Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Shunde Hospital of Guangzhou University of Chinese Medicine, Shunde, Guangdong, China; Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Phytomedicine. 2019 Oct;63:152968. doi: 10.1016/j.phymed.2019.152968. Epub 2019 May 21.
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. pylori infection induced-gastric cancer are not fully elucidated.
We investigated the effects of H. pylori infection in gastric cancer; and the preventive mechanisms of ART, ARTS and DHA.
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. pylori-induced 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.
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-κB activation.
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-κB signaling pathway. Our findings provide a molecular justification of using ART and its derivatives for the prevention and treatment of gastric cancer.
胃癌发病率高，是全球癌症相关死亡率的主要原因。幽门螺杆菌（H. pylori）感染常见于胃癌发病的早期阶段，可导致慢性胃炎。青蒿素（ART）及其衍生物（ARTS、青蒿琥酯和 DHA、二氢青蒿素）是一类新型强效抗疟药，据报道具有预防和抗胃癌作用。然而，ART 及其衍生物在 H. pylori 感染诱导的胃癌中的化学预防作用的潜在机制尚未完全阐明。
我们研究了 H. pylori 感染对胃癌的影响；以及 ART、ARTS 和 DHA 的预防机制。
采用肉汤微量稀释法测定 H. pylori 的生长，采用脲酶测定法评估其对胃癌细胞的黏附作用。通过 Western blot、实时 PCR、流式细胞术和 ELISA 分别评估蛋白和 mRNA 水平、活性氧（ROS）产生以及炎症细胞因子的产生。此外，建立了 MNU（N-甲基-N-亚硝基脲）和 H. pylori 诱导的胃癌小鼠模型，用于研究 ART 及其衍生物的抗癌作用及其作用机制。
ART、DHA 和 ARTS 抑制了 H. pylori 和胃癌细胞的生长，抑制了 H. pylori 对胃癌细胞的黏附作用，并降低了 H. pylori 增强的 ROS 产生。此外，ART、DHA 和 ARTS 显著降低了小鼠模型中的肿瘤发生率、肿瘤结节数量和肿瘤大小。在这三种化合物中，DHA 发挥了最有效的化学预防作用。机制研究表明，ART 和其衍生物能有效抑制 NF-κB 激活。
ART、DHA 和 ARTS 对 H. pylori 诱导的胃癌发生具有强大的预防作用。这些作用至少部分归因于抑制 NF-κB 信号通路。我们的研究结果为使用 ART 及其衍生物预防和治疗胃癌提供了分子依据。
