In Silico and In Vitro Studies on the Mechanisms of Chinese Medicine Formula (Yiqi Jianpi Jiedu Formula) in the Treatment of Hepatocellular Carcinoma

Abstract

Objective. Traditional Chinese medicine (TCM) is an important part of the comprehensive treatment of hepatocellular carcinoma (HCC), and Chinese materia medica formulas with the effect of “Yiqi Jianpi” (replenishing qi and strengthening spleen) or “Jiedu” (removing toxicity) have been proved to be effective in treating HCC. However, mechanisms of these formulas in treating HCC remain unclear. In this paper, our goal is to explore the antitumor activity and its molecular mechanisms of Yiqi Jianpi Jiedu (YQJPJD) formula against HCC. Methods. The bioactive ingredients and targets of YQJPJD formula and HCC targets were screened by five Chinese materia medicas and two disease databases, respectively. The network pharmacology was utilized to construct the relationship network between YQJPJD formula and HCC, and the mechanisms were predicted by the protein-protein interaction (PPI) network, pathway enrichment analysis, bioinformatics, and molecular docking. Numerous in vitro assays were performed to verify the effect of YQJPJD formula on HCC cells, cancer-associated targets, and PI3K/Akt pathway. Results. The network relationship between YQJPJD formula and HCC suggested that YQJPJD formula mainly regulated the potential therapeutic targets of HCC by several key bioactive ingredients (e.g., quercetin, luteolin, baicalein, and wogonin). PPI network, bioinformatics, and molecular docking analyses displayed that YQJPJD formula may play an anti-HCC effect through key targets such as MAPK3, RAC1, and RHOA. Additionally, pathway analysis demonstrated that YQJPJD formula could play an anti-HCC effect via multiple pathways (e.g., PI3K-Akt and hepatitis B). Experimental results showed that YQJPJD formula could effectively inhibit the proliferation, migration, and invasion of HCC cells and promote HCC cell apoptosis in a concentration-dependent manner. Moreover, YQJPJD formula could decrease the mRNA expression of β-catenin, MAPK3, and RHOA and the protein expression of phosphorylated PI3K and Akt. Conclusion. YQJPJD formula mainly exerts its anti-HCC effect through multiple bioactive ingredients represented by quercetin, as well as multiple pathways and targets represented by PI3K/Akt pathway, β-catenin, MAPK3, and RHOA.

Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1

“…Several in vivo and in vitro experiments have shown that Chinese herbal formulas are based on invigorating qi, strengthening the spleen, tonifying the kidneys, and removing toxins and blood stasis. Therefore, TCM treatments considerably reduces proliferation, survival, and progression of HCC cells by regulating key signaling pathways such as PI3K/Akt, β-catenin, MAPK3, and RHOA[ 30 - 32 ]. SPXJ formula has been shown to stabilize tumors, improve patients’ quality of life, and resist recurrence and metastasis in the clinical treatment of liver cancer[ 33 , 34 ].…”

Anhydroicaritin suppresses tumor progression via the PI3K/AKT signaling pathway in hepatocellular carcinoma

“…Huang et al demonstrated that Huanglian Jiedu decoction, one of the most commonly used classic TCM formulae, could remarkably suppress HCC cells growth in vitro and vivo [ 9 ]. Wu et al showed that Yiqi Jianpi Jiedu formula exerts its anti-HCC effect of HCC by β-catenin, mitogen-activated protein kinase 3 (MAPK3), PI3K/AKT pathway and ras homolog family member A (RHOA) [ 10 ]. Liu et al demonstrated that astragalus membranaceus directly down-regulated MT1G through daidzein to promote ferroptosis of HCC cells and improved prognosis for HCC [ 11 ].…”