Objective  To explore the pharmacologically active components, core targets, and molecular mechanism of the medicine pair of Ezhu-Sanleng in the treatment of prostate cancer (PCa).

Methods  The pharmacologically active components and target interactions of Ezhu-Sanleng were obtained based on the HERB and PubChem databases. The disease targets of PCa were obtained from Genecards, OMIM, PharmGkb, TTD, and DrugBank databases. The common targets were identified by taking the intersection of drug targets and disease targets. The Ezhu-Sanleng active components and PCa targets network was constructed by Cytoscape 3.9.0 software. The intersection targets were imported into the STRING database to build a protein-protein interaction network (PPI). Gene gontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted on potential targets. Finally, molecular docking validation of core targets and key pharmacologically active components was performed by AutoDockTools 1.5.7 software and other softwares.

Results  A total of 72 pharmacologically active components and 760 effective active component targets were screened. There were 13 001 disease-related targets for PCa and the intersection targets were 659. The key core components of the drug included curcumenone, sapindoside B, sanshool, (2s)-3', 4'-methylenedioxy-5, 7-dimethoxyflavane, apigenin, gaillardin, kaempferol, Sanleng acid, demethoxycurcumin, and 5, 7, 2', 3'-tetrahydroxyflavone. PPI network analysis identified SRC, TP53, MAPK3, MAPK1, STAT3, HSP90AA1, AKT1, PIK3R1, RHOA, and GRB2 as core targets. GO and KEGG enrichment analyses showed that Ezhu-Sanleng in the treatment of PCa mainly involved signaling pathways related to cell proliferation, apoptosis, migration, and signal transduction. Molecular docking results revealed a strong binding affinity between the core targets and active components.

Conclusion   This study elucidated the key active components of Ezhu-Sanleng and their interactions with potential targets in the anti-PCa context. It highlights the characteristic of multiple components interacting with multiple targets, providing valuable references for further study of Ezhu-Sanleng in the treatment of PCa.

1.Lycken M, Drevin L, Garmo H, et al. The use of palliative medications before death from prostate cancer: Swedish population-based study with a comparative overview of European data[J]. Eur J Cancer, 2018, 88: 101-108. DOI: 10.1016/j.ejca.2017.10.023.

2.Badal S, Aiken W, Morrison B, et al. Disparities in prostate cancer incidence and mortality rates: solvable or not?[J]. Prostate, 2020, 80(1): 3-16. DOI: 10.1002/pros.23923.

3.Kim J, Freeman K, Ayala A, et al. Cardiovascular impact of androgen deprivation therapy: from basic biology to clinical practice[J]. Curr Oncol Rep, 2023, 25(9): 965-977. DOI: 10.1007/s11912-023-01424-2.

4.刘雪丽, 周学锋, 王君瑜, 等. 中药抗肿瘤作用机制研究进展[J]. 中国药师, 2016, 19(6): 1158-1162. [Liu XL, Zhou XF, Wang JY, et al. Research progress in anti-tumor mechanism of traditional Chinese medicine[J]. China Pharmacist, 2016, 19(6): 1158-1162.] DOI: 10.3969/j.issn.1008-049X.2016.06.043.

5.周仲瑛. 中医内科学(第2版)[M]. 北京: 中国中医药出版社, 2017: 3. [Zhou ZY. Internal medicine of traditional Chinese medicine (2nd edition)[M]. Beijing: China Press of Traditional Chinese Medicine, 2017: 3.]

6.贾英杰. 中西医结合肿瘤学[M]. 武汉: 华中科技大学出版社, 2009: 11. [Jia YJ. Integrated Chinese and western medicine oncology[M]. Wuhan: Huazhong University of Science & Technology Press, 2009: 11.]

7.杜芳, 鱼麦侠, 胡博帆, 等. 三棱-莪术药对抗肿瘤临床应用及作用机制研究进展[J]. 中国医药导报, 2023, 20(2): 39-42. [Du F, Yu MX, Hu BF, et al. Research progress on clinical application and mechanism of Chinese medicine pair of Sparganii Rhizoma-Curcumae Rhizoma against tumor[J]. China Medical Herald, 2023, 20(2): 39-42.] DOI: 10.20047/j.issn1673-7210.2023.02.08.

8.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, 682. [Chen XJ, Wei J, Su H, et al. New research progress on pharmacological effects of Curcumae Rhizoma[J]. Journal of Pharmaceutical Research, 2018, 37(11): 664-668, 682.] DOI: 10.13506/j.cnki.jpr.2018.11.011.

9.冯娅茹, 张文婷, 李二文, 等. 三棱化学成分及药理作用研究进展[J]. 中草药, 2017, 48(22): 4804-4818. [Feng YR, Zhang WT, Li EW, et al. Research progress on chemical constituents and pharmacological activities of Sparganium stoloniferum[J]. Chinese Traditional and Herbal Drugs, 2017, 48(22): 4804-4818.] DOI: 10.7501/j.issn.0253-2670.2017.22.033.

