Yun Xinming, Zhang Qin, Fang Yulai, Lv Changjun, Chen Qingyong, Chu Yuyao, Zhu Yanrong, Wei Zhifeng, Xia Yufeng, Dai Yue
Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Biochem Pharmacol. 2022 Aug;202:115138. doi: 10.1016/j.bcp.2022.115138. Epub 2022 Jun 11.
Madecassic acid (MA), a triterpene compound isolated from Centella Asiatica herbs, has previously been shown to attenuate colitis induced by DSS in mice. In the present study, we address whether and how MA ameliorates colitis-associated colorectal cancer (CAC), which accounts for a considerable proportion of colorectal cancer.
CAC was induced by AOM/DSS in mice, and MA was administered orally once a day. To identify the source cells of IL-17 and the target cells for MA reducing the expression of IL-17 in the colons of CAC mice, single-cell suspensions were prepared from the colons of CAC mice and analyzed by flow cytometry. An adoptive transfer experiment was performed to verify the importance of the decreasing γδT17 cell population in the anti-CAC effect of MA.
Oral administration of MA reduced the burden and incidence of tumors in the CAC mice. MA decreased the number of MDSCs in the colon tissues of CAC mice and ameliorated anti-tumor immune responses. MA could prevent the migration of MDSCs by inhibiting the activation of γδT17 cells and the expression of chemokines. The population of activated-γδT17 cells in the tumor microenvironment of CAC mice positively correlated with the number of MDSCs and tumors as well as tumor load. Moreover, the anti-CAC effect of MA was significantly counteracted by the adoptive transfer of γδT17 cells.
MA alleviates CAC by blocking the recruitment of MDSCs to increase the population of anti-tumor immune cells in tumor microenvironment via inhibition of the activation of γδT17 cells.
羟基积雪草苷（MA）是从积雪草中分离出的一种三萜类化合物，此前已证明其可减轻小鼠中由葡聚糖硫酸钠（DSS）诱导的结肠炎。在本研究中，我们探讨MA是否以及如何改善结肠炎相关的结直肠癌（CAC），这在结直肠癌中占相当大的比例。
通过氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导小鼠患CAC，并每天口服一次MA。为了确定白细胞介素-17（IL-17）的来源细胞以及MA降低CAC小鼠结肠中IL-17表达的靶细胞，从CAC小鼠的结肠中制备单细胞悬液并通过流式细胞术进行分析。进行过继转移实验以验证减少γδT17细胞群体在MA抗CAC作用中的重要性。
口服MA可减轻CAC小鼠的肿瘤负担和发病率。MA减少了CAC小鼠结肠组织中髓源性抑制细胞（MDSCs）的数量，并改善了抗肿瘤免疫反应。MA可通过抑制γδT17细胞的活化和趋化因子的表达来阻止MDSCs的迁移。CAC小鼠肿瘤微环境中活化的γδT17细胞群体与MDSCs的数量、肿瘤数量以及肿瘤负荷呈正相关。此外，γδT17细胞的过继转移显著抵消了MA的抗CAC作用。
MA通过抑制γδT17细胞的活化，阻断MDSCs的募集，以增加肿瘤微环境中抗肿瘤免疫细胞的数量，从而减轻CAC。
