gingerol and Liver-Neoplasms

To explore gingerol's potential mechanism for treating liver cancer using network pharmacology and molecular docking technology and to conduct in-vitro experiments of human liver cancer cell HepG2 to verify important signalling pathways.. We obtained potential targets of gingerol derivatives (6-gingerol, 8-gingerol and 10-gingerol) from PubChem and SwissTargetPrediction websites and collected related targets for liver cancer with the help of GeneCards. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on key targets using the DAVID data platform and combined with Cytoscape 3.7.1 software to construct a component-target-signal pathway interaction map to study its mechanism of action. Subsequently, the components and key proteins were molecularly docked through Autodock Vina software. Finally, the important signal pathways were verified by HepG2 cell in-vitro experiments.. A total of 318 drug targets were screened for gingerol derivatives, and 2509 gene targets related to liver cancer were collected. The Venn diagram showed that there were 104 intersection targets between gingerol derivatives and liver cancer. Module analysis results show that these intersection targets can be divided into 5 modules and 49 nodes. Bioinformatics analysis found that GO obtained 20 important functional items including cancer cell proliferation, protein kinase activity, phosphotransferase activity and kinase activity; KEGG enrichment analysis yielded a total of 20 key signal pathways including the PI3K-Akt signalling pathway. The results of molecular docking show that the binding energy of gingerol derivatives has good binding activity with PI3K and Akt. In-vitro experimental results show that gingerol derivatives and compound gingerol (compound gingerol is composed of 6-gingerol, 8-gingerol and 10-gingerol in a ratio of 7:1.5:1.5) can produce HepG2 cell proliferation inhibition, and each administration group can significantly increase the apoptosis rate of HepG2 cells and the fluorescence intensity of the nucleus and block the cell cycle in the S phase; the results of Western Blot and real-time quantitative PCR show that gingerol derivatives and compound gingerol can down-regulate the expression of Akt and p-Akt and up-regulate the expression of Bax/Bcl-2. And the effect of compound gingerol is more obvious than that of gingerol derivatives.. The results of network pharmacology and experimental validation suggest that gingerol derivatives and compound gingerol can act against liver cancer by acting on the PI3K-Akt signalling pathway.

Topics: Catechols; Drugs, Chinese Herbal; Fatty Alcohols; Humans; Liver Neoplasms; Molecular Docking Simulation; Network Pharmacology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

Benjakul [BEN], a Thai Traditional medicine preparation, is composed of five plants: Piper chaba fruit [PC], Piper sarmentosum root [PS], Piper interruptum stem [PI], Plumbago indica root [PL] and Zingiber officinale rhizome [ZO]. From selective interviews of folk doctors in Southern Thailand, it was found that Benjakul has been used for cancer patients.. To investigate cytotoxicity activity of Benjakul preparation [BEN] and its ingredients against three human cancer cell lines, large lung carcinoma cell line (COR-L23), cervical cancer cell line (Hela) liver cancer cell line (HepG2) as compared with normal lungfibroblast cell (MRC-5) by using SRB assay.. The extraction as imitated the method used by folk doctors was done by maceration in ethanol and boiling in water Bioassay guided isolation was used isolated cytotoxic compound.. The ethanolic extracts of PL, ZO, PC, PS, BEN and PS showed specific activity against lung cancer cell (IC50 = 3.4, 7.9, 15.8, 18.4, 19.8 and 32.91 microg/ml) but all the water extracts had no cytotoxic activity. Three active ingredients [6-gingerol, plumbagin and piperine as 0.54, 4.18 and 7.48% w/w yield of crude extract respectively] were isolated from the ethanolic extract of BEN and they also showed cytotoxic activity with plumbagin showing the highest cytotoxic activity against COR-L23, HepG2, Hela and MRC-5 (IC50 = 2.55, 2.61, 4.16 and 11.54 microM respectively).. These data results may support the Thai traditional doctors who are using Benjakul to treat cancer patients and three of its constituents (6-gingerol, plumbagin and piperine) are suggested to be used as biomarkers for standardization of this preparation.

