人参总皂苷调控NK细胞活性促进5-氟尿嘧啶抗肿瘤的作用

doi:10.6040/j.issn.1671-7554.0.2017.1010

摘要/Abstract

摘要： 目的探讨人参总皂苷(TSPG)调控NK细胞活性促进5-氟尿嘧啶抗肿瘤的作用机制。方法建立小鼠肝脏原位移植瘤模型,随机分为模型组、TSPG组、5-Fu组及TSPG+5-Fu组,给药观察14 d。实验结束分离肝脏并剥离肿瘤,计算肿瘤体积、肿瘤质量、抑瘤率;应用HE染色观察肿瘤组织病理变化;采用免疫组化检测NK细胞在肿瘤组织中的浸润情况;通过流式细胞技术检测肝脏、脾脏中NK细胞含量;应用实时定量PCR检测肿瘤组织中穿孔素、颗粒酶B的 mRNA表达水平。结果与模型组比较,各给药组肿瘤体积及质量均显著降低(P<0.05),肿瘤组织出现明显坏死;TSPG组NK细胞在肿瘤组织浸润增加(P<0.05);TSPG组与TSPG+5-Fu组肝脏、脾脏中NK细胞的含量均升高(P<0.05),肿瘤组织中穿孔素、颗粒酶B的mRNA表达水平亦升高(P<0.05)。结论 TSPG可以增强5-Fu抗肿瘤的作用疗效,其机制可能与TSPG提高荷瘤小鼠体内NK细胞的数量及杀伤活性有关。

关键词: 人参总皂苷, 5-氟尿嘧啶, 肝脏原位移植瘤, NK细胞

Abstract: Objective To explore the inhibitory effects of total saponins of Panax ginseng(TSPG)combined with 5-fluorouracil(5-Fu)on orthotopic transplantation tumors and the mechanism. Methods The orthotopic transplantation tumor models were established and randomly divided into 4 groups: model group, TSPG group, 5-Fu group and TSPG+5-Fu group. After 14 days, the livers were harvested and tumors were separated. The tumor weight, volume and tumor inhibition rate were determined. The pathological changes were observed with HE staining. The infiltration of NK cells in tumor tissues was observed with immunohistochemical method. The proportions of NK cells in the liver and spleen were assessed with flow cytometry. The mRNA expressions of perforin and granzyme B in tumor tissues were detected with real-time PCR. Results Compared with the model group, the other groups had significantly lower/smaller tumor volume and weight(P<0.05)and more obvious necrosis. The infiltration of NK cells increased in the TSPG group(P<0.05). The proportions of NK cells in the liver and spleen, and the mRNA expressions of perforin and Granzyme B increased in the TSPG group and TSPG+5-Fu group(P<0.05). Conclusion TSPG promotes the antitumor effects of 5-Fu, which may be explained by the increased number of NK cells and cytotoxity.

Key words: Total saponins of Panax ginseng, 5-fluorouracil, Orthotopic liver transplantation tumor, NK cell

中图分类号:

R574

马冉冉,韩琛,王朝霞,王兆朋,高誉欣,周淑萍,张月英,李小兵,刘恒铫,王恒孝. 人参总皂苷调控NK细胞活性促进5-氟尿嘧啶抗肿瘤的作用[J]. 山东大学学报 (医学版), 2018, 56(4): 43-50.

MA Ranran, HAN Chen, WANG Zhaoxia, WANG Zhaopeng, GAO Yuxin, ZHOU Shuping, ZHANG Yueying, LI Xiaobing, LIU Hengyao, WANG Hengxiao. Total saponins of Panax ginseng promoting the anticancer activity of 5-Fluorouracil by mediating NK cell activity[J]. Journal of Shandong University (Health Sciences), 2018, 56(4): 43-50.

