Kojja Venkateswarlu, Rudraram Vanitha, Kancharla Bhanukiran, Siva Hemalatha, Tangutur Anjana Devi, Nayak Prasanta Kumar
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India.
Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India.
Comput Biol Chem. 2024 Oct;112:108168. doi: 10.1016/j.compbiolchem.2024.108168. Epub 2024 Aug 7.
Despite progress in diagnosis and treatment strategies, breast cancer remains a primary risk to female health as indicated by second most cancer-deaths globally caused by this cancer. High risk mutation is linked to prognosis of breast cancer. Due to high resistance of breast cancer against current therapies, there is necessity of novel treatment strategies. Sirtuins are signaling proteins belonging to histone deacetylase class III family, known to control several cellular processes. Therefore, targeting sirtuins could be one of the approaches to treat breast cancer. Several plants synthesize phytoestrogens which exhibit structural and physiological similarities to estrogens and have been recognized to possess anticancer activity. In our study, we investigated several phytoestrogens for sirtuin inhibition by conducting molecular docking studies, and in-vitro studies against breast cancer cell lines. In molecular docking studies, we identified coumestrol possessing high binding energy with sirtuin proteins 1-3 as compared to other phytoestrogens. The molecular dynamic studies showed stable interaction of ligand and protein with higher affinity at sirtuin proteins 1-3 binding sites. In cell proliferation assay and colony formation assay using breast cancer cell lines (MCF-7 and MDAMB-231) coumestrol caused significant reduction in cell proliferation and number of colonies formed. Further, the flow cytometric analysis showed that coumestrol induces intracellular reactive oxygen species and the western blot analysis revealed reduction in the level of SIRT-1 expression in breast cancer cell lines. In conclusion, in-silico data and in-vitro studies suggest that the phytoestrogen coumestrol has sirtuin inhibitory activity against breast cancer.
尽管在诊断和治疗策略方面取得了进展，但乳腺癌仍然是女性健康的主要风险，全球因这种癌症导致的癌症死亡人数位居第二就表明了这一点。高风险突变与乳腺癌的预后相关。由于乳腺癌对当前疗法具有高度抗性，因此有必要采用新的治疗策略。沉默调节蛋白是属于III类组蛋白去乙酰化酶家族的信号蛋白，已知可控制多种细胞过程。因此，靶向沉默调节蛋白可能是治疗乳腺癌的方法之一。几种植物合成的植物雌激素与雌激素在结构和生理上具有相似性，并且已被认为具有抗癌活性。在我们的研究中，我们通过进行分子对接研究以及针对乳腺癌细胞系的体外研究，研究了几种植物雌激素对沉默调节蛋白的抑制作用。在分子对接研究中，我们发现与其他植物雌激素相比，香豆雌酚与沉默调节蛋白1-3具有高结合能。分子动力学研究表明，配体与蛋白质在沉默调节蛋白1-3结合位点具有稳定的相互作用且亲和力更高。在使用乳腺癌细胞系（MCF-7和MDAMB-231）的细胞增殖试验和集落形成试验中，香豆雌酚导致细胞增殖和形成的集落数量显著减少。此外，流式细胞术分析表明香豆雌酚可诱导细胞内活性氧的产生，蛋白质免疫印迹分析显示乳腺癌细胞系中SIRT-1表达水平降低。总之，计算机模拟数据和体外研究表明，植物雌激素香豆雌酚对乳腺癌具有沉默调节蛋白抑制活性。