10.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. [Chen GF. Study on the relationship between breast cancer with blood stasis syndrome and molecular typing and prognosis[J]. Modern Medicine Journal of China, 2019, 21(7): 5-8.] DOI: 10.3969/j.issn.1672-9463.2019.07.002.

11.Yuan C, Wang MH, Wang F, et al. Network pharmacology and molecular docking reveal the mechanism of Scopoletin against non-small cell lung cancer[J]. Life Sci, 2021, 270: 119105. DOI: 10.1016/j.lfs.2021.119105.

12.Liu J, Liu J, Tong X, et al. Network pharmacology prediction and molecular docking-based strategy to discover the potential pharmacological mechanism of Huai Hua San against ulcerative colitis[J]. Drug Des Devel Ther, 2021, 15: 3255-3276. DOI: 10.2147/DDDT.S319786.

13.Li C, Pan J, Xu C, et al. A preliminary inquiry into the potential mechanism of Huang-Lian-Jie-Du decoction in treating rheumatoid arthritis via network pharmacology and molecular docking[J]. Front Cell Dev Biol, 2022, 9: 740266. DOI: 10.3389/fcell.2021.740266.

14.Li XH, Tang H, Tang Q, et al. Decoding the mechanism of Huanglian Jiedu decoction in treating pneumonia based on network pharmacology and molecular docking[J]. Front Cell Dev Biol, 2021, 9: 638366. DOI: 10.3389/fcell.2021. 638366.

15.Zeng Z, Hu J, Jiang J, et al. Network pharmacology and molecular docking-based prediction of the mechanism of Qianghuo Shengshi decoction against rheumatoid arthritis[J]. Biomed Res Int, 2021, 2021: 6623912. DOI: 10.1155/2021/6623912.

16.Xia Y, Yu B, Ma C, et al. Yu Gan Long reduces rat liver fibrosis by blocking TGF-beta1/Smad pathway and modulating the immunity[J]. Biomed Pharmacother, 2018, 106: 1332-1338. DOI: 10.1016/j.biopha.2018.07.081.

17.Shi L, Tu YJ, Xia Y, et al. TEEG induced A549 cell autophagy by regulating the PI3K/AKT/mTOR signaling pathway[J]. Anal Cell Pathol (Amst), 2019, 2019: 7697610. DOI: 10.1155/2019/7697610.

18.Xia WR, Khan I, Li XA, et al. Adaptogenic flower buds exert cancer preventive effects by enhancing the SCFA-producers, strengthening the epithelial tight junction complex and immune responses[J]. Pharmacol Res, 2020, 159: 104809. DOI: 10.1016/j.phrs.2020.104809.

19.欧凯西, 刘捷, 余成浩. 基于网络药理学研究三棱-莪术药对抗子宫内膜癌的作用机制及实验验证[J]. 中药药理与临床, 2022, 38(4): 73-79, 143. [Ou KX, Liu J, Yu CH. Mechanism of herbal couple Sanleng-Ezhu against endometrial cancer based on network pharmacology and experimental verification[J]. Pharmacology and Clinics of Chinese Materia Medica, 2022, 38(4): 73-79, 143.] DOI: 10.13412/j.cnki.zyyl.20211130.002.

20.Yin YK, Feng L, Wang L, et al. The role of curcumae rhizoma-sparganii rhizoma medicated serum in epithelial-mesenchymal transition in the triple negative breast cancer: pharmacological role of CR-SR in the TBNC[J]. Biomed Pharmacother, 2018, 99: 340-345. DOI: 10.1016/j.biopha.2017.11.139.

21.Sezer ED, Oktay LM, Karadadaş E, et al. Assessing anticancer potential of blueberry flavonoids, quercetin, kaempferol, and gentisic acid, through oxidative stress and apoptosis parameters on HCT-116 cells[J]. J Med Food, 2019, 22(11): 1118-1126. DOI: 10.1089/jmf.2019.0098.

22.Green WJ, Ball G, Hulman G, et al. KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach[J]. Br J Cancer, 2016, 115(2): 236-242. DOI: 10.1038/bjc.2016.169.

23.Zhang YM, Chen JQ, Fang WX, et al. Kaempferol suppresses androgen-dependent and androgen- independent prostate cancer by regulating Ki67 expression[J].Mol Biol Rep, 2022, 49(6): 4607-4617. DOI: 10.1007/s11033-022-07307-2.

24.Wang XN, Zhu JJ, Yan HM, et al. Kaempferol inhibits benign prostatic hyperplasia by resisting the action of androgen[J]. Eur J Pharmacol, 2021, 907: 174251. DOI: 10.1016/j.ejphar.2021.174251.

