基于网络药理学和分子对接探究三棱-莪术抗乳腺癌的作用机制

doi:10.3976/j.issn.1002-4026.2022.05.004

山东科学 ›› 2022, Vol. 35 ›› Issue (5): 26-36.doi: 10.3976/j.issn.1002-4026.2022.05.004

基于网络药理学和分子对接探究三棱-莪术抗乳腺癌的作用机制

刘雪婷^1a(), 孙小慧², 朱建敏²^,^*(), 李林^1b, 李文悦^1b

1.山东中医药大学 a.中医学院;b.第一临床医学院,山东济南 250013
2.山东中医药大学附属医院,山东济南 250014

收稿日期:2021-11-02 出版日期:2022-10-20 发布日期:2022-10-10
通信作者: 朱建敏 E-mail:liuxueting1112021@126.com;jinjin20021023@126.com
作者简介:刘雪婷(1996—),女,硕士研究生,研究方向为乳腺甲状腺疾病。E-mail: liuxueting1112021@126.com
基金资助:
山东省自然科学基金博士基金(ZR2017BH107);山东省齐鲁卫生与健康杰出青年人才项目(鲁卫人字[2020]3号);山东中医药大学附属医院朝阳人才项目;济南市临床医学科技创新计划(202019157);山东省中医药科技发展计划(2019-0160);山东省中医药科技发展计划(2019-0090)

Mechanism of the anti-breast cancer effect of Sparganii Rhizoma-Curcumae Rhizoma herbal pair based on network pharmacology and molecular docking

LIU Xue-ting^1a(), SUN Xiao-hui², ZHU Jian-min²^,^*(), LI Lin^1b, LI Wen-yue^1b

1. a.College of Traditional Chinese Medicine;b.The First Clinical Medical College,Shandong University of Traditional Chinese Medicine, Jinan 250013,China
2. Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014,China

Received:2021-11-02 Online:2022-10-20 Published:2022-10-10
Contact: ZHU Jian-min E-mail:liuxueting1112021@126.com;jinjin20021023@126.com

摘要/Abstract

摘要：

运用网络药理学和分子对接探究三棱-莪术药对抗乳腺癌的有效活性成分及分子机制。通过中药系统药理学数据库与分析平台检索并筛选出三棱、莪术的有效活性成分和对应作用靶点,运用OMIM数据库、GeneCards数据库检索乳腺癌的疾病靶点。运用Cytoscape 3.7.2软件绘制药物-成分-疾病-靶点网络图。利用STRING数据库构建蛋白质-蛋白质相互作用(protein- protein interaction,PPI)网络,使用Cytoscape中MCODE插件进行分析并筛选出前10个核心靶点。借助DAVID数据库对作用靶点进行基因本体及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)通路富集分析,并绘制成分-靶点-通路网络图。最后通过AutoDock Vina等软件进行分子对接,验证核心成分与核心靶点的相互作用。结果表明,通过筛选得出7种活性成分、73个作用靶点,三棱-莪术与乳腺癌共同靶点43个。核心成分为常春藤皂苷元、β-谷甾醇、芒柄花黄素、豆甾醇、反式软骨酸,PPI网络显示其核心靶点为JUN、CASP3、PTGS2、ESR1、MPK14、PPARG、SIRT1、NOS3、TGFB1、NOS2。KEGG富集分析得到72条通路,根据P值筛选出与乳腺癌相关的前20条,主要涉及PI3K-Akt通路、VEGF通路、p53通路、MAPK通路等。分子对接显示活性成分与核心靶点之间有较好的结合力。研究表明三棱-莪术药对抗乳腺癌具有多成分、多靶点、多通路的特点,为该药对在临床中的应用提供了理论依据。

关键词: 网络药理学, 分子对接, 三棱-莪术, 乳腺癌, 作用机制

Abstract:

