Zhang Anle, Zheng Yuanhong, Que Zujun, Zhang Lingling, Lin Shengchao, Le Vanminh, Liu Jianwen, Tian Jianhui
Department of Molecular & Cellular Pharmacology, Biomedical Nanotechnology Center, State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
J Cancer Res Clin Oncol. 2014 Nov;140(11):1883-90. doi: 10.1007/s00432-014-1744-x. Epub 2014 Jul 1.
Tumor cells have developed multiple mechanisms to escape immune recognition mediated by T cells. Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme inducing immune tolerance, is involved in tumor escape from host immune systems in mice. Astragaloside IV (AS-IV), an extract from a commonly used Chinese medicinal plant Astragalus membranaceus, has been shown to be capable of restoring the impaired T-cell functions in cancer patients. The purpose of this study was to investigate the mechanisms underlying the anticancer properties of AS-IV.
Here, we used IDO-overexpressed murine Lewis lung carcinoma cells to establish an orthotopic lung cancer model in C57BL/6 mice. Next, tumor growth was evaluated in several different treatment groups: control (saline), AS-IV, paclitaxel, and 1-methyl tryptophan (an inhibitor of IDO). We then analyzed the percentages of various immune cell subsets among the splenic lymphocytes of lung cancer mice by flow cytometry. The level of IDO was measured by real-time PCR and Western blot.
We showed that the growth of tumor was suppressed by AS-IV treatment in vivo. AS-IV also could down-regulate regulatory T cells (Tregs) and up-regulate cytotoxic T lymphocytes (CTLs) in vivo and in vitro. Consistent with its ability to interfere with T-cell immunity, AS-IV blocked IDO induction both in vitro and in vivo.
The results of these studies indicate that AS-IV has in vivo anticancer activity and can enhance the immune response by inhibiting the Tregs frequency and induce the activity of CTLs, which might be related to the inhibition of IDO expression.
肿瘤细胞已发展出多种机制来逃避由T细胞介导的免疫识别。吲哚胺2,3-双加氧酶（IDO）是一种诱导免疫耐受的色氨酸分解代谢酶，参与小鼠肿瘤从宿主免疫系统的逃逸。黄芪甲苷（AS-IV）是常用中药材黄芪的提取物，已被证明能够恢复癌症患者受损的T细胞功能。本研究的目的是探讨AS-IV抗癌特性的潜在机制。
在此，我们使用IDO过表达的小鼠Lewis肺癌细胞在C57BL/6小鼠中建立原位肺癌模型。接下来，在几个不同的治疗组中评估肿瘤生长：对照组（生理盐水）、AS-IV、紫杉醇和1-甲基色氨酸（IDO抑制剂）。然后，我们通过流式细胞术分析肺癌小鼠脾淋巴细胞中各种免疫细胞亚群的百分比。通过实时PCR和蛋白质免疫印迹法测量IDO水平。
我们表明，AS-IV治疗在体内可抑制肿瘤生长。AS-IV在体内和体外还可下调调节性T细胞（Tregs）并上调细胞毒性T淋巴细胞（CTLs）。与其干扰T细胞免疫的能力一致，AS-IV在体外和体内均阻断IDO的诱导。
这些研究结果表明，AS-IV具有体内抗癌活性，可通过抑制Tregs频率增强免疫反应并诱导CTLs的活性，这可能与抑制IDO表达有关。
