Network Pharmacology Study of Compound Ligustrazine in Gastric Cancer Therapy

XU Wei, DENG Zhaomin, WANG Xin, JIANG Hao

Abstract

To explore the potential role and mechanism of compound tetramethylpyrazine in gastric cancer therapy by using network pharmacology analysis combined with gene function annotation and clinical data analysis.

Methods 

SwissTargetPrediction database was used to screen the potential drug action sites of compound tetramethylpyrazine, and the OMIM and Genecard databases were used in combination to obtain gastric cancer-related targets. Intersection analysis was performed to identify potential therapeutic targets. Subsequently, the method of ClusterProfiler was used to perform functional annotation of the downstream targets of intersection. In addition, The Cancer Genome Atlas (TCGA) database was used to obtain the original data of gastric cancer patients, and the immune infiltration analysis, miRNA analysis, transcriptional regulation analysis of key genes, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), nomogram model construction, and genome-wide association studies (GWAS) were performed.

Results 

Through network pharmacological screening, we found 14 potential therapeutic targets through which tetramethylpyrazine acted on gastric cancer. Functional annotation showed that these targets were mainly involved in the pathways for hormone metabolism, drug metabolism, and signal transduction. Based on log rank test, the expression of the key genes, ELANE and MPO, showed significant difference in the comparison of gastric cancer survival curves (P<0.05), and were closely associated with immune cell infiltration. In addition, GSEA and GSVA results suggested that ELANE and MPO might influence the development of gastric cancer through multiple signaling pathways.

Conclusion 

In this study, by using multiple analysis methods in an integrated way, we found that ligustrazine may have therapeutic effects on gastric cancer by regulating the potential targets of ELANE and MPO, as well as the relevant signaling pathways.

 

Keywords: Gastric cancer, Ligustrazine, MPO, ELANE

 

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References


CORREA P. Gastric cancer: overview. Gastroenterol Clin North Am, 2013,42(2): 211–217. doi: 10.1016/j.gtc.2013.01.002.Epub2013Feb21.

SEXTON R E, Al HALLAK M N, DIAB M, et al. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev, 2020, 39(4): 1179–1203. doi: 10.1007/s10555-020-09925-3. Epub2020Sep7.

CHEN D, FU M, CHI L, et al. Prognostic and predictive value of a pathomics signature in gastriccancer. Nat Commun, 2022, 13(1): 6903. doi: 10.1038/s41467-022-34703-w.

JIANG R, XU J, ZHANG Y, et al. Ligustrazine alleviate acute lung injury through suppressing pyroptosis and apoptosis of alveolar macrophages. Front Pharmacol, 2021, 12: 680512. doi: 10.3389/fphar.2021.680512.

MU Q, YAO K, SYEDA M Z, et al. Ligustrazine nanoparticle hitchhiking on neutrophils for enhanced therapy of cerebral ischemia-reperfusion injury. Adv Sci (Weinh), 2023, 10(19): e2301348. doi: 10.1002/advs. 202301348.

ZHENG Q, HUANG Y Y, ZHU P C, et al. Ligustrazine exerts cardioprotection in animal models of myocardial ischemia/reperfusion injury: preclinical evidence and possible mechanisms. Front Pharmacol, 2018, 9: 729. doi: 10.3389/fphar.2018.00729.

PAN J, SHANG J F, JIANG G Q, et al. Ligustrazine induces apoptosis of breast cancer cells in vitro and in vivo. J Cancer Res Ther, 2015, 11(2): 454–458. doi: 10.4103/0973-1482.147378.

CHEN J, WANG W, WANG H, et al. Combination treatment of ligustrazine piperazine derivate DLJ14 and adriamycin inhibits progression of resistant breast cancer through inhibition of the EGFR/PI3K/Akt survival pathway and induction of apoptosis. Drug Discov Ther, 2014, 8(1): 33–41. doi: 10.5582/ddt.8.33.

XIE H J, ZHAO J, ZHUO-MA D, et al. Inhibiting tumour metastasis by DQA modified paclitaxel plus ligustrazine micelles in treatment of non-small-cell lung cancer. Artif Cells Nanomed Biotechnol, 2019, 47(1): 3465–3477. doi: 10.1080/21691401.2019.1653900.

ZOU Y, ZHAO D, YAN C, et al. Novel ligustrazine-based analogs of piperlongumine potently suppress proliferation and metastasis of colorectal cancer cells in vitro and in vivo. J Med Chem, 2020, 63(2): 880–881. doi: 10.1021/acs.jmedchem.9b02072.

QI M. Bibliometric analysis of research progress on tetramethylpyrazine and its effects on ischemia-reperfusion injury. Pharmacol Ther, 2024, 259: 108656. doi: 10.1016/j.pharmthera.2024.108656.

ZHA G F, QIN H L , YOUSSIF B G M, et al. Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance. Eur J Med Chem, 2017, 135: 34–48. doi: 10.1016/j.ejmech.2017.04.025.

AI Y, ZHU B, REN C, et al. Discovery of new monocarbonyl Ligustrazine-Curcumin hybrids for intervention of drug-sensitive and drug-resistantlungcancer. J Med Chem, 2016, 59(5): 1747–1760. doi: 10.1021/acs.jmedchem.5b01203.

ZOU J, GAO P, HAO X, et al. Recent progress in the structural modification and pharmacological activities of ligustrazine derivatives. Eur J Med Chem, 2021, 147: 150–162. doi: 10.1016/j.ejmech.2018.01.097. QU

Z, HAN Y, ZHU Q, et al. A novel neutrophil extracellular traps signature for overall survival prediction and tumor microenvironment identification in gastric cancer. J Inflamm Res, 2023, 16: 3419–3436. doi: 10.2147/JIR.S417182.

SONG S, ZHAO Y, FU T, et al. ELANE promotes M2 macrophage polarization by down-regulating PTEN and participates in the lung cancer progression. Immunol Invest, 2023, 52(1): 20–34. doi: 10.1080/08820139. 2022.2115379.

CUI C, CHAKRABORTY K, TANG X A, et al. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis. Cell, 2021, 184(12): 3163–3177. doi: 10.1016/j.cell.2021.04.016.

CHEN S, CHEN H, DU Q, et al. Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds. Front Physiol, 2020, 11: 433. doi: 10.3389/fphys.2020.00433.

PANAGOPOULOS V, LIAPIS V, ZINONOS I, et al. Peroxidase enzymes inhibit osteoclast differentiation and bone resorption. Mol Cell Endocrinol, 2017, 440: 8–15. doi: 10.1016/j.mce.2016.11.007.

PETRUSKA J M, MOSEBROOK D R, JAKAB G J, et al. Myeloperoxidase-enhanced formation of (±)-trans-7, 8-dihydroxy-7, 8-dihydrobenzo [a]pyrene-DNA adducts in lung tissue in vitro: a role of pulmonary inflammation in the bioactivation of a procarcinogen. Carcinogenesis, 1992, 13(7): 1075–1081. doi: 10.1093/carcin/13.7.1075.


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