基于网络药理学的女贞子-黄芪药对的抗癌机制
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摘要
目的:筛选女贞子-黄芪药对抗癌治疗的主要活性成分,预测活性成分的作用靶点,建立药物成分-活性成分-作用靶点网络,进一步探讨女贞子-黄芪药对抗癌治疗的潜在作用机制。方法:采用中药系统药理学技术平台(TCMSP)中筛选女贞子-黄芪的潜在活性成分,采用Dis Ge NET数据库与人类孟德尔遗传数据库(Online Mendelian Inheritance in Man,OMIM)预测和筛选其治疗癌症的作用靶点,采用omicshare平台(http://www. omicshare. com/)对药物靶点和疾病靶点进行匹配。借助Cytoscape软件构建"药物-活性成分-关键作用靶点"网络。采用String数据库构建蛋白质相互作用网络。采用DAVID数据库对女贞子-黄芪关键作用靶点进行生物功能及代谢通路分析。结果:通过筛选得到33个药物活性成分,共涉及203个作用靶点,与疾病靶点有关的活性成分为14个,主要通过调控ERBB2,AR,SRC,EGFR,ESR1等靶蛋白及癌症中的蛋白多糖通路、癌症通路、癌症中的微小mRNA(micro RNA)等通路等发挥抗癌治疗作用。结论:女贞子-黄芪药对对癌症的治疗作用体现了中药多成分-多靶点-多途径的特点,为阐释其抗癌治疗的作用机制与物质基础提供了科学依据。
Objective: To screen out active ingredients,and predict the anti-cancer targets of Ligustri Lucidi Fructus-Astragali Radix based on the " herbs-active ingredient-action targets " network. Method: The traditional Chinese medicine( TCM) system pharmacology platform( TCMSP) was employed to screen out the active ingredients and putative targets of anti-cancer of glossy privet fruit and astragalus. Dis Ge NET database and Online Mendelian Inheritance in Man( OMIM database) were employed to predict the targets for treating cancer,and then " herbs-active ingredients-key targets " network was constructed by using Cytoscape software. The omicshare platform was employed to match the putative targets of ingredients and the targets for treating cancer.Finally,the protein interaction network of key targets was constructed by using String database,and the analysis of biological functions and pathways of them was carried out by using DAVID database. Result: Totally 33 drug active ingredients were screened out,involving a total of 203 targets,and 14 of them were related to cancer. These 14 key targets played an therapeutic role in treating cancer by regulating target proteins,such as ERBB2,AR,SRC,EGFR,ESR1,as well as proteoglycans in cancer,cancer pathways,microRNAs in cancer and other pathways.Conclusion: The therapeutic mechanism of Ligustri Lucidi Fructus-Astragali Radix reflects the multi-component,multi-target,and multi-pathway characteristics of TCMs,providing the scientific basis for further study and the material basis of Ligustri Lucidi Fructus-Astragali Radix against cancer.
Objective: To screen out active ingredients,and predict the anti-cancer targets of Ligustri Lucidi Fructus-Astragali Radix based on the " herbs-active ingredient-action targets " network. Method: The traditional Chinese medicine( TCM) system pharmacology platform( TCMSP) was employed to screen out the active ingredients and putative targets of anti-cancer of glossy privet fruit and astragalus. Dis Ge NET database and Online Mendelian Inheritance in Man( OMIM database) were employed to predict the targets for treating cancer,and then " herbs-active ingredients-key targets " network was constructed by using Cytoscape software. The omicshare platform was employed to match the putative targets of ingredients and the targets for treating cancer.Finally,the protein interaction network of key targets was constructed by using String database,and the analysis of biological functions and pathways of them was carried out by using DAVID database. Result: Totally 33 drug active ingredients were screened out,involving a total of 203 targets,and 14 of them were related to cancer. These 14 key targets played an therapeutic role in treating cancer by regulating target proteins,such as ERBB2,AR,SRC,EGFR,ESR1,as well as proteoglycans in cancer,cancer pathways,microRNAs in cancer and other pathways.Conclusion: The therapeutic mechanism of Ligustri Lucidi Fructus-Astragali Radix reflects the multi-component,multi-target,and multi-pathway characteristics of TCMs,providing the scientific basis for further study and the material basis of Ligustri Lucidi Fructus-Astragali Radix against cancer.
引文
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[23]辛敏,陈健,郭艳红.毛蕊异黄酮对膀胱癌细胞凋亡和PI3K/Akt信号通路的影响[J].广东医学,2015,36(5):690-693.
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[28]王娟,刘军权,陈复兴,等.β-谷甾醇对人共刺激细胞杀伤胃癌SGC-7901细胞的影响及其机制的探讨[J].免疫学杂志,2014,30(7):578-584.
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[30]李聪,胡强,张燕翔,等.槲皮素的药理学活性研究进展[J].湖北中医杂志,2018,40(6):63-66.
