Artemisinin and its derivatives prevent Helicobacter pylori-induced gastric carcinogenesis via inhibition of NF-κB signaling
Artemisinin and its derivatives prevent Helicobacter pylori-induced gastric carcinogenesis via inhibition of NF-κB signaling
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青蒿素及其衍生物通过抑制 NF-κ B 信号传导预防幽门螺杆菌诱导的胃癌发生
DOI：
10.1016/j.phymed.2019.152968
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发表时间：
2019-10-01
期刊：
影响因子：
7.9
通讯作者：
Wang, Dawei
中科院分区：
文献类型：
--
作者：
Su, Tao;Li, Fangyuan;Wang, Dawei
背景：胃癌发病率高，是全球癌症相关死亡的主要原因。幽门螺杆菌(Hp)感染常见于胃癌发病的早期阶段，可诱发慢性胃炎。青蒿素(ART)及其衍生物(ARTS、青蒿琥酯和DHA、双氢青蒿素)是一类新型的有效抗疟疾药物，已被报道具有预防和抗胃癌的作用。目的：研究幽门螺杆菌感染在胃癌中的作用，以及ART、ARTS和DHA的预防机制。方法：采用肉汤宏观稀释法测定Hp的生长，用尿素酶法检测其与胃癌细胞的粘附性。分别用Western印迹、实时定量聚合酶链式反应、流式细胞仪和酶联免疫吸附试验检测细胞内蛋白质和mRNA水平、活性氧(ROS)的产生和炎性细胞因子的产生。结果：ART、DHA和ARTS均能抑制幽门螺杆菌和胃癌细胞的生长，抑制幽门螺杆菌与胃癌细胞的黏附，减少幽门螺杆菌诱导的ROS的产生。此外，在小鼠模型中，ART、DHA和ARTS显著降低了肿瘤发生率、肿瘤结节数量和肿瘤大小。在这三种化合物中，DHA的化学预防作用最强。结论：ART、DHA和ARTS对幽门螺杆菌诱导的胃癌有较强的预防作用。这些效应至少部分归因于对核因子-kappaB信号通路的抑制。我们的发现为使用ART及其衍生物预防和治疗胃癌提供了分子依据。
Background: Gastric cancer has a high morbidity and is a leading cause of cancer-related mortality worldwide. Helicobacter pylori (H. pylori) infection is commonly found in the early stage of gastric cancer pathogenesis, which induces chronic gastritis. Artemisinin (ART) and its derivatives (ARTS, artesunate and DHA, dihydroartemisinin), a new class of potent antimalarials, have been reported to exert both preventive and anti-gastric cancer effects. However, the underlying mechanisms of the chemopreventive effects of ART and its derivatives in H. pylon infection induced-gastric cancer are not fully elucidated.Purpose: We investigated the effects of H. pylori infection in gastric cancer; and the preventive mechanisms of ART, ARTS and DHA.Methods: The H. pylori growth was determined by the broth macro-dilution method, and its adhesion to gastric cancer cells was evaluated by using the urease assay. The protein and mRNA levels, reactive oxygen species (ROS) production, as well as the production of inflammatory cytokines were evaluated by Western blot, real-time PCR, flow cytometry and ELISA, respectively. Moreover, an in vivo MNU (N-methyl-N-nitroso-urea) and H. pyloriinduced gastric adenocarcinoma mouse model was established for the investigation of the cancer preventive effects of ART and its derivaties, and the underlying mechanisms of action.Results: ART, DHA and ARTS inhibited the growth of H. pylori and gastric cancer cells,suppressed H. pylori adhesion to the gastric cancer cells, and reduced the H. pylori-enhanced ROS production. Moreover, ART, DHA and ARTS significantly reduced tumor incidence, number of tumor nodules and tumor size in the mouse model. Among these three compounds, DHA exerted the most potent chemopreventive effect. Mechanistic studies showed that ART and its derivatives potently inhibited the NF-kappa B activation.Conclusion: ART, DHA and ARTS have potent preventive effects in H. pylori-induced gastric carcinogenesis. These effects are, at least in part, attributed to the inhibition of NF-kappa B signaling pathway. Our findings provide a molecular justification of using ART and its derivatives for the prevention and treatment of gastric cancer.