Pharmacological Mechanisms Underlying the Hepatoprotective Effects of Ecliptae herba on Hepatocellular Carcinoma

Abstract

Background. The number of hepatocellular carcinoma (HCC) cases worldwide has increased significantly. As a traditional Chinese medicine (TCM) with a long history, Ecliptae herba (EH) has been widely used in HCC patients in China, but its hepatoprotective mechanism is still unclear. Methods. In this study, we applied a network pharmacology-based strategy and experimental verification to systematically unravel the underlying mechanisms of EH against HCC. First, six active ingredients of EH were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) by the ADME method. Subsequently, 52 potential targets of 6 active ingredients acting on HCC were screened from various databases, including TCMSP, DGIdb, SwissTargetPrediction, CTD, and GeneCards. Then, by constructing protein-protein interaction (PPI) network from STRING, we displayed the intricate connections among these 52 targets through Cytoscape software. We also applied enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, to provide an outline and set of concepts for describing gene functions and the advanced functions of biological systems of these 52 targets from genomic and molecular level information. Finally, molecular docking and biological experiments were used to reconfirm these results. Results. We hypothesized that EH might exert anti-HCC activity by acting on hub genes, including RELA, MMP9, PTGS2, ESR1, EGFR, AR, AKT1, HIF1A, AHR, CYP3A4, ABCG2, and MMP2. Moreover, based on GO and KEGG analysis, we speculated that EH may exert hepatoprotective effects on HCC through the following mechanisms: regulation of the PI3K-AKT signaling pathway to promote apoptosis and inhibit the abnormal proliferation of HCC, downregulation of HIF-1A expression by activating the HIF-1 signaling pathway, prevention of HCC by regulating lipid metabolism, and inhibition of nonalcoholic fatty liver disease (NAFLD) by the cytochrome P450 subfamily. Subsequent biological experiments verified that EH inhibits the PI3K-AKT signaling pathway through its active ingredients, quercetin, and wedelolactone, thereby inhibiting the proliferation of HCC cells and promoting the apoptosis of HCC cells. Conclusions. The network pharmacological strategy provides an efficient method to systematically explore the pharmacological mechanism of EH in HCC. Our study demonstrated that the anti-HCC proliferation activity of EH is mainly exerted by two active ingredients (quercetin and wedelolactone), which inhibit the proliferation of HCC cells (HepG2 and Huh-7) by inhibiting PI3K-AKT signaling.

Integrated System Pharmacology Approaches to Elucidate Multi-Target Mechanism of Solanum surattense against Hepatocellular Carcinoma

“…Additionally, activating the PI3K-AKT pathway can modulate HIF1A expression [ 30 ]. According to a series of network pharmacology studies, S. surattense may have inhibition in HCC via directly influencing cancer, metabolic, and immune-related pathways [ 31 ].…”

Multilevel data integration and molecular docking approach to systematically elucidate the underlying pharmacological mechanisms of Er-Zhi-Wan against hepatocellular carcinoma

“…Furthermore, multiple active components in EZW have been reported to exhibit substantial anticancer activity in various tumors. Pan et al [ 18 ] showed that coumarin wedelolactone, a characteristic component of EH, inhibited the proliferation of HCC cell lines (HepG2 and Huh-7) by inhibiting the PI3K/AKT signaling pathway. Additionally, demethylwedelolactone, a coumarin component of EH, inhibited the lung metastasis of MDA-MB-231 breast cancer cells in a nude mouse model [ 45 ].…”

“…Clinically, as an adjuvant drug, TCM has shown good efficacy in HCC patients, significantly reducing the incidence, preventing the recurrence, and improving the overall survival of HCC patients [11][12][13][14]. In addition, modern pharmacological studies have shown that TCM or TCMderived natural medicines can effectively suppress the development and progression of HCC in vitro and in vivo [15][16][17][18]. Due to this unique feature, TCM is considered a promising therapeutic strategy for the treatment of complex diseases, including liver cancer.…”

“…Hu et al [ 22 ] revealed that FLL extract induced apoptosis and cellular senescence in human hepatoma cells by upregulating p21, confirming that FLL is a potential anticancer herb for the treatment of HCC. Moreover, our previous study showed that EH extract could inhibit the proliferation of HCC cells by inhibiting PI3K-AKT signaling [ 18 ]. However, few studies have comprehensively investigated the molecular mechanisms involved in EZW in the treatment of HCC.…”

Elucidating the pharmacological mechanism by which Si-Wu-Tang induces cellular senescence in breast cancer via multilevel data integration

“…With the rapid development of systems biology and integrative pharmacology techniques, the emergence of network pharmacology has provided opportunities for breakthroughs in TCM research [ 13 ]. This method has been successfully used to elucidate the multitarget effects of TCM in various diseases, effectively bridging the gap between research on Western and Chinese medicine [ 14 , 15 ].…”