[31]刘明学,魏光辉.槲皮素的药理学作用及临床应用前景[J].中国药房,2010,21(27):2581-2583.
[32]孙阳,于水澜,吴勃岩,等.槲皮素自微乳的抗肿瘤作用及其机制分析[J].中国实验方剂学杂志,2018,24(14):97-101.
[33]仇丽红,赵梅香,黄洁,等. C-erbB2基因生物学特性研究进展[J].现代肿瘤医学,2007,15(1):102-105.
[34]牟兆新,侯振江. C-erbB2基因在恶性肿瘤中的研究进展[J].中国煤炭工业医学杂志,2006,9(1):4-6.
[35]Mendelsohn J,Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer[J]. J Clin Oncol,2003,21(14):2787-2799.
[36]Nicholson R I,Gee J M,Harper M E. EGFR and cancer prognosis[J]. Europ J Cancer,2001,37(14):9-15.
[37]Kobayashi S,Boggon T J,Dayaram T,et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib[J]. N Engl J Med,2005,352(8):786-792.
[38]TENG X Y,LIU G Q,DIAO X L,et al. CAG repeats in the androgen receptor gene are shorter in patients with pulmonary,esophageal or bladder carcinoma and longer in women with uterine leiomyoma[J]. Oncol Rep,2010,23(3):811-818.
[39]Koochekpour S. Androgen receptor signaling and mutations in prostate cancer[J]. Asian J Androl,2010,12(5):639-657.
[40]杜晓煜,唐丹凤,郑莉萍,等.原癌基因c-src相关信号通路的研究进展[J].生殖与避孕,2010,30(4):269-273.
[41]Wooster R,Stratton M R. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome13q12-13[J]. Science,1994,265(5181):2088-2090.
[42]高雅茹,郝敏. Rap1在妇科恶性肿瘤中的研究进展[J].中华临床医师杂志:电子版,2016,10(9):1308-1311.
[43]陈安安,汪炬.肿瘤中雌激素信号转导通路的研究进展[J].中国病理生理杂志,2012,28(3):570-576.
[44]郭树鹏,杨柳,张莉琳,等. HIF-1α信号通路在肿瘤细胞调控中的研究进展[J].现代生物医学进展,2015,15(16):3145-3148.
[2]王辉,孙桂芝,花宝金.中医药防治肿瘤的源流、现状和发展趋势[J].中华中医药学刊,2012,30(9):1973-1975.
[3]秦红霖,高月.女贞子化学成分及药理研究进展[J].中药新药与临床药理,2007,18(1):84-85.
[4]刘亭亭,王萌.女贞子化学成分与药理作用研究进展[J].中国实验方剂学杂志,2014,20(14):228-234.
[5]邓晓霞,李清宋,陈中,等.黄芪抗肿瘤作用机制的研究进展[J].中药新药与临床药理,2016,27(2):307-312.
[6]胡兵,沈克平.黄芪抗肿瘤作用及机制研究[J].中药材,2008,31(3):461-465.
[7]Hopkins A L. Network pharmacology[J]. Nature Biotechnol,2007,25(10):1110-1111.
[8]RU J,LI P,WANG J,et al. TCMSP:a database of systems pharmacology for drug discovery from herbal medicines[J]. J Chem,2014,6(1):13.
[9]Gfeller D,Grosdidier A,Wirth M,et al. Swiss Target Prediction:a web server for target prediction of bioactive small molecules[J]. Nucleic Acids Res,2014,42(Web+Server):32-38.
[10]Pin珘ero J, Queralt-Rosinach N, Bravoà, et al.Dis Ge NET:a discovery platform for the dynamical exploration of human diseases and their genes[J].Database,2015,2015(3):28.
[11]Hamosh A,Scott A F,Amberger J,et al. Online Mendelian Inheritance in Man(OMIM), a knowledgebase of human genes and genetic disorders[J]. Nucl Acids Res,2005,33(1):514-517.
[12]Szklarczyk D, Franceschini A, Wyder S, et al.STRING v10:protein protein interaction networks,integrated over the tree of life[J]. Nucleic Acids Res,2015,43(Database issue):447.
[13]HUANG D W, Sherman B T, Lempicki R A.Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J]. Nature Protocols,2009,4(1):44-57.
[14]陈天君,Thakar A,陈明伟. GP化疗联合贞芪扶正胶囊治疗NSCLC的临床观察[J].时珍国医国药,2012,23(9):2264-2265.
[15]景明,李沛清,刘俊田,等.贞芪扶正分散片对肿瘤化疗的增效和减毒作用研究[J].时珍国医国药,2010,21(3):604-605.
[16]付廷雄,唐求,聂彬.贞芪扶正胶囊配合放疗治疗老年晚期非小细胞肺癌[J].药物流行病学杂志,2008,17(1):4-6.
