Preliminary Study on the Mechanism of Carvacrol Regulating Hepatocellular Carcinoma Based on Network Pharmacology

Author(s): Sha Li, Haixia Zhao*, Lidao Bao*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 11 , 2019

Become EABM
Become Reviewer

Graphical Abstract:

Animated Abstract:


Objective: To predict and analyze the target of anti-Hepatocellular Carcinoma (HCC) in the active constituents of Safflower by using network pharmacology.

Methods: The active compounds of safflower were collected by TCMSP, TCM-PTD database and literature mining methods. The targets of active compounds were predicted by Swiss Target Prediction server, and the target of anti-HCC drugs was collected by DisGeNET database. The target was subjected to an alignment analysis to screen out Carvacrol, a target of safflower against HCC. The mouse HCC model was established and treated with Carvacrol. The anti-HCC target DAPK1 and PPP2R2A were verified by Western blot and co-immunoprecipitation.

Results: A total of 21 safflower active ingredients were predicted. Carvacrol was identified as a possible active ingredient according to the five principles of drug-like medicine. According to Carvacrol's possible targets and possible targets of HCC, three co-targets were identified, including cancer- related are DAPK1 and PPP2R2A. After 20 weeks of Carvacrol treated, Carvacrol group significantly increased on DAPK1 levels and decreased PPP2R2A levels in the model mice by Western blot. Immunoprecipitation confirmed the endogenous interaction between DAPK1 and PPP2R2A.

Conclusion: Safflower can regulate the development of HCC through its active component Carvacrol, which can affect the expression of DAPK1 and PPP2R2A proteins, and the endogenous interactions of DAPK1 and PPP2R2A proteins.

Keywords: Safflower, carvacrol, network pharmacology, hepatocellular carcinoma, DAPK1, immunoprecipitation.

