Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B–treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B–treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. Mol Cancer Ther; 9(3); 718–30

中文翻译：

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Alisol B，一种新型肌质/内质网 Ca2+ ATPase 泵抑制剂，可诱导自噬、内质网应激和细胞凋亡

新出现的证据表明自噬调节剂具有治疗潜力。本研究旨在从传统中草药中鉴定出新型自噬诱导剂作为潜在的抗肿瘤药物。使用基于图像的筛选和生物活性引导纯化，我们确定了泽泻根茎中的 alisol B 23-acetate、alisol A 24-acetate 和 alisol B 作为自噬的新型诱导剂，其中 alisol B 是最有效的天然产物. 在多个癌细胞系中，我们发现 alisol B 处理的细胞显示出自噬通量增加和自噬体形成，导致细胞周期停滞在 G1 期和细胞死亡。Alisol B 诱导内部储存的钙动员，通过激活雷帕霉素途径的 CaMKK-AMPK-哺乳动物靶点导致自噬。而且，钙稳态的破坏会在 alisol B 处理的细胞中诱导内质网应激和未折叠蛋白反应，导致细胞凋亡。最后，通过计算虚拟对接分析和生化分析，我们发现 alisol B 的分子靶点是肌质/内质网 Ca2+ ATPase。这项研究提供了对新型抗肿瘤化合物的细胞毒性机制的详细见解。摩尔癌症治疗; 9(3); 718–30 这项研究提供了对新型抗肿瘤化合物的细胞毒性机制的详细见解。摩尔癌症治疗; 9(3); 718–30 这项研究提供了对新型抗肿瘤化合物的细胞毒性机制的详细见解。摩尔癌症治疗; 9(3); 718–30