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Mechanisms of Compound Kushen Injection for the Treatment of Lung Cancer Based on Network Pharmacology.

ABSTRACT: Background:Compound Kushen Injection (CKI) is a Chinese patent drug that shows good efficacy in treating lung cancer (LC). However, its underlying mechanisms need to be further clarified. Methods:In this study, we adopted a network pharmacology method to gather compounds, predict targets, construct networks, and analyze biological functions and pathways. Moreover, molecular docking simulation was employed to assess the binding potential of selected target-compound pairs. Results:Four networks were established, including the compound-putative target network, protein-protein interaction (PPI) network of LC targets, compound-LC target network, and herb-compound-target-pathway network. Network analysis showed that 8 targets (CHRNA3, DRD2, PRKCA, CDK1, CDK2, CHRNA5, MMP1, and MMP9) may be the therapeutic targets of CKI in LC. In addition, molecular docking simulation indicated that CHRNA3, DRD2, PRKCA, CDK1, CDK2, MMP1, and MMP9 had good binding activity with the corresponding compounds. Furthermore, enrichment analysis indicated that CKI might exert a therapeutic role in LC by regulating some important pathways, namely, pathways in cancer, proteoglycans in cancer, PI3K-Akt signaling pathway, non-small-cell lung cancer, and small cell lung cancer. Conclusions:This study validated and predicted the mechanism of CKI in treating LC. Additionally, this study provides a good foundation for further experimental studies and promotes the reasonable application of CKI in the clinical treatment of LC.

SUBMITTER: Meng Z

PROVIDER: S-EPMC6558614 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mechanisms of Compound Kushen Injection for the Treatment of Lung Cancer Based on Network Pharmacology.

Meng Ziqi Z Liu Xinkui X Wu Jiarui J Zhou Wei W Wang Kaihuan K Jing Zhiwei Z Liu Shuyu S Ni Mengwei M Zhang Xiaomeng X

Evidence-based complementary and alternative medicine : eCAM 20190528

<h4>Background</h4>Compound Kushen Injection (CKI) is a Chinese patent drug that shows good efficacy in treating lung cancer (LC). However, its underlying mechanisms need to be further clarified.<h4>Methods</h4>In this study, we adopted a network pharmacology method to gather compounds, predict targets, construct networks, and analyze biological functions and pathways. Moreover, molecular docking simulation was employed to assess the binding potential of selected target-compound pairs.<h4>Result ...[more]

PMID: 31275410

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Project description:BackgroundBreast cancer (BC) is one of the most common malignant tumors in women and poses a serious threat to their health. Compound Kushen injection (CKI) has shown therapeutic effects on a variety of cancers, including BC, and it can significantly improve the lives of patients. However, the underlying mechanism remains unclear and needs to be fully elucidated.MethodsThe active constituents of CKI were identified through a literature review, and the anti-BC targets of CKI were determined using multiple databases and a ChIP data analysis. Subsequently, the target was analyzed on the DAVID database through GO and KEGG to identify the key pathway that CKI affects to exhibit anti-BC activity. In addition, MCF-7 and MDA-MB-231 cells were treated with CKI for 24 and 48 hours at five concentrations, and the effects of CKI on cell proliferation and apoptosis were measured using MTT and annexin V/propidium iodide staining assays, respectively. The genes and protein identified to be involved in this pathway were verified using real-time quantitative PCR (qPCR) and western blot(WB) in BC cells.ResultsTwelve CKI anti-BC targets were obtained by a comprehensive analysis of the targets collected in the databases and results from the ChIP analysis. Bioinformatics analysis was performed for 12 targets. KEGG analysis showed that the 12 targets were mainly related to the VEGF, ErbB, and TNF signaling pathways. We focused our study on the VEGF signaling pathway as the p-value for the VEGF signaling pathway was the lowest among the three pathways. In vitro experiments showed that CKI significantly inhibited the proliferation of BC cells and induced apoptosis. Furthermore, qPCR and WB experiments showed that the expression of VEGF signaling pathway genes PIK3CA and NOS3 were significantly increased meanwhile SRC was significantly decreased after CKI intervention.ConclusionCKI significantly inhibited the proliferation of BC cells and induced apoptosis. The main mechanism for the anti-BC effect of CKI may be that it regulates the VEGF signaling pathway by increasing the expression of PIK3CA, SRC, and NOS3. Macrozamin and lamprolobine may be the main active components of CKI against BC.

Project description:Traditional Chinese Medicine (TCM) preparations are often extracts of single or multiple herbs containing hundreds of compounds, and hence it has been difficult to study their mechanisms of action. Compound Kushen Injection (CKI) is a complex mixture of compounds extracted from two medicinal plants and has been used in Chinese hospitals to treat cancer for over twenty years. To demonstrate that a systematic analysis of molecular changes resulting from complex mixtures of bioactives from TCM can identify a core set of differentially expressed (DE) genes and a reproducible set of candidate pathways. We used in vitro cancer models to measure the effect of CKI on cell cycle phases and apoptosis, and correlated those phenotypes with CKI induced changes in gene expression. We treated two cancer cell lines with or without CKI and assessed the resulting phenotypes by employing cell viability and proliferation assays. Based on these results, we carried out high-throughput transcriptome data analysis to identify genes and candidate pathways perturbed by CKI. We integrated these differential gene expression results with previously reported results and carried out validation of selected differentially expressed genes. CKI induced cell-cycle arrest and apoptosis in the cancer cell lines tested. In these cells CKI also altered the expression of 363 core candidate genes associated with cell cycle, apoptosis, DNA replication/repair, and various cancer pathways. Of these, 7 are clinically relevant to cancer diagnosis or therapy, 14 are cell cycle regulators, and most of these 21 candidates are downregulated by CKI. Comparison of our core candidate genes to a database of plant medicinal compounds and their effects on gene expression identified one-to-one, one-to-many and many-to-many regulatory relationships between compounds in CKI and DE genes. By identifying genes and promising candidate pathways associated with CKI treatment based on our transcriptome-based analysis, we have shown that this approach is useful for the systematic analysis of molecular changes resulting from complex mixtures of bioactives.

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Mechanisms of Compound Kushen Injection for the Treatment of Lung Cancer Based on Network Pharmacology.

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Mechanisms of Compound Kushen Injection for the Treatment of Lung Cancer Based on Network Pharmacology.

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