A network pharmacology approach to investigate the anticancer mechanism of cinobufagin against hepatocellular carcinoma via downregulation of EGFR-CDK2 signaling

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.

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Integrating Network Pharmacology and Experimental Models to Investigate the Efficacy of Coptidis and Scutellaria Containing Huanglian Jiedu Decoction on Hepatocellular Carcinoma

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500093 ◽

2020 ◽

Vol 48 (01) ◽

pp. 161-182 ◽

Cited By ~ 4

Author(s):

Jihan Huang ◽

Wei Guo ◽

Fan Cheung ◽

Hor-Yue Tan ◽

Ning Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Experimental Models ◽

Network Pharmacology ◽

Disease Networks ◽

Cycle Arrest ◽

Single Target ◽

Induced Apoptosis

Unlike Western medicines with single-target, the traditional Chinese medicines (TCM) always exhibit diverse curative effects against multiple diseases through its “multi-components” and “multi-targets” manifestations. However, discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM remain to be challenged. In the current study, we, for the first time, applied an integrated strategy by combining network pharmacology with experimental evaluation, for exploration and demonstration of the therapeutic potentials and the underlying possible mechanisms of a classic TCM formula, Huanglian Jiedu decoction (HLJDD). First, the herb–compound, compound–protein, protein–pathway, and gene–disease networks were constructed to predict the major therapeutic diseases of HLJDD and explore the underlying molecular mechanisms. Network pharmacology analysis showed the top one predicted disease of HLJDD treatment was cancer, especially hepatocellular carcinoma (HCC) and inflammation-related genes played an important role in the treatment of HLJDD on cancer. Next, based on the prediction by network pharmacology analysis, both in vitro HCC cell and in vivo orthotopic HCC implantation mouse models were established to validate the curative role of HLJDD. HLJDD exerted its antitumor activity on HCC in vitro, as demonstrated by impaired cell proliferation and colony formation abilities, induced apoptosis and cell cycle arrest, as well as inhibited migratory and invasive properties of HCC cells. The orthotopic HCC implantation mouse model further demonstrated the remarkable antitumour effects of HLJDD on HCC in vivo. In conclusion, our study demonstrated the effectiveness of integrating network pharmacology with experimental study for discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM.

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Therapeutic Efficacy Evaluation and Underlying Mechanisms Prediction of Jianpi Liqi Decoction for Hepatocellular Carcinoma

Journal of Surgical Oncology ◽

10.31487/j.jso.2021.02.04 ◽

2021 ◽

pp. 1-11

Author(s):

Shi Bing Su ◽

Xiaole Chen ◽

Peng Wang ◽

Yunquan Luo ◽

Yi Yu Lu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Signaling Pathways ◽

Karnofsky Performance Status ◽

Performance Status ◽

Network Pharmacology ◽

Therapeutic Effects ◽

Efficacy Evaluation ◽

Underlying Mechanisms ◽

Multiple Signaling

Objective: The aim of this study was to assess the therapeutic effects of Jianpi Liqi decoction (JPLQD) in hepatocellular carcinoma (HCC) and explore its underlying mechanisms. Methods: The characteristics and outcomes of HCC patients with intermediate stage B who underwent sequential conventional transcatheter arterial chemoembolization (cTACE) and radiofrequency ablation (RFA) only or in conjunction with JPLQD were analysed retrospectively. The plasma proteins were screened using label-free quantitative proteomics analysis. The effective mechanisms of JPLQD were predicted through network pharmacology approach and partially verified by ELISA. Results: Clinical research demonstrated that the Karnofsky Performance Status (KPS), traditional Chinese medicine (TCM) syndrome scores, neutropenia and bilirubin, median progression-free survival (PFS), and median overall survival (OS) in HCC patients treated with JPLQD were superior to those in patients not treated with JPLQD (all P<0.05). The analysis of network pharmacology, combined with proteomics, suggested that 52 compounds targeted 80 potential targets, which were involved in the regulation of multiple signaling pathways, especially affecting the apoptosis-related pathways including TNF, p53, PI3K-AKT, and MAPK. Plasma IGFBP3 and CA2 were significantly up-regulated in HCC patients with sequential cTACE and RFA therapy treated with JPLQD than those in patients not treated with JPLQD (P<0.001). The AUC of the IGFBP3 and CA2 panel, estimated using ROC analysis for JPLQD efficacy evaluation, was 0.867. Conclusion: These data suggested that JPLQD improves the quality of life, prolongs the overall survival, protects liver function in HCC patients, and exhibits an anticancer activity against HCC. IGFBP3 and CA2 panels may be potential therapeutic targets and indicators in the efficacy evaluation for JPLQD treatment, and the effective mechanihsms involved in the regulation of multiple signaling pathways, possibly affected the regulation of apoptosis.