参考文献

[1] Usmani A, Mishra A, Ahmad M. Nanomedicines: a theranostic approach for hepatocellular carcinoma[J]. Artif Cells Nanomed Biotechnol, 2018, 46(4): 680-690.
[2] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108.
[3] Kumral A, Giris M, Soluk-Tekkes, et al. Effect of olive leaf extract treatment on doxorubicin-induced cardiac, hepatic and renal toxicity in rats[J]. Pathophysiology, 2015, 22(2): 117-123.
[4] Ren M, Ye L, Hao X, et al. Polysaccharides from tricholoma matsutakeand lentinus edodes enhance 5-fluorouracilmediated H22 cell growth inhibition[J]. Tradit Chin Med, 2014, 34(3): 309-316.
[5] 康安, 钱静, 单进军, 等. 人参总皂苷主要成分大鼠体内药动学研究[J]. 中草药, 2015, 46(20): 3045-3050. KANG An, QIAN Jing, SHAN Jinjun, et al. In vivo pharmacokinetic study on total saponins from roots of Panax ginseng in rats[J]. Chinese Traditional and Herbal Drugs, 2015, 46(20): 3045-3050.
[6] 罗林明, 石雅宁, 姜懿纳, 等. 人参抗肿瘤作用的有效成分及其机制研究进展[J]. 中草药, 2017, 48(3): 582-596. LUO Linming, SHI Yaning, JIANG Yina, et al. Advance in components with antitumor effect of Panax ginseng and their mechanisms[J]. Chinese Traditional and Herbal Drugs, 2017, 48(3): 582-596.
[7] 贾执瑛, 谢燮, 王晓艳, 等. 人参主要成分对大鼠免疫功能的比较研究[J]. 中国中药杂志, 2014, 39(17): 3363-3366.
[8] Jia H, Zhao T, Zou D, et al. Therapeutic injection of a C-Type CpG ODN induced an antitumor immune response in C57/BL6 mice of orthotopically transplanted hepatocellular carcinoma[J]. Oncol Res, 2016, 23(6): 321-326.
[9] Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients[J]. Clin Immunol, 2008, 129(3): 428-437.
[10] Chen H, Zhidan W, Xia R, et al. Scorpion venom activates natural killer cells in hepatocellular carcinoma via the NKG2D-MICA pathway[J]. Int Immunopharmacology, 2016, 35: 307-314. doi: 10.1016/j.intimp.2016.03.045.
[11] Ke M, Wang H, Zhou Y, et al. SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice[J]. Oncotarget, 2016, 7(31): 49509-49526.
[12] 周娅红. 人参总皂苷对免疫低下小鼠免疫功能的影响[J]. 中国中医急症, 2010, 19(9): 1559-1561.
[13] Shim JY, Kim H, Kim HD, et al. Protective action of the immunomodulator ginsan against carbon tetrachloride-induced liver injury via control of oxidative stress and the inflammatory response[J]. Toxicol Appl harm, 2010, 242(3): 318-325.
[14] Sung SY, Hsieh CL, Wu D, et al. Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance[J]. Curr Probl Cancer, 2007, 31(2): 36-100.
[15] 姚蓉蓉, 王艳红. 肝细胞肝癌免疫微环境的研究进展[J]. 中国临床医学, 2014, 1(4): 487-497.
[16] Tosello-Trampont A, Surette FA, Ewald SE, et al. Immunoregulatory role of NK cells in tissue inflammation and regeneration[J]. Front Immunol, 2017, 20(8): 301-310.
[17] Marquardt N, Béziat V, Nyström S, et al. Cutting edge: identification and characterization of human intrahepatic CD49a⁺ NK cells[J]. J Immunol, 2015, 194(6): 2467-2471.
[18] Sojka DK1, Plougastel-Douglas B, Yang L, et al. Tissue-resident natural killer(NK)cells are cell lineages distinct from thymic and conventional splenic NK cells[J]. Elife, 2014, 3: e01659. doi: 10.7554/eLife.01659.
[19] Woodsworth DJ, Dreolini L, Abraham L, et al. Targeted cell-to-cell delivery of protein payloads via the granzyme-perforin pathway[J]. Mol Ther Methods Clin Dev, 2017, 7: 132-145. doi: 10.1016/j.omtm.2017.10.003.
[20] Li Q, Kobayashi M, Kawada T, et al. Effect of ziram on natural killer, lymphokine-activated killer, and cytotoxic T lymphocyte activity[J]. Archives of Toxicology 2012, 86(3): 475-481.
[21] Li Q, Kobayashi M, Inagaki H, et al. A day trip to a forest park increases human natural killer activity and the expression of anti-cancer proteins in male subjects[J]. J Biol Regul Homeost Agents, 2010, 24(2): 157-165.
[22] 曹雪涛, 高福, 龚非力, 等. 免疫学前沿. [M]. 3版. 北京: 人民卫生出版社, 2014: 82.
[23] Zhou Z, Yu X, Zhang J, et al. TLR7/8 agonists promote NK-DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma[J]. Cancer Lett, 2015, 369(2): 298-306.
[24] Nguyen-Pham TN, Yang DH, Nguyen TA, et al. Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy[J]. Cell Mol Immunol, 2012, 9(1): 45-53.
[25] Gao J, Duan Z, Zhang L, et al. Failure recovery of circulating NKG2D+CD56dimNK cells in HBV-associated hepatocellular carcinoma after hepatectomy predicts early recurrence[J]. Oncoimmunology, 2016, 5(1): e1048061. eCollection 2016.
[26] Sun C, Sun HY, Xiao WH, et al. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy[J]. Acta Pharmacol Sin, 2015, 36(10): 1191-1199.