Topics: Alkaloids; Benzodioxoles; Catechols; Cell Line, Tumor; Fatty Alcohols; Female; Humans; Liver Neoplasms; Lung Neoplasms; Medicine, East Asian Traditional; Naphthoquinones; Phytotherapy; Piper; Piperidines; Plant Extracts; Plants, Medicinal; Plumbaginaceae; Polyunsaturated Alkamides; Thailand; Uterine Cervical Neoplasms; Zingiber officinale

6-Gingerol, a major phenolic compound derived from ginger, has been known to possess anticarcinogenic activities. However, the mechanisms are not well understood. In our previous study, it was demonstrated that lysosome and mitochondria may be the primary targets for 6-gingerol in HepG2 cells. Therefore, the aim was to evaluate lysosome-mitochondria cross-signaling in 6-gingerol-induced apoptosis. Apoptosis was detected by Hoechst 33342 and TUNEL assay after 24 h treatment, and the destabilization of lysosome and mitochondria were early upstream initiating events. This study showed that cathepsin D played a crucial role in the process of apoptosis. The release of cathepsin D to the cytosol appeared to be an early event that preceded the release of cytochrome c from mitochondria. Moreover, inhibition of cathepsin D activity resulted in suppressed release of cytochrome c. To further determine the involvement of oxidative stress in 6-gingerol-induced apoptosis, the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH) were examined. Taken together, these results suggest that cathepsin D may be a positive mediator of 6-gingerol induced apoptosis in HepG2 cells, acting upstream of cytochrome c release, and the apoptosis may be associated with oxidative stress.

Topics: Apoptosis; Catechols; Cathepsin D; Cytochromes c; Fatty Alcohols; Glutathione; Hep G2 Cells; Humans; Liver Neoplasms; Lysosomes; Mitochondria; Oxidative Stress; Reactive Oxygen Species

We previously demonstrated that 6-shogaol and 6-gingerol, two active compounds in ginger (Zingiber officinale), possess antiinvasive activity against highly metastatic hepatoma cells. The aims of this study were to evaluate the inhibitory effect and molecular mechanism underlying the transcription and translation of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) in Hep3B cells as well as the antiangiogenic activity of 6-gingerol and 6-shogaol.. By gelatin zymography and luciferase reporter gene assays, we found that 6-gingerol and 6-shogaol regulate MMP-2/-9 transcription. Moreover, 6-gingerol directly decreased expression of uPA, but the 6-shogaol-mediated decrease in uPA was accompanied by up-regulation of plasminogen activator inhibitor (PAI)-1. 6-Gingerol and 6-shogaol concentrations of ≥ 10 μM and ≥ 2.5 μM, respectively, significantly inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling, the activation of NF-κB, and the translocation of NF-κB and STAT3. Incubation of 6-gingerol or 6-shogaol with human umbilical vein endothelial cells or rat aortas significantly attenuated tube formation.. 6-Shogaol and 6-gingerol effectively inhibit invasion and metastasis of hepatocellular carcinoma through diverse molecular mechanisms, including inhibition of the MAPK and PI3k/Akt pathways and NF-κB and STAT3 activities to suppress expression of MMP-2/-9 and uPA and block angiogenesis.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Hepatocellular; Catechols; Fatty Alcohols; Humans; Interleukin-8; Liver Neoplasms; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; NF-kappa B; Phosphatidylinositol 3-Kinases; Plasminogen Activator Inhibitor 1; Proto-Oncogene Proteins c-akt; Rats; STAT3 Transcription Factor; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator; Vascular Endothelial Growth Factor A

Hepatocellular carcinoma is the most common type of liver cancer and is highly metastatic. Metastasis is considered to be the major cause of death in cancer patients. Ginger is a natural dietary rhizome with anti-oxidative, anti-inflammatory, and anti-carcinogenic activities. The aims of this study were to evaluate the anti-invasion activity of 6-shogaol and 6-gingerol, two compounds found in ginger, on hepatoma cells.. The migratory and invasive abilities of phorbol 12-myristate 13-acetate (PMA)-treated HepG2 and PMA-untreated Hep3B cells were both reduced in a dose-dependent manner by treatment with 6-shogaol and 6-gingerol. Upon incubation of PMA-treated HepG2 cells and PMA-untreated Hep3B cells with 6-shogaol and 6-gingerol, matrix metalloproteinase (MMP)-9 activity decreased, whereas the expression of tissue inhibitor metalloproteinase protein (TIMP)-1 increased in both cell types. Additionally, urokinase-type plasminogen activator activity was dose-dependently decreased in Hep3B cells after incubation with 6-shogaol for 24 h. Analysis with semi-quantitative reverse transcription-PCR showed that the regulation of MMP-9 by 6-shogaol and 6-gingerol and the regulation of TIMP-1 by 6-shogaol in Hep3B cells may on the transcriptional level.. These results suggest that 6-shogaol and 6-gingerol might both exert anti-invasive activity against hepatoma cells through regulation of MMP-9 and TIMP-1 and that 6-shogaol could further regulate urokinase-type plasminogen activity.

Topics: Carcinoma, Hepatocellular; Catechols; Fatty Alcohols; Hep G2 Cells; Humans; Liver Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Zingiber officinale