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Interpreting the Pharmacological Mechanisms of Huachansu Capsules on Hepatocellular Carcinoma Through Combining Network Pharmacology and Experimental Evaluation.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most fatal cancers across the world. Chinese medicine has been used as adjunctive or complementary therapy for the management of HCC. Huachansu belongs to a class of toxic steroids isolated from toad venom that has important anti-cancer property. This study was aimed to identify the bioactive constituents and molecular targets of Huachansu capsules (HCSCs) for treating HCC using network pharmacology analysis and experimental assays. The major bioactive components of HCSCs were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A series of network pharmacology methods including target prediction, pathway identification, and network establishment were applied to identify the modes of action of HCSCs against HCC. Furthermore, a series of experiments, including MTT, clonogenic assay, 3-D transwell, wound healing assay, as well as flow cytometry, were conducted to verify the inhibitory ability of HCSCs on HCC in vitro. The results showed that 11 chemical components were identified from HCSCs. The network pharmacological analysis showed that there were 82 related anti-HCC targets and 14 potential pathways for these 11 components. Moreover, experimental assays confirmed the inhibitory effects of HCSCs against HCC in vitro. Taken together, our study revealed the synergistic effects of HCSCs on a systematic level, and suggested that HCSCs exhibited anti-HCC effects in a multi-component, multi-target, and multi-pathway manner.

SUBMITTER: Huang J

PROVIDER: S-EPMC7145978 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Interpreting the Pharmacological Mechanisms of Huachansu Capsules on Hepatocellular Carcinoma Through Combining Network Pharmacology and Experimental Evaluation.

Huang Jihan J Chen Feiyu F Zhong Zhangfeng Z Tan Hor Yue HY Wang Ning N Liu Yuting Y Fang Xinyuan X Yang Tao T Feng Yibin Y

Frontiers in pharmacology 20200403

Hepatocellular carcinoma (HCC) is one of the most fatal cancers across the world. Chinese medicine has been used as adjunctive or complementary therapy for the management of HCC. Huachansu belongs to a class of toxic steroids isolated from toad venom that has important anti-cancer property. This study was aimed to identify the bioactive constituents and molecular targets of Huachansu capsules (HCSCs) for treating HCC using network pharmacology analysis and experimental assays. The major bioactiv ...[more]

PMID: 32308626

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Project description:Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality, but the therapies remain limited. Bupi Yishen Formula (BYF) - a patent traditional Chinese medicine (TCM) formula - has been proved to be effective for CKD treatment in a high-quality clinical trial. However, BYF's underlying mechanism is unclear. Thus, we aimed to reveal BYF pharmacological mechanism against CKD by network pharmacology and experimental studies. Network pharmacology-based analysis of the drug-compound-target interaction was used to predict the potential pharmacological mechanism and biological basis of BYF. We performed a comprehensive study by detecting the expression levels of fibrotic and inflammatory markers and main molecules of candidate signal pathway in adenine-induced CKD rats and TGF-β1-induced HK-2 cells with the treatment of BYF by western blotting and RT-qPCR analyses. Using small interfering RNA, we assessed the effect of BYF on the TLR4-mediated NF-κB mechanism for CKD renal fibrosis and inflammation. Network pharmacology analysis results identified 369 common targets from BYF and CKD. Based on these common targets, the BYF intervention pathway was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We found that Toll-like receptor (TLR) and NF-κB signaling pathways were enriched. Then, we demonstrated that BYF significantly improved the adenine-induced CKD rat model condition by kidney dysfunction improvement and reversing renal fibrosis and inflammation. Subsequently, we investigated BYF's effect on the TLR4/NF-κB signaling pathway. We found that TLR4 and phospho-NF-κB (p-p65 and p-IKβα) expression was significantly upregulated in adenine-induced CKD rats, then partially downregulated by BYF. Furthermore, BYF inhibited fibrotic and inflammatory responses, as well as TLR4, p-p65, and p-IKβα in TGF-β1-induced HK-2 cells. Additionally, the BYF inhibitory effect on fibrosis and inflammation, and NF-κB pathway activation were significantly reduced in TGF-β1-induced HK-2 cells transfected with TLR4 siRNA. Altogether, these findings demonstrated that the suppression of TLR4-mediated NF-κB signaling was an important anti-fibrotic and anti-inflammatory mechanism for BYF against CKD. It also provided a molecular basis for new CKD treatment drug candidates.

Project description:ObjectiveArsenic trioxide (Pishuang, Pishi, arsenolite, As2O3, and CAS 1327-53-3), a naturally occurring and toxic mineral as a drug for more than 2000 years in China, has been found to have a valuable function in hepatocellular carcinoma (HCC) in recent years. However, its exact mechanism remains to be elucidated. Therefore, this study was intended to explore the potential anti-HCC mechanism of arsenic trioxide through network pharmacology.MethodsThe potential targets of arsenic trioxide were collected from PubChem and TargetNet. HCC targets were obtained from the GeneCards database. Then, a protein-protein interaction (PPI) network of arsenic trioxide and HCC common targets was established using STRING. GO and KEGG pathway enrichment analyses were performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Finally, an arsenic trioxide-target-pathway-HCC network was built by Cytoscape 3.2.1, and network topological analysis was carried out to screen the key candidate targets.ResultsA total of 346 corresponding targets of arsenic trioxide and 521 HCC-related targets were collected. After target mapping, a total of 52 common targets were obtained. GO analysis showed that the biological process was mainly involved in the negative regulation of cellular senescence, response to tumor necrosis factor, and cellular response to hypoxia. Molecular functions included NF-kappa B binding, enzyme binding, p53 binding, and transcription factor binding. Cellular components mainly were replication fork, ESC/E(Z) complex, RNA polymerase II transcription factor complex, and organelle membrane. KEGG pathways were mainly enriched in the PI3K-Akt signaling pathway, VEGF signaling pathway, p53 signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, AMPK signaling pathway, NF-kappa B signaling pathway, FoxO signaling pathway, ErbB signaling pathway, and MAPK signaling pathway. In the arsenic trioxide-target-pathway-HCC network, targets such as AKT1, RAF1, RELA, TP53, and PTEN had a higher degree. Conclusions. Our study showed that key targets of arsenic trioxide were mainly involved in multiple biological processes and pathways. It provided a theoretical basis for the screening of drug targets.

Dataset Information

Interpreting the Pharmacological Mechanisms of Huachansu Capsules on Hepatocellular Carcinoma Through Combining Network Pharmacology and Experimental Evaluation.

Publications

Interpreting the Pharmacological Mechanisms of Huachansu Capsules on Hepatocellular Carcinoma Through Combining Network Pharmacology and Experimental Evaluation.

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