Liuwei Dihuang pills suppress hepatocellular carcinoma via PI3K/AKT/TP53 pathway: Integrating network pharmacology, metabolomics, and experimental validation
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Published on: April 7, 2023
Hongxin Cai1, Qi Hu2, Zhiying Song2
1Modern Industrial College of Traditional Chinese Medicine and Health, Lishui University, Lishui, 323000, China; Medical College of Jiaxing University, Jiaxing University, Jiaxing, 314001, China; School of Pharmaceutical Science, Nanchang University, Nanchang 330006, China; Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 430030, Wuhan, China.
Abstract:
Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited treatment options. Liuwei Dihuang Pills (LWPs), a classic Traditional Chinese Medicine formula, have demonstrated potential anti-tumor effects; however, their bioactive components and mechanisms of action against HCC remain unclear. Network pharmacology identified 20 core targets of LWPs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated pro-apoptotic activity via the PI3K/AKT and TP53 pathways. In vivo studies confirmed tumor growth inhibition, biochemical index regulation, and regulation of the PI3K/AKT/TP53 axis. Metabolomics revealed alterations in amino acid and carbohydrate metabolism. In vitro, LWPs-containing serum (LWPs-S) on the PI3K/AKT/TP53 pathway, suppressing Huh7 cell proliferation, migration, and invasion, inducing G1-phase arrest, elevating reactive oxygen species (ROS) levels, and engaging apoptosis-related pathways. Among various extracts, LWPs alcohol extract emerged as the principal anti-HCC fraction. A total of 77 components were identified in LWPs alcohol extract, including 17 blood‑absorbed and 6 tumor‑absorbed plant monomer compounds. Molecular docking demonstrated strong binding affinities of specific monomers from LWPs alcohol extract to PI3K, AKT and TP53. Collectively, these findings elucidate how LWPs promote HCC apoptosis through key pathways and provide experimental evidence supporting the pivotal role of the alcohol extract, offering a scientific basis for the rational development of LWPs.
Insights
Liuwei Dihuang Pills (LWPs) show anti-cancer effects against hepatocellular carcinoma (HCC) by promoting apoptosis via the PI3K/AKT/TP53 pathway. The alcohol extract of LWPs is identified as the key anti-HCC component.
Area of Science:
- Traditional Chinese Medicine
- Pharmacology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) presents a significant global health burden with limited therapeutic strategies.
- Liuwei Dihuang Pills (LWPs), a traditional Chinese medicine, exhibit potential anti-tumor properties, but their mechanisms against HCC are not fully understood.
Purpose of the Study:
- To investigate the bioactive components and mechanisms of Liuwei Dihuang Pills (LWPs) in treating hepatocellular carcinoma (HCC).
- To elucidate the role of LWPs in regulating key signaling pathways and cellular processes involved in HCC progression.
Main Methods:
- Network pharmacology identified 20 core targets, with pathway analysis (GO, KEGG) pointing to PI3K/AKT and TP53 pathways.
- In vivo and in vitro studies utilized cell lines, animal models, metabolomics, and molecular docking to assess anti-HCC effects and mechanisms.
- Analysis of LWPs alcohol extract identified active components and their binding affinities to target proteins.
Main Results:
- LWPs demonstrated tumor growth inhibition and regulated the PI3K/AKT/TP53 axis in vivo.
- In vitro, LWPs suppressed Huh7 cell proliferation, migration, invasion, induced G1 arrest, increased ROS, and triggered apoptosis.
- LWPs alcohol extract was the primary anti-HCC fraction, with identified components showing strong binding to PI3K, AKT, and TP53.
Conclusions:
- LWPs promote HCC apoptosis through the PI3K/AKT/TP53 pathway.
- The alcohol extract of LWPs is crucial for its anti-HCC activity.
- These findings provide a scientific foundation for developing LWPs as a targeted therapy for HCC.
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