To explore the active ingredients and mechanisms of Sparganii Rhizoma-Curcumae Rhizoma herbal pair in breast cancer using network pharmacology and molecular docking. The effective active ingredients and corresponding targets of Sparganii Rhizoma and Curcumae Rhizoma were searched and screened using the traditional Chinese medicine systems pharmacology database and analysis platform,and the disease targets of breast cancer were searched using the OMIM and GeneCards databases. Cytoscape 3.7.2 software was used to construct a visual network diagram of drug-ingredient-disease-targets. A protein-protein interaction network (PPI) was constructed using STRING database platform, and the MCODE plug-in in Cytoscape was used for analysis to screen the top 10 core targets. Gene ontology and Kyoto encyclopedia of genes and genomes(KEGG) enrichment pathway analyses of the targets of action were performed using DAVID database, and the network diagram of ingredient-target-pathway was plotted. Finally, molecular docking was performed using autodock Vina and other software to verify the interaction between the core ingredients and the core targets. Seven active components and 73 action targets were obtained through screening. There were 43 common targets of Sparganii Rhizoma and Curcumae Rhizoma and breast cancer. The active components were hederagenin, beta-sitosterol, formononetin, stigmasterol, and trans-gondoic acid. The PPI network showed that the key targets were JUN, CASP3, PTGS2, ESR1, MPK14, PPARG, SIRT1, NOS3, TGFB1 and NOS2. The KEGG pathway enrichment analysis revealed 72 items. According to the P values, the first 20 items related to breast cancer were eliminated via screened, including the PI3K-Akt signaling pathway, VEGF signaling pathway, p53 signaling pathway, and MAPK signaling pathway. The molecular docking results showed that the active ingredients had strong binding ability in docking with the core targets. Therefore, our results suggest that Sparganii Rhizoma-Curcumae Rhizoma herbal pair has characteristics of a multi-ingredient, multi-target, and multi-pathway on breast cancer, which provides a theoretical basis for its clinical application in the future.

Key words: network pharmacology, molecular docking, Sparganii Rhizoma-Curcumae Rhizoma, breast cancer, mechanism

中图分类号:

R285

刘雪婷, 孙小慧, 朱建敏, 李林, 李文悦. 基于网络药理学和分子对接探究三棱-莪术抗乳腺癌的作用机制[J]. 山东科学, 2022, 35(5): 26-36.

LIU Xue-ting, SUN Xiao-hui, ZHU Jian-min, LI Lin, LI Wen-yue. Mechanism of the anti-breast cancer effect of Sparganii Rhizoma-Curcumae Rhizoma herbal pair based on network pharmacology and molecular docking[J]. Shandong Science, 2022, 35(5): 26-36.

