Wang Rongbo, Lee Yeong-Geun, Dhandapani Sanjeevram, Baek Nam-In, Kim Kwang-Pyo, Cho Yeong-Eun, Xu Xingyue, Kim Yeon-Ju
Graduate School of Biotechnology, and College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea.
Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea.
Pharmacol Res. 2023 Jan;187:106610. doi: 10.1016/j.phrs.2022.106610. Epub 2022 Dec 12.
Gastric cancer (GC) occurs in the gastric mucosa, and its high morbidity and mortality make it an international health crisis. Therefore, novel drugs are needed for its treatment. The use of natural products and their components in cancer treatments has shown promise. Therefore, this study aimed to evaluate the effect of 8-paradol, a phenolic compound isolated from ginger (Zingiber officinale Roscoe), on GC and determine its underlying mechanisms of action. In this study, repeated column chromatography was conducted on ginger EtOH extract to isolate gingerol and its derivatives. The cytotoxicity of the eight ginger compounds underwent a (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) tetrazolium reduction (MTT) assay. 8-paradol showed the most potent cytotoxicity effect among the isolated ginger compounds. The underlying mechanism by which 8-paradol regulated specific proteins in AGS cells was evaluated by proteomic analysis. To validate the predicted mechanisms, AGS cells and thymus-deficient nude mice bearing AGS xenografts were used as in vitro and in vivo models of GC, respectively. The results showed that the 8-paradol promoted PINK1/Parkin-associated mitophagy, mediating cell apoptosis. Additionally, the inhibition of mitophagy by chloroquine (CQ) ameliorated 8-paradol-induced mitochondrial dysfunction and apoptosis, supporting a causative role for mitophagy in the 8-paradol-induced anticancer effect. Molecular docking results revealed the molecular interactions between 8-paradol and mitophagy-/ apoptosis-related proteins at the atomic level. Our study provides strong evidence that 8-paradol could act as a novel potential therapeutic agent to suppress the progression of GC by targeting mitophagy pathway.
胃癌（GC）发生于胃黏膜，其高发病率和死亡率使其成为一场国际健康危机。因此，需要新型药物来治疗胃癌。天然产物及其成分在癌症治疗中的应用已显示出前景。因此，本研究旨在评估从生姜（姜科植物姜）中分离出的酚类化合物8-姜辣素对胃癌的影响，并确定其潜在作用机制。在本研究中，对生姜乙醇提取物进行反复柱色谱分离以得到姜辣素及其衍生物。对这八种生姜化合物的细胞毒性进行了（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐）四氮唑还原（MTT）测定。8-姜辣素在分离出的生姜化合物中显示出最强的细胞毒性作用。通过蛋白质组学分析评估了8-姜辣素调节AGS细胞中特定蛋白质的潜在机制。为了验证预测的机制，分别使用AGS细胞和携带AGS异种移植瘤的胸腺缺陷裸鼠作为胃癌的体外和体内模型。结果表明，8-姜辣素促进PINK1/Parkin相关的线粒体自噬，介导细胞凋亡。此外，氯喹（CQ）抑制线粒体自噬改善了8-姜辣素诱导的线粒体功能障碍和细胞凋亡，支持线粒体自噬在8-姜辣素诱导的抗癌作用中起因果作用。分子对接结果揭示了8-姜辣素与线粒体自噬/凋亡相关蛋白在原子水平上的分子相互作用。我们的研究提供了强有力的证据，表明8-姜辣素可能作为一种新型潜在治疗剂，通过靶向线粒体自噬途径来抑制胃癌的进展。
