Graduate School of Pharmaceutical Sciences , Chiba University , 1-8-1 Inohana , Chuo-ku , Chiba 260-8675 , Japan.
Temko Corporation , Tokyo 168-0062 , Japan.
J Nat Prod. 2018 May 25;81(5):1235-1240. doi: 10.1021/acs.jnatprod.7b01031. Epub 2018 Apr 25.
Notch signaling plays a crucial role in differentiation and cell maintenance, but once aberrantly activated, it contributes to cancer progression. Notch inhibitors were isolated from plant extracts and tested using an originally constructed cell-based assay system. We isolated eight compounds from Nerium indicum that showed inhibition of the Notch signaling pathway. HES1 and HES5 are target genes of the Notch signaling pathway, and oleandrin (1) decreased the protein levels of HES1 and HES5 in assay cells. Oleandrin (1) showed potent cytotoxicity against HPB-ALL cells and decreased HES1 and the Notch intracellular domain in these cells. The main mechanism of action of 1 appears to be inhibition of Notch signaling by acceleration of Notch intracellular domain degradation.
Notch 信号通路在细胞分化和维持中起着至关重要的作用，但一旦异常激活，就会促进癌症的进展。Notch 抑制剂是从植物提取物中分离出来的，并使用最初构建的基于细胞的测定系统进行了测试。我们从夹竹桃中分离出 8 种化合物，这些化合物显示出对 Notch 信号通路的抑制作用。HES1 和 HES5 是 Notch 信号通路的靶基因，而欧夹竹桃苷（1）降低了测定细胞中 HES1 和 HES5 的蛋白水平。欧夹竹桃苷（1）对 HPB-ALL 细胞表现出很强的细胞毒性，并降低了这些细胞中的 HES1 和 Notch 细胞内结构域。1 的主要作用机制似乎是通过加速 Notch 细胞内结构域的降解来抑制 Notch 信号通路。