图/表 10

图1

图2

图3

图4

表1

表2

表3

图5

表4

图6

参考文献 30

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA: A Cancer Journal for Clinicians, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660. doi: 10.3322/caac.21660 pmid: 33538338
[2]	TRAN S, HICKEY M, SAUNDERS C, et al. Nonpharmacological therapies for the management of menopausal vasomotor symptoms in breast cancer survivors[J]. Supportive Care in Cancer, 2021, 29(3): 1183-1193. DOI: 10.1007/s00520-020-05754-w. doi: 10.1007/s00520-020-05754-w
[3]	卢泰成, 许博文, 李杰. 王清任活血化瘀法在肿瘤治疗中的应用[J]. 世界中医药, 2021, 16(10): 1616-1619. DOI: 10.3969/j.issn.1673-7202.2021.10.023. doi: 10.3969/j.issn.1673-7202.2021.10.023
[4]	陈桂芬. 血瘀证乳腺癌与分子分型及预后关系的相关性研究[J]. 中国现代医药杂志, 2019, 21(7): 5-8. DOI: 10.3969/j.issn.1672-9463.2019.07.002. doi: 10.3969/j.issn.1672-9463.2019.07.002
[5]	寇露露, 刘海霞, 邵妤, 等. 三棱、莪术抗肿瘤生物活性研究[J]. 吉林中医药, 2017, 37(7): 722-724. DOI: 10.13463/j.cnki.jlzyy.2017.07.021. doi: 10.13463/j.cnki.jlzyy.2017.07.021
[6]	陈晓军, 韦洁, 苏华, 等. 莪术药理作用的研究新进展[J]. 药学研究, 2018, 37(11): 664-668. DOI: 10.13506/j.cnki.jpr.2018.11.011. doi: 10.13506/j.cnki.jpr.2018.11.011
[7]	李林, 陆兔林, 卞慧敏, 等. 莪术活血化瘀有效物质研究[J]. 上海中医药大学学报, 2004, 18(3): 40-42. DOI: 10.16306/j.1008-861x.2004.03.014. doi: 10.16306/j.1008-861x.2004.03.014
[8]	尹定聪, 杨华升. 莪术油抗肿瘤作用的研究进展[J]. 中医药导报, 2018, 24(3): 62-63. DOI: 10.13862/j.cnki.cn43-1446/r.2018.03.020. doi: 10.13862/j.cnki.cn43-1446/r.2018.03.020
[9]	袁甜, 崔琳琳, 王莹, 等. 中药网络药理学最新进展[J]. 中医药学报, 2021, 49(1): 101-106. DOI: 10.19664/j.cnki.1002-2392.210023. doi: 10.19664/j.cnki.1002-2392.210023
[10]	HSIN K Y, GHOSH S, KITANO H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J]. PLoS One, 2013, 8(12): e83922. DOI: 10.1371/journal.pone.0083922. doi: 10.1371/journal.pone.0083922
[11]	CHENG L, SHI L, WU J, et al. A hederagenin saponin isolated from Clematis ganpiniana induces apoptosis in breast cancer cells via the mitochondrial pathway[J]. Oncology Letters, 2018, 15(2):1797-1743. DOI: 10.3892/ol.2017.7494. doi: 10.3892/ol.2017.7494
[12]	RAMALINGAM S, PACKIRISAMY M, KARUPPIAH M, et al. Effect of β-sitosterol on glucose homeostasis by sensitization of insulin resistance via enhanced protein expression of PPRγ and glucose transporter 4 in high fat diet and streptozotocin-induced diabetic rats[J]. Cytotechnology, 2020, 72(3): 357-366. DOI: 10.1007/s10616-020-00382-y. doi: 10.1007/s10616-020-00382-y pmid: 32124158
[13]	GAUTAM M, THAPA R K, GUPTA B, et al. Phytosterol-loaded CD44 receptor-targeted PEGylated nano-hybridPhyto-liposomes for synergistic chemotherapy[J]. Expert Opinion on Drug Delivery, 2020, 17(3): 423-434. DOI: 10.1080/17425247.2020.1727442. doi: 10.1080/17425247.2020.1727442
[14]	WU X Y, XU H, WU Z F, et al. Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models[J]. Oncotarget, 2015, 6(42): 44563-44578. DOI: 10.18632/oncotarget.6310. doi: 10.18632/oncotarget.6310 pmid: 26575424
[15]	贾绍华, 刘丽娜, 颜廷华. 芒柄花素诱导人乳腺癌MCF-7细胞凋亡及其氧化应激的机制[J]. 华西药学杂志, 2020, 35(4): 385-391. DOI: 10.13375/j.cnki.wcjps.2020.04.009. doi: 10.13375/j.cnki.wcjps.2020.04.009
[16]	WU Q H, WU W D, FU B S, et al. JNK signaling in cancer cell survival[J]. Medicinal Research Reviews, 2019, 39(6): 2082-2104. DOI: 10.1002/med.21574. doi: 10.1002/med.21574 pmid: 30912203
[17]	YADAV P, YADAV R, JAIN S, et al. Caspase-3: A primary target for natural and synthetic compounds for cancer therapy[J]. Chemical Biology & Drug Design, 2021, 98(1): 144-165. DOI: 10.1111/cbdd.13860. doi: 10.1111/cbdd.13860
[18]	PENG Y L, WANG Y, TANG N, et al. Andrographolide inhibits breast cancer through suppressing COX-2 expression and angiogenesis via inactivation of p300 signaling and VEGF pathway[J]. Journal of Experimental & Clinical Cancer Research, 2018, 37(1): 1-14. DOI: 10.1186/s13046-018-0926-9. doi: 10.1186/s13046-018-0926-9
[19]	YANG W, HE X, HE C J, et al. Impact of ESR1 polymorphisms on risk of breast cancer in the Chinese Han population[J]. Clinical Breast Cancer, 2021, 21(3): e235-e242. DOI: 10.1016/j.clbc.2020.10.003. doi: 10.1016/j.clbc.2020.10.003 pmid: 33281037
[20]	GAO S, DING B S, LOU W Y. microRNA-dependent modulation of genes contributes to ESR1's effect on ERα positive breast cancer[J]. Frontiers in Oncology, 2020, 10: 753. DOI: 10.3389/fonc.2020.00753. doi: 10.3389/fonc.2020.00753 pmid: 32500028
[21]	GU G W, TIAN L, HERZOG S K, et al. Hormonal modulationof ESR1 mutant metastasis[J]. Oncogene, 2021, 40(5): 997-1011. DOI: 10.1038/s41388-020-01563-x. doi: 10.1038/s41388-020-01563-x
[22]	DASHTI S, TAHERIAN-ESFAHANI Z, KHOLGHI-OSKOOEI V, et al. In silico identification of MAPK14-related lncRNAs and assessment of their expression in breast cancer samples[J]. Scientific Reports, 2020, 10(1): 1-12. DOI: 10.1038/s41598-020-65421-2. doi: 10.1038/s41598-020-65421-2
[23]	WANG L P, SHI H M, LIU Y, et al. Cystathionine-γ-lyase promotes the metastasis of breast cancer via the VEGF signaling pathway[J]. International Journal of Oncology, 2019, 55(2): 473-487. DOI: 10.3892/ijo.2019.4823. doi: 10.3892/ijo.2019.4823
[24]	SIA D, ALSINET C, NEWELL P, et al. VEGF signaling in cancer treatment[J]. Current Pharmaceutical Design, 2014, 20(17): 2834-2842. DOI: 10.2174/13816128113199990590. doi: 10.2174/13816128113199990590 pmid: 23944367
[25]	WALDNER M J, NEURATH M F. Targeting the VEGF signaling pathway in cancer therapy[J]. Expert Opinion on Therapeutic Targets, 2012, 16(1): 5-13. DOI: 10.1517/14728222.2011.641951. doi: 10.1517/14728222.2011.641951 pmid: 22239434
[26]	MARTÍNEZ-REZA I, DÍAZ L, GARCÍA-BECERRA R. Preclinical and clinical aspects of TNF-α and its receptors TNFR1 and TNFR2 in breast cancer[J]. Journal of Biomedical Science, 2017, 24(1): 1-8. DOI: 10.1186/s12929-017-0398-9. doi: 10.1186/s12929-017-0398-9
[27]	LIU W J, LU X Q, SHI P G, et al. TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway[J]. Scientific Reports, 2020, 10(1): 1-11. DOI: 10.1038/s41598-020-58642-y. doi: 10.1038/s41598-020-58642-y
[28]	欧宏宇, 朱海宏, 朱文君, 等. 抗菌肽LL-37通过激活p53信号通路诱导胃癌AGS细胞凋亡[J]. 安徽医科大学学报, 2021, 56(4): 571-576. DOI: 10.19405/j.cnki.issn1000-1492.2021.04.013. doi: 10.19405/j.cnki.issn1000-1492.2021.04.013
[29]	罗浩泉, 林忠顺, 黄小林. 乳腺良恶性肿瘤患者血清催乳素水平变化研究[J]. 中国医学创新, 2018, 15(12): 123-125. DOI: 10.3969/j.issn.1674-4985.2018.12.035. doi: 10.3969/j.issn.1674-4985.2018.12.035
[30]	BORCHERDING D C, HUGO E R, FOX S R, et al. Suppression of breast cancer by small molecules that block the prolactin receptor[J]. Cancers, 2021, 13(11): 2662. DOI: 10.3390/cancers13112662. doi: 10.3390/cancers13112662

