Integrating Network Pharmacology and Pharmacological Evaluation for Deciphering the Action Mechanism of Herbal Formula Zuojin Pill in Suppressing Hepatocellular Carcinoma.

Fan Cheung,Hor-Yue Tan,Wei Guo,Jihan Huang,Yibin Feng,Feiyu Chen,Ning Wang

doi:10.3389/fphar.2019.01185

Abstract

Hepatocellular carcinoma (HCC) is a kind of complicated disease with an increasing incidence all over the world. A classic Chinese medicine formula, Zuojin pill (ZJP), was shown to exert therapeutic effects on HCC. However, its chemical and pharmacological profiles remain to be elucidated. In the current study, network pharmacology approach was applied to characterize the action mechanism of ZJP on HCC. All compounds were obtained from the corresponding databases, and active compounds were selected according to their oral bioavailability and drug-likeness index. The potential proteins of ZJP were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database and the traditional Chinese medicine integrated database (TCMID), whereas the potential genes of HCC were obtained from OncoDB.HCC and Liverome databases. The potential pathways related to genes were determined by gene ontology (GO) and pathway enrichment analyses. The compound-target and target-pathway networks were constructed. Subsequently, the potential underlying action mechanisms of ZJP on HCC predicted by the network pharmacology analyses were experimentally validated in HCC cellular and orthotopic HCC implantation murine models. A total of 224 components in ZJP were obtained, among which, 42 were chosen as bioactive components. The compound-target network included 32 compounds and 86 targets, whereas the target-pathway network included 70 proteins and 75 pathways. The in vitro and in vivo experiments validated that ZJP exhibited its prominent therapeutic effects on HCC mainly via the regulation of cell proliferation and survival though the EGFR/MAPK, PI3K/NF-κB, and CCND1 signaling pathways. In conclusion, our study suggested combination of network pharmacology prediction with experimental validation may offer a useful tool to characterize the molecular mechanism of traditional Chinese medicine (TCM) ZJP on HCC.

Highlights

As the third predominant cause of cancer-related death in the world, hepatocellular carcinoma (HCC) is a kind of complicated disease with various risk factors, such as hepatitis B viral or hepatitis C viral infection, obesity, and alcohol abuse (Ferlay et al, 2015)
A total of 224 components in Zuojin pill (ZJP) were obtained from traditional Chinese medicine systems pharmacology (TCMSP) database, 48 of which belong to coptidis Rhizoma (CR) and 176 to evodiae fructus (EF) (Supplement 2)
The pharmacological mechanism by which ZJP inhibited Hepatocellular carcinoma (HCC) was investigated with the combination of network pharmacology prediction and experimental validation

Summary

Introduction

As the third predominant cause of cancer-related death in the world, hepatocellular carcinoma (HCC) is a kind of complicated disease with various risk factors, such as hepatitis B viral or hepatitis C viral infection, obesity, and alcohol abuse (Ferlay et al, 2015). As most HCC patients are diagnosed at middle or later disease stages, only sorafenib treatment is still feasible for these patients. Traditional Chinese medicine (TCM) has been used clinically in Asia for more than 2,000 years. As one of the most popular complementary and alternative medicine modalities in China, TCM has been gradually accepted by non-Chinese due to its prominent efficacy, rich resource, and less toxicity. There have been many TCM formulas used alone or as an adjuvant to conventional chemotherapy in the clinical treatment of cancers (Kim et al, 2012; Xu et al, 2012a; Gavaraskar et al, 2015)

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Discussion

Conclusion