相关文章 13

[1]	孙丽娜,杜晓晓,张红娟,孟金来. 人类白细胞抗原G调控蜕膜自然杀伤细胞促进滋养细胞侵袭[J]. 山东大学学报 (医学版), 2022, 60(6): 41-45.
[2]	李涛,杨春林,杜通,李亨,王聪聪,李晓丽,段瑞生,张蓬. 糖尿病对重症肌无力NK细胞亚型及功能的影响[J]. 山东大学学报 (医学版), 2022, 60(5): 31-36.
[3]	单婧,王晓秋,李大金. NK细胞参与子宫内膜异位症及其不孕的分子机制[J]. 山东大学学报 (医学版), 2021, 59(8): 8-13.
[4]	李湘青,殷欣,赵雪莲,赵培庆. NK细胞亚群CD56^bright在帕金森患者外周血中的表达及临床意义[J]. 山东大学学报 (医学版), 2021, 59(2): 34-40.
[5]	贾新转,张娜,郭丽娜,赵素英,董翠,魏兰. 醋酸泼尼松治疗URSA对临床结局及NK细胞表型的影响[J]. 山东大学学报（医学版）, 2016, 54(5): 62-65.
[6]	姚铁柱,马景涛,郭丽敏. 尼可地尔治疗5-氟尿嘧啶诱发冠脉痉挛1例报道[J]. 山东大学学报（医学版）, 2016, 54(3): 95-96.
[7]	王尧, 陈艳红, 陈宏. 结肠癌患者外周血DPYD基因多态性与5-FU敏感性和毒副作用相关性分析[J]. 山东大学学报（医学版）, 2014, 52(S1): 18-21.
[8]	褚倩倩1，许刚2，任桂杰1，徐霞1，胡中一1，刘永青1，苑辉卿1，田克立1. 过氧化物酶体增殖物激活受体γ激动剂对增强人结肠癌化疗敏感性的作用[J]. 山东大学学报(医学版), 2012, 50(1): 66-71.
[9]	李玉生，黄黎，吕其军，余永勤. 干扰素α-2b联合5-氟尿嘧啶对人肝癌细胞生物学行为的影响[J]. 山东大学学报(医学版), 2011, 49(9): 48-.
[10]	王合丽1，孙学梅2，孙正芸1，王娜1，林霞1. 妊娠期糖尿病母亲新生儿T细胞亚群及NK细胞活性的变化及其与血糖相关的研究[J]. 山东大学学报(医学版), 2011, 49(4): 4-.
[11]	黄先亮1,董白桦1,胡微煦2,王庆杰2,宋丙凤2,王春娥2,刘佳2,孔北华1,曲迅2. 妊娠早期CD56brightCD16- NK细胞CD49d和CD11b的表达分析[J]. 山东大学学报(医学版), 2010, 48(5): 97-100.
[12]	张栋1，李翠静2，李林军1，席延卫1，黄桂华1. pH依赖-时滞型5-FU微丸大鼠结肠定位释药研究[J]. 山东大学学报(医学版), 2010, 48(12): 46-50.
[13]	丁印鲁,付勤烨,唐思锋,王静源,张建良,李占元,李兆亭 . 血管生成抑制剂SU6668联合5-Fu对人结肠癌裸鼠移植瘤肝转移的影响[J]. 山东大学学报(医学版), 2007, 45(2): 168-170.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed