State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China.
Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, China.
Int J Mol Sci. 2023 Jan 23;24(3):2279. doi: 10.3390/ijms24032279.
Colorectal carcinoma (CRC) is a kind of malignant tumor closely related to ulcerative colitis. Xanthone derivatives are one of the most promising therapeutic drugs which have been used in phase I/II clinical trials for cancer therapy. Our previous study indicated that the aerial parts of Michx. Hulten (GA) was rich in xanthones and showed a good therapeutic effect on ulcerative colitis in mice, suggesting that GA xanthones might have some therapeutic or ameliorative effects on CRC. However, no relevant study has been reported. This study aims to find the effective substances of GA inhibiting CRC and clarify their mechanism. Solvent extraction, column chromatographic separation, and LC-MS analysis were used to characterize the 70% EtOH extract of GA and track xanthones abundant fraction XF. MTT assay was carried out to clarify the activity of GA fractions; the result showed XF to be the main active fraction. LC-MS analysis was executed to characterize XF, 38 xanthones were identified. Network pharmacology prediction, in vitro activity screening, and molecular docking assay were combined to predict the potential mechanism; the PI3K/Akt/mTOR signaling pathway was found to be most important. Western blot assay on the main active xanthones 1,3,5-trihydroxyxanthone (), 1,3,5,8-tetrahydroxyxanthone (), 1,5,8-trihydroxy-3-methoxyxanthone (), and 1,7-dihydroxy-3,8-dimethoxyxanthone () was used to verify the above prediction; these xanthones were found to inhibit the PI3K/Akt/mTOR signaling pathway, and played a significant role among them through Western blot assay using PI3K/AKT/mTOR agonist IGF-1. In conclusion, this study demonstrated that GA xanthones were effective compounds of GA inhibiting CRC by regulating PI3K/Akt/mTOR signaling pathway transduction, at least. Importantly, 1,3,5,8-tetrahydroxyxanthone (), the most abundant active xanthone in GA, might be a candidate drug for CRC.
结直肠癌（CRC）是一种与溃疡性结肠炎密切相关的恶性肿瘤。黄烷酮衍生物是最有前途的治疗药物之一，已在癌症治疗的 I/II 期临床试验中使用。我们之前的研究表明，Michx. Hulten（GA）的地上部分富含黄烷酮，对小鼠溃疡性结肠炎有很好的治疗作用，这表明 GA 黄烷酮可能对 CRC 有一定的治疗或改善作用。然而，目前尚无相关研究报道。本研究旨在寻找抑制 CRC 的 GA 有效物质，并阐明其机制。采用溶剂萃取、柱色谱分离和 LC-MS 分析方法对 GA 的 70%乙醇提取物和富含黄烷酮的富分 XF 进行了表征。MTT 法测定 GA 各馏分的活性，结果表明 XF 是主要的活性馏分。采用 LC-MS 分析对 XF 进行了表征，鉴定出 38 种黄烷酮。结合网络药理学预测、体外活性筛选和分子对接试验，预测了潜在的作用机制；发现 PI3K/Akt/mTOR 信号通路最重要。对主要活性黄烷酮 1,3,5-三羟基黄烷酮（）、1,3,5,8-四羟基黄烷酮（）、1,5,8-三羟基-3-甲氧基黄烷酮（）和 1,7-二羟基-3,8-二甲氧基黄烷酮（）进行了 Western blot 检测，验证了上述预测；这些黄烷酮被发现抑制了 PI3K/Akt/mTOR 信号通路，通过使用 IGF-1 的 PI3K/AKT/mTOR 激动剂进行 Western blot 检测，发现 发挥了重要作用。总之，本研究表明，GA 黄烷酮通过调节 PI3K/Akt/mTOR 信号通路转导，是抑制 CRC 的有效 GA 化合物，至少。重要的是，GA 中含量最丰富的活性黄烷酮 1,3,5,8-四羟基黄烷酮（）可能是 CRC 的候选药物。