序号	生物过程	基因数	P值
1	对雌二醇的反应	8	2.51×10^-9
2	缺乏配体的外源性凋亡信号通路	6	2.02×10^-9
3	对药物的反应	10	4.89×10^-8
4	RNA聚合酶Ⅱ启动子转录的正调控	14	4.45×10^-7
5	RNA聚合酶Ⅱ启动子起始转录	7	1.99×10^-6
6	类固醇激素介导的信号通路	5	1.21×10^-5
7	血管生成	7	1.80×10^-5
8	转录DNA模板正调控	9	3.45×10^-5
9	对脂多糖的反应	6	5.31×10^-5
10	缺氧反应	6	6.65×10^-5

序号	分子功能	基因数	P值
1	酶结合	14	8.27×10^-13
2	类固醇激素受体	7	4.84×10^-9
3	类固醇结合	5	5.57×10^-7
4	RNA聚合酶II转录因子活性,配体激活序列特异性DNA结合	5	1.84×10^-6
5	序列特异性DNA结合	9	3.50×10^-5
6	蛋白质同源二聚活性	10	6.21×10^-5
7	转录因子结合	7	6.78×10^-5
8	核心启动子序列特异性DNA结合	4	1.65×10^-4
9	蛋白质结合	34	3.54×10^-4
10	半胱氨酸型内肽酶活性参与细胞凋亡过程	3	4.63×10^-4

序号	细胞组分	基因数	P值
1	膜筏	6	1.06×10^-4
2	细胞质	19	1.83×10^-4
3	核	25	1.93×10^-4
4	传递神经元	6	2.05×10^-4
序号	细胞组分	基因数	P值
5	核质	17	2.63×10^-4
6	线粒体外膜	5	3.77×10^-4
7	胞膜微囊	4	4.50×10^-4
8	核染色质	5	9.96×10^-4
9	线粒体	10	2.84×10^-3
10	内质网	7	1.12×10^-2

基于网络药理学和分子对接探究三棱-莪术抗乳腺癌的作用机制

Mechanism of the anti-breast cancer effect of Sparganii Rhizoma-Curcumae Rhizoma herbal pair based on network pharmacology and molecular docking

RichHTML

PDF (PC)

赞

可视化

摘要/Abstract

引用本文

使用本文

图/表 10

参考文献 30

相关文章 15

Metrics

本文评价

推荐阅读 0

PDB编号	核心靶点	有效活性成分	结合自由能/(kJ·mol^-1)
6OSN	JUN	常春藤皂苷元	-5.3
		反式软骨酸	-5.2
		β-谷甾醇	-6.2
PDB编号	核心靶点	有效活性成分	结合自由能/(kJ·mol^-1)
		芒柄花黄素	-5.4
		豆甾醇	-6.3
2DKO	CASP3	常春藤皂苷元	-8.1
		反式软骨酸	-5.1
		β-谷甾醇	-7.7
		芒柄花黄素	-6.5
		豆甾醇	-8.2
3NT1	PTGS2	常春藤皂苷元	-9.2
		反式软骨酸	-5.9
		β-谷甾醇	-9.1
		芒柄花黄素	-9.3
		豆甾醇	-8.7

[1]	孙京甜, 刘峰, 张喆, 张玉福, 马鑫慧, 李庆军, 王晓, 董红敬. 菊花用药规律分析及其核心药物组合协同药理活性研究[J]. 山东科学, 2025, 38(1): 1-8.
[2]	韩惠杰, 刘辉, 赵永波, 王松坡. 基于网络药理学和实验验证探讨槲皮素通过p53信号通路抗结直肠癌的作用机制[J]. 山东科学, 2025, 38(1): 32-43.
[3]	范伟, 沈川琳, 张轩铭, 杜兴硕, 展文, 孙晨, 靳梦, 李晓彬, 张思晨, 孙博通, 何秋霞. 基于网络药理学和分子对接技术预测西洋参抗衰老的作用机制[J]. 山东科学, 2024, 37(6): 42-50.
[4]	严谨, 李翡, 吴克明, 杨皓博. 新加苁蓉菟丝汤通过线粒体自噬途径促卵泡发育的分子机制[J]. 山东科学, 2024, 37(5): 25-34.
[5]	林圣华, 薛畅, 马宏林, 范伟, 沈川琳, 陈佳瑜, 孙博通, 杜兴硕, 展文, 李晓彬, 张姗姗, 靳梦, 何秋霞. 基于网络药理学和分子对接技术揭示血府逐瘀口服液抗血栓的活性成分和作用机制[J]. 山东科学, 2024, 37(4): 26-33.
[6]	马诗经, 何春艳, 关天竹, 姚雪霜, 张俊鹏. 基于高脂血症斑马鱼模型和网络药理学探讨黄鳝肽抗高脂血症的作用机制[J]. 山东科学, 2024, 37(3): 27-38.
[7]	魏泽坤, 杨雨洁, 刘双, 王燕, 董红敬, 刘春梅. 基于GEO数据库结合网络药理学及分子对接逆向挖掘干预肝癌的中药[J]. 山东科学, 2024, 37(3): 39-47.
[8]	刘双, 董红敬, 陈盼盼, 王晓. 天然多酚类成分缓解高尿酸血症及其机制研究进展[J]. 山东科学, 2024, 37(2): 12-19.
[9]	罗雅琴, 黄伟. 黄芩及其有效成分治疗溃疡性结肠炎机制研究进展[J]. 山东科学, 2024, 37(2): 20-28.
[10]	刘可春, 王勇澄, 臧晓涵, 夏青, 张云, 张姗姗, 孙晨. 网络药理学和斑马鱼模型在中药药效物质及作用机制研究中的应用进展[J]. 山东科学, 2024, 37(2): 29-35.
[11]	付朝举, 成果, 林登梅, 李军, 张楠楠. 阔叶十大功劳抗炎作用机制的实验研究及网络药理学分析[J]. 山东科学, 2024, 37(1): 24-31.
[12]	陈春, 祁大庆, 潘靖文. 基质细胞评分的胃癌临床意义及胃复春胶囊干预机制[J]. 山东科学, 2023, 36(6): 38-47.
[13]	慕娜娜, 廖彬彬, 李镇, 李吉品, 李伊花, 王莹, 陈旭冰. 基于网络药理学和分子对接技术探究地胆草治疗溃疡性结肠炎的作用机制[J]. 山东科学, 2023, 36(6): 48-55.
[14]	王一帆, 张喆, 田财军. 基于网络药理学和分子对接探讨三黄泻心汤治疗阿尔茨海默病的机制[J]. 山东科学, 2023, 36(5): 19-26.
[15]	付梦雅, 敖慧豪, 卜超, 朋汤义, 吴德玲, 韩燕全, 洪燕. 基于指纹图谱和网络药理学的干姜质量标志物预测分析[J]. 山东科学, 2023, 36(4): 35-41.