶点抗癌特征。较强的DNMT1结合支持这样一种机制：芦丁可能解除对肿瘤抑制基因的甲基化依赖性沉默，而这些基因表达降低与不良生存相关，尤其在WA血统患者中。集落形成实验显示，芦丁在乳腺癌细胞中表现出强效的抗增殖活性，特别是在来源于WA血统患者的细胞中。定量PCR分析表明，芦丁抑制来源于WA血统患者细胞中的DNMT1基因表达。我们的计算机模拟（in-silico）研究结果将芦丁鉴定为一种高亲和力DNMT1抑制剂，具有多通路抗癌潜力，支持黄酮介导的表观遗传重编程在缩小乳腺癌差异方面的作用。我们的体外研究结果提示，芦丁通过抑制DNMT1最终抑制TNBC细胞增殖。这些结果为在血统来源的乳腺癌模型中进一步开展机制验证提供了依据，并支持将S. mombin来源的黄酮类化合物开发为低毒性、与血统相关的候选治疗药物。
查看英文原文 English abstract
Women of West African (WA) ancestry disproportionately experience poor breast cancer outcomes, even when diagnosed with the estrogen receptor (ER)-positive subtype. Recent chromatin accessibility analyses reveal ancestry-specific upregulation of DNA methyltransferase1 (DNMT1), with elevated DNMT1 levels in WA patients correlating with worse survival. Given the traditional use of Spondias mombin in WA populations for breast cancer, and the known epigenetic activity of flavonoids, we investigated the therapeutic potential of its major flavonoid, rutin and sought to delineate a probable mechanism of anticancer action. Seventeen breast cancer-related molecular targets were screened using molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. Rutin's binding interactions were analyzed in detail using 2D/3D interaction mapping, hydrogen-bond profiling, and stability metrics. Rutin demonstrated strong potential binding affinity to 10 of 17 breast cancer targets, with the most favorable interaction observed with DNMT1, surpassing those with HER2, mTOR, AKT1, and EGFR. Docking analyses identified multiple stabilizing hydrogen-bond interactions within the DNMT1 catalytic pocket, suggesting direct inhibition of enzymatic activity. Rutin also engaged key regulators of proliferation (CDK4, Cyclin D1), angiogenesis (VEGF-A), and DNA repair (BRCA1/2), indicating a multi-targeted anticancer profile. The strong DNMT1binding supports a mechanism in which rutin may relieve methylation-dependent silencing of tumor suppressor genes, whose reduced expression associates with poor survival, particularly among patients of WA ancestry. Colony-forming assays reveal that rutin exhibits potent antiproliferative activity in breast cancer cells, particularly those derived from patients of WA ancestry. Quantitative PCR analyses show that rutin inhibits DNMT1 gene expression in cells derived from patients of WA ancestry. Our in-silico findings identify rutin as a high-affinity DNMT1inhibitor with multi-pathway anticancer potential, supporting a role for flavonoid-mediated epigenetic reprogramming in reducing breast cancer disparities. Our in vitro findings suggest that rutin inhibits DNMT1 to ultimately suppress TNBC cell proliferation. These results justify further mechanistic validation in ancestry-derived breast cancer models and support the development of S. mombin -derived flavonoids as low-toxicity, ancestry-relevant therapeutic candidates.
利益披露 Disclosure
A. J. Olanrewaju, None..
E. Fraser, None..
J. Enya, None..
L. Arietarhire, None..
E. Olugbogi, None..
T. Afolabi, None..
O. Soremekun, None..
M. Hall, None..
O. Amobi, None..
V. Chinedu, None..
J. Khalaf, None..
J. De Anda, None..
S. Angeloni, None..
U. Soto, None.