New withanolides with TRAIL-sensitizing effect from Physalis pubescens L.
New withanolides with TRAIL-sensitizing effect from Physalis pubescens L.
复制标题
来自酸浆的具有 TRAIL 敏化作用的新型茄内酯。
作者：
Chen LX;Xia GY;He H;Huang J;Qiu F;Zi XL
毛酸浆这种植物结出营养和健康的果实，称为带壳番茄或毛樱桃。然而，其生物活性成分在很大程度上是未知的。从毛白杨（P. pubescens L.）的提取物中分离得到4个新的withanasteroid甾体化合物（1-4）和1个已知的withanasteroid（5）。并通过广泛的光谱分析确定了它们的化学结构。化合物1、3和5对四种人肾细胞癌（RCC）细胞系（即786-O、A-498、Caki-2和ACHN）显示出有效的生长抑制作用。其中化合物1的活性最强，IC_（50）为0.30 ~ 0.77 μM。进一步的实验表明，1可使肿瘤坏死因子相关凋亡配体（tumor necrosis factor related apoptosis ligand，TRAIL）诱导的人肾细胞癌细胞786-O凋亡敏感，并增加C/EBP同源蛋白（C/EBP homologous protein，CHOP）和死亡受体5（death receptor-5，DR 5）的表达，从而激活DR 5和caspase-8/3介导的凋亡途径。分子对接分析表明，化合物1能与TRAIL/DR 5复合物通过氢键稳定结合。这些结果表明，新的withanalcohol（1）是存在于毛白杨中的一个先导抗癌化合物。对肾癌的防治具有重要意义。
Physalis pubescens L. plant produces nutritious and healthy fruits, called husk tomato or hairy ground cherry. However, its bioactive components are largely unknown. Four new withanolide steroids (1-4) together with one known withanolide (5) were isolated from the extract of P. pubescens L. and their chemical structures were established by extensive spectroscopic analyses. Compounds 1, 3 and 5 showed potent growth inhibitory effects against four human renal cell carcinoma (RCC) cell lines (i.e. 786-O, A-498, Caki-2 and ACHN). Among them, compound 1 was the most potent one with IC50s ranged from 0.30 to 0.77 μM. Further experiment showed that 1 sensitized human RCC cells 786-O to the tumor necrosis factor related apoptosis ligand (TRAIL)-induced apoptosis and increased the expression of C/EBP-homologous protein (CHOP) and death receptor-5 (DR5), leading to activation of the DR5 and caspase-8/3 mediated apoptosis pathway. Molecular docking analysis revealed that compound 1 could bind stably to the TRAIL/DR5 complex through hydrogen bonds. These results suggest that the new withanolide (1) is a lead anti-cancer compound existing in P. pubescens L. and deserves further investigation for RCC prevention and treatment.