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Systematic Investigation of Berberine for Treating Hepatocellular Carcinoma Based on Network Pharmacology

Digital Chinese Medicine ◽

10.1016/j.dcmed.2019.12.001 ◽

2019 ◽

Vol 2 (3) ◽

pp. 127-135

Author(s):

Mu Jie ◽

Liu Hai-Xia ◽

Tang Fei-Fei ◽

Liu Shu-Ling ◽

Feng Tian-Yi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Investigation ◽

Network Pharmacology

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Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190808152051 ◽

2020 ◽

Vol 19 (17) ◽

pp. 2120-2129 ◽

Cited By ~ 1

Author(s):

Sakineh Dadashpour ◽

Tuba T. Küçükkılınç ◽

Ayse Ercan ◽

Seyed J. Hosseinimehr ◽

Nima Naderi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Anticancer Agents ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Biological Evaluation ◽

Kinase Assay ◽

Drug Candidate ◽

Surface Receptors ◽

Anticancer Mechanism

Background: Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer. Objective: The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents. Methods: A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells. Results: Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition. Conclusion: Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.

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Molecular Mechanisms of TanshinoneIIA in Hepatocellular carcinomatherapy via WGCNA-based Network Pharmacology Analysis

10.21203/rs.3.rs-154091/v1 ◽

2021 ◽

Author(s):

Han Zhao ◽

Jing Guo ◽

Qingjia Chi ◽

Meng Fang

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Features ◽

Molecular Mechanisms ◽

Tanshinone Iia ◽

Network Pharmacology ◽

Specific Gene ◽

Advanced Tumor Stage ◽

Overlapping Genes ◽

Hub Genes ◽

Advanced Tumor

Abstract Background: Hepatocellular carcinoma (HCC) is a worldwide malignant tumor that caused irreversible consequences. The studies of Tanshinone IIA showed that Tanshinone IIA has played a notable role in HCC treatment. However, it is still to be investigated to discover the potential targets and associating mechanism of Tanshinone IIA against HCC. Methods: To analyze the correlation between genes and specific clinical features, we applied weighted gene co-expression network analysis (WGCNA), which can help us identify the targets of Tanshinone IIA related to the clinical features of Hepatocellular carcinoma. Results: We screened out 105 overlapping genes by integrating the predicted targets of Tanshinone IIA and the gene expression profile of HCC from the Cancer Genome Atlas (TCGA) database. For WGCNA, we used the RNA-seq profile of the overlapping genes and the related clinical information of HCC from TCGA. And 23 genes related to clinical tumor grade in the important module (R2 = 0.37) were imported for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) analysis. Compared to the key genes in the significant module from WGCNA with the high connectivity nodes from the PPI network, we can analyze three hub genes, AURKB, KIF11, and PLK1, for further verification. We tested the binding of Tanshinone IIA to the targets of Hepatocellular carcinoma using Autodock Vina. The survival curve validated that the three hub genes represented a poor prognosis. Receiver operating characteristic (ROC) curves demonstrated that the three hub genes were effective in diagnosis. The mRNA expression of the three hub genes was upregulated in the HCC than the normal. AURKB, KIF11 and PLK1 were further upregulated in advanced tumor stage and grade. Moreover, AURKB, KIF11 and PLK1 also had higher protein expression in HCC tissues. Conclusions: In the study, WGCNA revealed grade-specific gene modules, indicating that Tanshinone IIA probably plays its therapeutical effect in the differentiation process of HCC. And the study partly interpreted the pharmacological mechanism of Tanshinone IIA against HCC.

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Systematic Investigation of Scutellariae Barbatae Herba for Treating Hepatocellular Carcinoma Based on Network Pharmacology

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4365739 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Benjiao Gong ◽

Yanlei Kao ◽

Chenglin Zhang ◽

Fudong Sun ◽

Huishan Zhao

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Investigation ◽

Network Pharmacology ◽

Biological Processes ◽

Depth Analysis ◽

Neutrophil Degranulation ◽

Long Time ◽

Underlying Mechanisms ◽

Related Mortality ◽

Target Fishing

As the fifth most common type of malignant cancers globally, hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. As a long-time medicinal herb in Traditional Chinese Medicine (TCM), Scutellariae Barbatae Herba (SBH) has also been used for treating various cancers including HCC, but its underlying mechanisms have not been completely clarified. Presently, an innovative network-pharmacology platform was introduced to systematically elucidate the pharmacological mechanisms of SBH against HCC, adopting active ingredients prescreening, target fishing, and network analysis. The results revealed that SBH appeared to work on HCC probably through regulating 4 molecular functions, 20 biological processes, and hitting on 21 candidate targets involved in 40 pathways. By in-depth analysis of the first-ranked signaling pathway and hit genes, only TTR was highly and specially expressed in the liver tissue. TTR might play a crucial role in neutrophil degranulation pathway during SBH against HCC. Hence, TTR might become a therapeutic target of HCC. The study investigated the anti-hepatoma mechanisms of SBH from a holistic perspective, which provided a theoretical foundation for further experimental research and rational clinical application of SBH.

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Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/7518374 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 6

Author(s):

Chongyang Ma ◽

Tian Xu ◽

Xiaoguang Sun ◽

Shuang Zhang ◽

Shuling Liu ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Overall Survival ◽

Disease Free Survival ◽

Network Pharmacology ◽

Therapeutic Effects ◽

Potential Candidate ◽

Ppi Network ◽

Free Survival ◽

Disease Free

Liver cancer is the fourth leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) accounts for the greatest proportion of these deaths. Baicalein, a flavonoid isolated from the root of Scutellariae radix, is considered a potential candidate to treat HCC. However, the underlying molecular mechanisms remain poorly understood. In the present study, a network pharmacological approach was combined with microarray data (GSE95504) acquired from the Gene Expression Omnibus database to reveal the therapeutic mechanisms of action of baicalein at a systemic level. We identified 38 baicalein targets and 76 differently expressed genes (DEGs) following treatment with baicalein, including 55 upregulated and 21 downregulated genes. The DEGs were significantly enriched in the biological functions of apoptosis, endoplasmic reticulum stress, and PERK-mediated unfolded protein response. Protein-protein interaction (PPI) network construction and topological screening revealed a core module of PPIs including two baicalein targets, TP53 and CDK1, and two downregulated DEGs, HSPA1A and HSPA1B. Expression and survival data for these genes in the module derived from Gene Expression Profiling Interactive Analysis (GEPIA) were subjected to Kaplan–Meier analysis of overall survival and disease-free survival. Overexpression of CDK1, BRCA1, TUBB, HSPA1A, HSPA1B, and HSPA4 was associated with significantly worse overall survival, while overexpression of CDK1, CLU7, BRCA1, and TUBB was associated with significantly worse disease-free survival. These data suggest that baicalein exerts therapeutic effects against HCC via a PPI network involving TP53, CDK1, HSPA1A, and HSPA1B.

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Network Pharmacology-Based Study on the Mechanism of Scutellariae Radix for Hepatocellular Carcinoma Treatment

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8897918 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Qian Wang ◽

Yan Liang ◽

Can Peng ◽

Peng Jiang

Keyword(s):

Hepatocellular Carcinoma ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Enrichment Analysis ◽

Functional Enrichment ◽

Mechanistic Study ◽

Network Pharmacology ◽

Therapeutic Drug ◽

Active Components ◽

Scutellariae Radix

Hepatocellular carcinoma (HCC) is a malignant tumor without effective therapeutic drugs for most patients in advanced stages. Scutellariae Radix (SR) is a well-known anti-inflammatory and anticarcinogenic herbal medicine. However, the mechanism of SR against HCC remains to be clarified. In the present study, network pharmacology was utilized to characterize the mechanism of SR on HCC. The active components of SR and their targets were collected from the traditional Chinese medicine systems pharmacology database and the traditional Chinese medicine integrated database. HCC-related targets were acquired from the liver cancer databases OncoDB.HCC and Liverome. The gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. Component-component target and protein-protein interaction networks were set up. A total of 143 components of SR were identified, and 37 of them were considered as candidate active components. Fifty targets corresponding to 29 components of SR were mapped with targets of HCC. Functional enrichment analysis indicated that SR exerted an antihepatocarcinoma effect by regulating pathways in cancer, hepatitis B, viral carcinogenesis, and PI3K-Akt signaling. The holistic approach of network pharmacology can provide novel insights into the mechanistic study and therapeutic drug development of SR for HCC treatment.

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Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis

Cancer Cell International ◽

10.1186/s12935-020-01596-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Fengna Yan ◽

Miaomiao Feng ◽

Xinhui Wang ◽

Peng Wang ◽

Yuqing Xie ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Total Bilirubin Level ◽

Scratch Test ◽

Network Pharmacology ◽

Tunel Staining ◽

Red Blood Cell Count ◽

Independent Risk Factors ◽

Hcc Cells

Abstract Background Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) indicated for the treatment of hepatocellular carcinoma (HCC). Its potential targets and molecular mechanisms are not clear. Therefore, this study intends to explore the molecular mechanism of YFJP based on network pharmacology analysis and in vitro validation. Methods and results Through univariate and multivariate analyses and survival analysis in HCC patients with or without YFJP treatment we found that drinking alcohol, alfafeto protein ≥ 400 ng/l, baseline portal vein tumor thrombus and total bilirubin level ≥ 18.8 μM) were independent risk factors for poor prognosis, while red blood cell count ≥ 4 × 109/l and TCM treatment were independent protective factors. Besides, YFJP prolonged the cumulative survival of HCC patients. Using online pharmacological methods, we obtained 58 relevant compounds and molecular 53 targets. By using scratch test, Transwell assay, EdU assay, and TUNEL staining, we found that YFJP-containing serum repressed the migration, invasion and proliferation of HCC cells in vitro, and induced cell apoptosis. Moreover, YFJP diminished the gene expression of TP53, CCND1, p-EGFR, EGF, VEGFA, JUN, IL6, COX-2, AKT1, and MAPK1 in HCC cells, but elevated the expression of ESR1 and CASP3. Conclusions Taken together, results showed that YFJP attenuated HCC progression through mediating effects on HCC-related genes.

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