PO.CH01.05 · 化学
穿心莲内酯的A环类似物抑制wnt1信号并在乳腺癌和结直肠癌模型中表现出强效抗癌活性
A-ring analogs of Andrographolide inhibit wnt1 signaling and exhibit potent anticancer activity in breast and colorectal cancer models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
天然产物穿心莲内酯(andrographolide)是一种从穿心莲(Andrographis paniculata)植物中提取的半日花烷型二萜类化合物,作为抗癌治疗药物已被广泛研究,并被推测通过共价抑制NF-kB发挥作用:NF-kB是位于众多调控肿瘤存活和转移的细胞信号通路交汇点的转录因子。C-19羟基的官能团化已被证明可将其主要作用模式从抑制NF-kB转变为调控Wnt/beta-catenin信号通路。通过一系列12种穿心莲内酯的甲硅烷基和三苯甲基醚类似物,我们评估了它们在MDA-MB-231(三阴性乳腺癌)、MCF-7(转移性乳腺腺癌)、HCT-116(人结直肠癌)和HT-29(结直肠腺癌)细胞系中的抗增殖活性。这些化合物表现出比母体化合物穿心莲内酯更强的效力。我们观察到氯丁基类似物在HCT-116中具有独特的效力(IC50 = 0.32μM;24小时),以及氯代三苯甲基类似物(IC50 = 7.32μM;24小时)。在MDA-MB-231中,氯丁基类似物的IC50为10.11 μM,氯代三苯甲基的IC50为2.88 μM。三苯甲基醚类似物在NF-kB SEAP报告细胞实验中显示出剂量依赖性的SEAP表达抑制。此外,给予三苯甲基醚类似物后,在Wnt/beta-catenin报告细胞实验中,我们观察到在10 μM时荧光素酶表达降低。在研究了这一系列化合物与NF-κB和beta-catenin抑制(此前报道为穿心莲内酯或其类似物的细胞靶点的两种推测作用机制)相关的活性后,我们发现对C-19官能团化的细微修饰可极大地影响这些化合物的体外生物学特性。值得注意的是,三苯甲基类似物显示出对SEAP偶联NF-κB活性的显著抑制,并且与TPS(三苯基甲硅烷基)类似物相比,在与CHIR99021共同给药时抗增殖活性减弱,而两者唯一的区别仅在于将一个碳原子单一取代为硅原子。本研究强调了穿心莲内酯及其类似物潜在复杂的多重药理学作用,并突出了进一步研究本工作中先导化合物在其他类似体外和体内癌细胞模型中的重要性。
查看英文原文 English abstract
The natural product andrographolide, a labdane diterpenoid extracted from the plant Andrographis paniculata, has been extensively studied as an anticancer therapeutic, and is putatively known to function through covalent inhibition of NF-kB: a transcription factor at the crossroad of a myriad of cell signaling pathways that modulate tumor survival and metastasis. Functionalization of the C-19 hydroxyl has been shown to alter the primary mode of action from inhibition of NF-kB to modulation of the Wnt/beta-catenin signaling pathway. With a systematic series of 12 silyl and trityl ether analogs of Andrographolide, we evaluated their antiproliferative activity in MDA-MB-231 (triple-negative breast cancer), MCF-7 (metastatic breast adenocarcinoma), HCT-116 (human colorectal carcinoma), and HT-29 (colorectal adenocarcinoma) cell lines. These compounds displayed greater potency than the parent compound, andrographolide. We observe unique potency in HCT-116 with the chloro butyl analog (IC 50 = 0.32μM; 24 hr), and the chloro trityl analog (IC50 = 7.32μM; 24 hr). In MDA-MB-231, the chloro butyl analog exhibits an IC50 of 10.11 μM, and chloro trityl exhibits an IC50 of 2.88 μM. Trityl ether analogs in an NF-kB SEAP reporter cell experiment show inhibition of SEAP expression in a dose dependent fashion. Additionally, upon administration of trityl ether analogs, in a Wnt/beta-catenin reporter cell assay, we observe decreased luciferase expression at 10 μM. After investigating the activities of this series of compounds in connection to NF-κB and beta-catenin inhibition, two putative mechanisms of action previously reported as the cellular targets of andrographolide or its analogs, we find that subtle modifications to C-19 functionalization can greatly affect the in vitro biological profile of these compounds. Notably, the trityl analog displayed significant inhibition of SEAP-coupled NF-κB activity, and diminished antiproliferative activity with coadministration of CHIR99021 compared to the TPS (triphenylsilyl) analog with the only difference being the single substitution of a carbon to a silicon atom. This study underscores the potentially complex polypharmacology of andrographolide and its analogs and highlights the importance of further examination of the lead compounds from this work in other analogous in vitro and in vivo cancer cell models.
利益披露 Disclosure
R. Raval, None..
S. Xi, None..
R. Liu, None..
A. Yee, None..
A. Pak, None..
E. Njoo, None..
G. Johanning, None..
F. Wang-Johanning, None.