Wang, L.Y.; Zheng, S.S. Advances in predicting the prognosis of hepatocellular carcinoma recipients after liver transplantation. J. Zhejiang Univ. Sci. B, 2018, 19(7), 497-504.
[] [PMID: 29971988]
Shirata, C.; Hasegawa, K.; Kokudo, T.; Yamashita, S.; Yamamoto, S.; Arita, J.; Akamatsu, N.; Kaneko, J.; Sakamoto, Y.; Kokudo, N. Liver resection for hepatocellular carcinoma in patients with renal dysfunction. World J. Surg., 2018, 42(12), 4054-4062.
[] [PMID: 29947980]
Fang, T.; Fang, Y.; Xu, X.; He, M.; Zhao, Z.; Huang, P.; Yuan, F.; Guo, M.; Yang, B.; Xia, J. Actinidia chinensis Planch root extract attenuates proliferation and metastasis of hepatocellular carcinoma by inhibiting epithelial-mesenchymal transition. J. Ethnopharmacol., 2019, 231, 474-485.
[] [PMID: 30415058]
Nanda, A.; Suyila, Q.; Xian, L.; Xiulan, S. Hepatoprotective Mongolian prescription II enhances the antitumor effects of chemotherapeutics in hepatocellular carcinoma xenografts. Pathol. Res. Pract., 2017, 213(5), 531-540.
[] [PMID: 28416328]
Zhang, J.; Li, J.; Song, H.; Xiong, Y.; Liu, D.; Bai, X. Hydroxysafflor yellow A suppresses angiogenesis of hepatocellular carcinoma through inhibition of p38 MAPK phosphorylation. Biomed. Pharmacother., 2019, 109, 806-814.
[] [PMID: 30551534]
Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6, 13.
[] [PMID: 24735618]
Wu, Y.; Zhang, F.; Yang, K.; Fang, S.; Bu, D.; Li, H.; Sun, L.; Hu, H.; Gao, K.; Wang, W.; Zhou, X.; Zhao, Y.; Chen, J. SymMap: An integrative database of traditional Chinese medicine enhanced by symptom mapping. Nucleic Acids Res., 2019, 47(D1), D1110-D1117.
[] [PMID: 30380087]
Luo, H; Chen, J; Shi, L; Mikailov, M; Zhu, H; Wang, K DRAR-CPI: A server for identifying drug repositioning potential and adverse drug reactions via the chemical-protein interactome Nucleic acids research, 2011, 39(Web Server issue), W492-8.,
Boutet, E.; Lieberherr, D.; Tognolli, M.; Schneider, M.; Bansal, P.; Bridge, A.J.; Poux, S.; Bougueleret, L.; Xenarios, I. UniProtKB/Swiss-Prot, the manually annotated section of the uniprot knowledgebase: How to use the entry view. Methods Mol. Biol., 2016, 1374, 23-54.
[] [PMID: 26519399]
Piñero, J.; Bravo, À.; Queralt-Rosinach, N.; Gutiérrez-Sacristán, A.; Deu-Pons, J.; Centeno, E.; García-García, J.; Sanz, F.; Furlong, L.I. DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res., 2017, 45(D1), D833-D839.
[] [PMID: 27924018]
Zaru, R.; Magrane, M.; O’Donovan, C. From the research laboratory to the database: The Caenorhabditis elegans kinome in UniProtKB. Biochem. J., 2017, 474(4), 493-515.
[] [PMID: 28159896]
Zoete, V.; Daina, A.; Bovigny, C.; Michielin, O. SwissSimilarity: A web tool for low to ultra high throughput ligand-based virtual screening. J. Chem. Inf. Model., 2016, 56(8), 1399-1404.
[] [PMID: 27391578]
Shi, X.Q.; Yue, S.J.; Tang, Y.P.; Chen, Y.Y.; Zhou, G.S.; Zhang, J.; Zhu, Z.H.; Liu, P.; Duan, J.A. A network pharmacology approach to investigate the blood enriching mechanism of Danggui buxue Decoction. J. Ethnopharmacol., 2019, 235, 227-242.
[] [PMID: 30703496]
Han, B.; Li, C.; Meng, H.; Gomes Romeiro, F.; Mancuso, A.; Zhou, Z.; Levi Sandri, G.B.; Xu, Y.; Han, T.; Han, L.; Shao, L.; Qi, X. Efficacy and safety of external-beam radiation therapy for hepatocellular carcinoma: An overview of current evidence according to the different target population. Biosci. Trends, 2019, 13(1), 10-22.
[] [PMID: 30799321]
Ma, Y.; Feng, C.; Wang, J.; Chen, Z.; Wei, P.; Fan, A.; Wang, X.; Yu, X.; Ge, D.; Xie, H.; Liu, L.; Zhang, Q.; Li, X.H. Hydroxyl safflower yellow A regulates the tumor immune microenvironment to produce an anticancer effect in a mouse model of hepatocellular carcinoma. Oncol. Lett., 2019, 17(3), 3503-3510.
[] [PMID: 30867790]
Koutsioumpa, M.; Chen, H.W.; O’Brien, N.; Koinis, F.; Mahurkar-Joshi, S.; Vorvis, C.; Soroosh, A.; Luo, T.; Issakhanian, S.; Pantuck, A.J.; Georgoulias, V.; Iliopoulos, D.; Slamon, D.J.; Drakaki, A. MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer. Mol. Cancer Ther., 2018, 17(7), 1430-1440.
[] [PMID: 29703843]
Yadav, P.; Masroor, M.; Nandi, K.; Kaza, R.C.M.; Jain, S.K.; Khurana, N.; Saxena, A. Promoter methylation of BRCA1, DAPK1 and RASSF1A is Associated with increased mortality among indian women with breast cancer. Asian Pac. J. Cancer Prev., 2018, 19(2), 443-448.
[PMID: 29480000]
Thongchot, S.; Vidoni, C.; Ferraresi, A.; Loilome, W.; Yongvanit, P.; Namwat, N.; Isidoro, C. Dihydroartemisinin induces apoptosis and autophagy-dependent cell death in cholangiocarcinoma through a DAPK1-BECLIN1 pathway. Mol. Carcinog., 2018, 57(12), 1735-1750.
[] [PMID: 30136419]
Zhai, C.L.; Tang, G.M.; Qian, G.; Hu, H.L.; Wang, S.J.; Yin, D.; Zhang, S. MicroRNA-98 attenuates cardiac ischemia-reperfusion injury through inhibiting DAPK1 expression. IUBMB Life, 2019, 71(2), 166-176.
[] [PMID: 30419147]
Zhang, J.; Gao, D.; Zhang, H. Upregulation of miR-614 promotes proliferation and inhibits apoptosis in ovarian cancer by suppressing PPP2R2A expression. Mol. Med. Rep., 2018, 17(5), 6285-6292.
[] [PMID: 29532877]
Wang, Q.; Li, J.; Wu, W.; Shen, R.; Jiang, H.; Qian, Y.; Tang, Y.; Bai, T.; Wu, S.; Wei, L.; Zang, Y.; Zhang, J.; Wang, L. Smad4-dependent suppressor pituitary homeobox 2 promotes PPP2R2A-mediated inhibition of Akt pathway in pancreatic cancer. Oncotarget, 2016, 7(10), 11208-11222.
[] [PMID: 26848620]
Sivaranjani, A.; Sivagami, G.; Nalini, N. Chemopreventive effect of carvacrol on 1,2-dimethylhydrazine induced experimental colon carcinogenesis. J. Cancer Res. Ther., 2016, 12(2), 755-762.
[] [PMID: 27461646]
Barnwal, P.; Vafa, A.; Afzal, S.M.; Shahid, A.; Hasan, S.K. Alpashree; Sultana, S. Benzo(a)pyrene induces lung toxicity and inflammation in mice: prevention by carvacrol. Hum. Exp. Toxicol., 2018, 37(7), 752-761.
[] [PMID: 29019276]
Palabiyik, S.S.; Karakus, E.; Halici, Z.; Cadirci, E.; Bayir, Y.; Ayaz, G.; Cinar, I. The protective effects of carvacrol and thymol against paracetamol-induced toxicity on human hepatocellular carcinoma cell lines (HepG2). Hum. Exp. Toxicol., 2016, 35(12), 1252-1263.
[] [PMID: 26801986]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [1286 - 1295]
Pages: 10
DOI: 10.2174/1570180816666190516105906
Price: $65

Article Metrics

PDF: 20