Ma Wen-Lung, Chang Ning, Yu Yingchun, Su Yu-Ting, Chen Guan-Yu, Cheng Wei-Chung, Wu Yang-Chang, Li Ching-Chia, Chang Wei-Chun, Yang Juan-Cheng
Graduate Institute of Biomedical Sciences, Center for Tumor Biology, Department of Pharmacology, Chinese Medicine Research Center, Drug Development Center, and Graduate Institute of Chinese Medicine, Graduate Institute of Integrated Medicine, School of Medicine, China Medical University, Taichung, Taiwan.
Department of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics & Gynecology, China Medical University Hospital, Taichung, Taiwan.
Cancer Med. 2022 Jul;11(14):2824-2835. doi: 10.1002/cam4.4536. Epub 2022 May 11.
Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti-GCa effects in experimental models, are currently being investigated.
The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5-fluracil were applied onto AGS, SC-M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web-based GCa cohort for Ar expression association with prognosis was performed.
The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5-FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer-suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor-suppressing index (TSI) score of 90% over a 6-week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements.
胃癌（GCa）是一种有效治疗方法较少的恶性肿瘤。熊果酸（UA）是一种富含白花蛇舌草的生物活性三萜类化合物，已知可抑制胃癌但尚未确定靶点。细胞色素P450家族19A1（CYP19A1；也称为芳香化酶，Ar）与胃癌预后相关。相关地，目前正在研究能够阻止Ar表达并在实验模型中表现出抗胃癌作用的Ar沉默剂。
在Ar蛋白结晶过程中，将UA的对接模拟分数与Ar抑制剂（如来曲唑、依西美坦）进行比较。将白花蛇舌草乙醇提取物、UA或5-氟尿嘧啶应用于AGS、SC-M1、MKN45胃癌细胞进行癌症抑制试验。通过免疫印迹法检测药物处理后或基因敲低/过表达后的基因表达。这些处理也应用于MKN45植入瘤模型。进行了一项基于网络的胃癌队列研究，以分析Ar表达与预后的关系。
富含UA的白花蛇舌草乙醇提取物对胃癌细胞具有细胞毒性活性。与Ar的三维结构进行分子对接模拟显示UA具有优异的拟合分数。除了其Ar沉默能力外，UA还增加了细胞毒性并抑制了集落形成。此外，UA在体外协同促进了5-氟尿嘧啶（一种标准的胃癌治疗药物）方案。与这些结果一致，添加雌二醇并没有逆转UA的抗癌作用，这证实了UA作为一种Ar沉默剂发挥作用。此外，在异种移植瘤模型中单次给药时，UA在6周的治疗期内表现出90%的肿瘤抑制指数（TSI）评分。在临床环境中，发现来自TCGA（癌症基因组图谱）队列的胃癌肿瘤中Ar表达高于正常亲本组织，而高Ar表达与不良预后相关。总之，结果表明UA可通过沉默胃癌中的Ar表达来治疗胃癌。白花蛇舌草乙醇提取物可能是一种功能性食品补充剂。