25.孙佳良, 王佳, 薛新文, 等. 山奈酚阻滞JAK2/STAT3通路抑制宫颈癌细胞的增殖及糖酵解的作用研究[J]. 药物生物技术, 2023, 30(4): 368-373. [Sun JL, Wang J, Xue XW, et al. Inhibition of proliferation and glycolysis of cervical cancer cells by kaempferol blocking JAK2/STAT3 pathway[J]. Pharmaceutical Biotechnology, 2023, 30(4): 368-373.] DOI: 10.19526/j.cnki.1005-8915.20230408.

26.Fallahian F, Aghaei M, Abdolmohammadi MH, et al. Molecular mechanism of apoptosis induction by Gaillardin, a sesquiterpene lactone, in breast cancer cell lines: Gaillardin-induced apoptosis in breast cancer cell lines[J]. Cell Biol Toxicol, 2015, 31(6): 295-305. DOI: 10.1007/s10565-016-9312-6.

27.Roozbehani M, Abdolmohammadi MH, Hamzeloo-Moghadam M, et al. Gaillardin, a potent sesquiterpene lactone induces apoptosis via down-regulation of NF-κβ in gastric cancer cells, AGS and MKN45[J].J Ethnopharmacol, 2021, 281: 114529. DOI: 10.1016/j.jep.2021.114529.

28.卢文显. 无患子皂苷对人肝癌细胞HepG2增殖与凋亡的影响[J]. 天然产物研究与开发, 2018, 30(7): 1231-1234, 1279. [Lu WX. Proliferation and apoptosis effects of Sapindus-saponin on human hepatocellular carcinoma HepG2 cells[J]. Natural Product Research and Development, 2018, 30(7): 1231-1234, 1279.] DOI: 10.16333/j.1001-6880.2018.7.023.

29.Shi L, Sun G, Zhang Y. Demethoxycurcumin analogue DMC-BH exhibits potent anticancer effects on orthotopic glioblastomas[J]. Aging (Albany NY), 2020, 12(23): 23795-23807. DOI: 10.18632/aging.103981.

30.陈容, 时艳华. 芹菜素对子宫内膜癌HEC-1-B细胞增殖和凋亡的影响及其机制研究[J]. 天津医药, 2021, 49(11): 1138-1142. [Chen R, Shi YH. The effect and its mechanism of apigenin on proliferation and apoptosis of HEC-1-B cells[J]. Tianjin Medical Journal, 2021, 49(11): 1138-1142.] DOI: 10.11958/20210940.

31.王文静. 芹菜素促进卵巢癌化疗的减毒增效作用[D]. 大连: 大连理工大学, 2022. [Wang WJ. Apigenin synergistic enhancing anti-cancer effects of carboplatin and paclitaxel combination and reversing drug resistance on ovarian cancer[D]. Dalian: Dalian University of Technology, 2022.] DOI: 10.26991/d.cnki.gdllu.2022.003382.

32.Saad F. Src as a therapeutic target in men with prostate cancer and bone metastases[J]. BJU Int, 2009, 103(4): 434-440. DOI: 10.1111/j.1464-410X.2008.08249.x.

33.Shi W, Wang Y, Zhao Y, et al. Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies[J]. Sci Transl Med, 2023, 15(695): eadf6724. DOI: 10.1126/scitranslmed.adf6724.

34.Guo YJ, Pan WW, Liu SB, et al. ERK/MAPK signalling pathway and tumorigenesis[J]. Exp Ther Med, 2020, 19(3): 1997-2007. DOI: 10.3892/etm.2020.8454.

35.He M, Young CY. New approaches to target the androgen receptor and STAT3 for prostate cancer treatments[J]. Mini Rev Med Chem, 2009, 9(3): 395-400. DOI: 10.2174/ 1389557510909030395.

36.Owen KL, Brockwell NK, Parker BS. JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression[J]. Cancers (Basel), 2019, 11(12): 2002. DOI: 10.3390/cancers11122002.

37.Yang Y, Li J, Jing C, et al. Inhibition of neuroactive ligand-receptor interaction pathway can enhance immunotherapy response in colon cancer: an in silico study[J]. Expert Rev Anticancer Ther, 2023, 23(11): 1205-1215. DOI: 10.1080/14737140.2023.2245567.

38.Khezri MR, Jafari R, Yousefi K, et al. The PI3K/AKT signaling pathway in cancer: molecular mechanisms and possible therapeutic interventions[J]. Exp Mol Pathol, 2022, 127: 104787. DOI: 10.1016/j.yexmp.2022.104787.

39.Maly IV, Hofmann WA. Calcium and nuclear signaling in prostate cancer[J]. Int J Mol Sci, 2018, 19(4): 1237. DOI: 10.3390/ijms19041237.

40.Li X, Wei S, Niu S, et al. Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu decoction against sepsis[J]. Comput Biol Med, 2022, 144: 105389. DOI: 10.1016/j.compbiomed.2022.105389.