PDF(Pubmed)
Abstract：
Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC50 values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-β-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE\'s main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs.
摘要：
海洋天然产物为药物开发提供了巨大的潜力，但是海洋生物的有限供应构成了重大挑战。建立水产养殖通过促进活性成分的大规模生产，同时减少我们对野生种群的依赖和对当地环境的危害，为这一挑战提供了可持续的解决方案。充分利用水产养殖作为生物活性产品的来源，建立了一个无细胞系统，以靶向具有蛋白质调节活性的分子成分，包括拓扑异构酶II,HDAC,和微管蛋白聚合，使用水产养殖珊瑚的提取物。随后进行了体外研究，包括MTT测定，流式细胞术,共聚焦显微镜，和西方印迹，以及体内异种移植模型，以验证活性提取物的功效并进一步阐明其细胞毒性机制。使用NGS和基因修饰技术阐明调控蛋白。进行分子对接和SwissADME测定以评估小分子的药物相似性和药代动力学和药物化学相关特性。从落叶松（LCE）的提取物显示出有效的广谱活性，表现出显着的抑制微管蛋白聚合，对前列腺癌细胞的IC50值较低。流式细胞术和Western印迹分析显示LCE诱导细胞凋亡,凋亡蛋白裂解的caspase-3以及早期和晚期凋亡细胞的表达增加证明了这一点。在异种移植肿瘤实验中,LCE显著抑制肿瘤生长并减小肿瘤体积(PC3:43.9%;Du145:49.2%)和重量(PC3:48.8%;Du145:7.8%)。此外,LCE抑制前列腺癌细胞迁移，和侵袭上调上皮标志物E-cadherin并抑制EMT相关蛋白。此外，在PC3和Du145细胞中,LCE有效地减弱TGF-β诱导的EMT。生物活性指导分馏和SwissADME验证证实了LCE的主要成分，13-乙酰氧基克拉索化物（13-AC），具有开发抗癌药物的更大潜力。