[17]舒文,于廷和.贞芪扶正胶囊在卵巢癌化疗并发症预防中的效果观察[J].中药药理与临床,2016,32(6):201-204.
[18]张海平,赵慧峰,夏红蕾.贞芪扶正颗粒辅助治疗宫颈癌的临床观察[J].中国药房,2017,28(9):1174-1177.
[19]郑方,孙志强.贞芪扶正颗粒联合达沙替尼治疗BCR-ABL阳性白血病的临床观察[J].中国药房,2016,27(18):2482-2484.
[20]李科,张旭.贞芪扶正颗粒联合替吉奥胶囊治疗老年人晚期贲门癌的临床研究[J].中华老年医学杂志,2014,33(12):1314-1316.
[21]刘焕龙,陈雪彦,苏素文,等.注射用贞芪扶正对环磷酰胺的增效减毒作用研究[J].中药药理与临床,2008,24(4):50-52.
[22]张冬梅.毛蕊异黄酮-7-O-β-D-葡萄糖苷对人宫颈癌He La细胞凋亡及Bcl-2/Bax表达的影响[J].中草药,2015,46(10):1498-1502.
[23]辛敏,陈健,郭艳红.毛蕊异黄酮对膀胱癌细胞凋亡和PI3K/Akt信号通路的影响[J].广东医学,2015,36(5):690-693.
[24]周瑞娟,陈红风,叶媚娜,等.芒柄花素对不同亚型乳腺癌细胞增殖及细胞周期的影响[J].肿瘤防治研究,2012,39(9):1051-1055.
[25]盛佳钰,陈红风.芒柄花素联合MK2206对不同亚型乳腺癌细胞增殖和凋亡的影响[J].中华肿瘤防治杂志,2015,22(13):998-1003.
[26]李自全,孟祥娇.芒柄花素对人非小细胞肺癌细胞增殖、凋亡的影响及相关机制探讨[J].中国实验方剂学杂志,2016,22(20):138-142.
[27]张忠泉,邢煜君,胡国强,等.β-谷甾醇诱导人肝癌Hep G2细胞凋亡机制研究[J].中国中药杂志,2011,36(15):2145-2148.
[28]王娟,刘军权,陈复兴,等.β-谷甾醇对人共刺激细胞杀伤胃癌SGC-7901细胞的影响及其机制的探讨[J].免疫学杂志,2014,30(7):578-584.
[29]周玲玉.β-谷甾醇对人肺癌细胞增殖、凋亡影响的初步研究[D].重庆:重庆医科大学,2016.
[30]李聪,胡强,张燕翔,等.槲皮素的药理学活性研究进展[J].湖北中医杂志,2018,40(6):63-66.
[31]刘明学,魏光辉.槲皮素的药理学作用及临床应用前景[J].中国药房,2010,21(27):2581-2583.
[32]孙阳,于水澜,吴勃岩,等.槲皮素自微乳的抗肿瘤作用及其机制分析[J].中国实验方剂学杂志,2018,24(14):97-101.
[33]仇丽红,赵梅香,黄洁,等. C-erbB2基因生物学特性研究进展[J].现代肿瘤医学,2007,15(1):102-105.
[34]牟兆新,侯振江. C-erbB2基因在恶性肿瘤中的研究进展[J].中国煤炭工业医学杂志,2006,9(1):4-6.
[35]Mendelsohn J,Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer[J]. J Clin Oncol,2003,21(14):2787-2799.
[36]Nicholson R I,Gee J M,Harper M E. EGFR and cancer prognosis[J]. Europ J Cancer,2001,37(14):9-15.
[37]Kobayashi S,Boggon T J,Dayaram T,et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib[J]. N Engl J Med,2005,352(8):786-792.
[38]TENG X Y,LIU G Q,DIAO X L,et al. CAG repeats in the androgen receptor gene are shorter in patients with pulmonary,esophageal or bladder carcinoma and longer in women with uterine leiomyoma[J]. Oncol Rep,2010,23(3):811-818.
[39]Koochekpour S. Androgen receptor signaling and mutations in prostate cancer[J]. Asian J Androl,2010,12(5):639-657.
[40]杜晓煜,唐丹凤,郑莉萍,等.原癌基因c-src相关信号通路的研究进展[J].生殖与避孕,2010,30(4):269-273.
[41]Wooster R,Stratton M R. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome13q12-13[J]. Science,1994,265(5181):2088-2090.
[42]高雅茹,郝敏. Rap1在妇科恶性肿瘤中的研究进展[J].中华临床医师杂志:电子版,2016,10(9):1308-1311.
[43]陈安安,汪炬.肿瘤中雌激素信号转导通路的研究进展[J].中国病理生理杂志,2012,28(3):570-576.
[44]郭树鹏,杨柳,张莉琳,等. HIF-1α信号通路在肿瘤细胞调控中的研究进展[J].现代生物医学进展,2015,15(16):3145-3148.