Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, 07743 Jena, Germany.
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany.
Int J Mol Sci. 2022 Mar 10;23(6):2984. doi: 10.3390/ijms23062984.
The therapeutic activities of natural plant extracts have been well known for centuries. Many of them, in addition to antiviral and antibiotic effects, turned out to have anti-tumor activities by targeting different signaling pathways. The canonical Wnt pathway represents a major tumorigenic pathway deregulated in numerous tumor entities, including colon cancer. Here, we investigated the acylphloroglucinols hyperforin (HF) from St. John's wort ( L.) and myrtucommulone A (MC A) from myrtle () and semi-synthetic derivatives thereof (HM 177, HM 297, HM298) for their effects on Wnt/β-catenin signaling. None of these substances revealed major cytotoxicity on STF293 embryonic kidney and HCT116 colon carcinoma cells at concentrations up to 10 μM. At this concentration, HF and HM 177 showed the strongest effect on cell proliferation, whereas MC A and HM 177 most prominently inhibited anchorage-independent growth of HCT116 cells. Western blot analyses of active β-catenin and β-catenin/TCF reporter gene assays in STF293 cells revealed inhibitory activities of HF, MC A and HM 177. In line with this, the expression of endogenous Wnt target genes, Axin and Sp5, in HCT116 cells was significantly reduced. Our data suggest that the acylphloroglucinols hyperforin, myrtucommulone A and its derivative HM 177 represent potential new therapeutic agents to inhibit Wnt/β-catenin signaling in colon cancer.
天然植物提取物的治疗活性已为人所知数百年。除了抗病毒和抗生素作用外，其中许多还通过靶向不同的信号通路，被证明具有抗肿瘤活性。经典的 Wnt 通路是一种主要的肿瘤发生途径，在包括结肠癌在内的许多肿瘤实体中失调。在这里，我们研究了贯叶连翘（L.）中的酰基间苯三酚化合物金丝桃素（HF）和桃金娘中的桃金娘烯酮 A（MCA）及其半合成衍生物（HM177、HM297、HM298）对 Wnt/β-连环蛋白信号通路的影响。在高达 10 μM 的浓度下，这些物质对 STF293 胚胎肾和 HCT116 结肠癌细胞均无明显的细胞毒性。在该浓度下，HF 和 HM177 对细胞增殖的影响最强，而 MCA 和 HM177 则最显著地抑制了 HCT116 细胞的无锚定依赖性生长。STF293 细胞中活性 β-连环蛋白和β-连环蛋白/TCF 报告基因分析的 Western blot 分析显示 HF、MCA 和 HM177 具有抑制活性。与此一致的是，HCT116 细胞中内源性 Wnt 靶基因 Axin 和 Sp5 的表达显著降低。我们的数据表明，酰基间苯三酚化合物金丝桃素、MCA 及其衍生物 HM177 可能是抑制结肠癌中 Wnt/β-连环蛋白信号的新治疗剂。
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