gigantol and Liver-Neoplasms

Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.

Topics: Antineoplastic Agents; Bibenzyls; Carcinoma, Hepatocellular; Cell Proliferation; Click Chemistry; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Oxidative Stress; Phenol; Pyruvate Carboxylase; Structure-Activity Relationship

Hepatocellular carcinoma (HCC) is a common clinical malignant disease and the second leading cause of cancer-related death worldwide. Dendrobium is a commonly applied nourishing drug in traditional Chinese medicine. Gigantol is a phenolic compound extracted from Dendrobium. The compound has attracted attention for its anticancer effects. However, the mechanism of gigantol in HCC has not been extensively explored.. Potential targets of gigantol were predicted by SwissTargetPrediction. HCC-related genes were obtained from the GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), Therapeutic Target Database (TTD) and DrugBank databases. The "gigantol-target-disease" network was constructed using Cytoscape software. Protein interaction network analysis was performed using STRING software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were executed utilizing the. Three core genes were screened from 32 closely linked genes. Pathway analysis yielded many signaling pathways associated with cancer. The CCK-8 assay and EdU assay indicated that gigantol suppressed the growth of HCC cells. The wound healing assay and Matrigel invasion assay showed the inhibition of migration and metastasis of HCC cells by gigantol. We verified from molecular docking and protein level that gigantol can exert regulatory effects through three targets, ESR1, XIAP and HSP90AA1. Furthermore, Western blot results tentatively revealed that gigantol may inhibit HCC progression through the HSP90/Akt/CDK1 pathway.. Our results confirms anti-HCC proliferation activity of gigantol through PI3K pathway described in existing literature by different experimental approaches. Furthermore, it has discovered other proteins regulated by the drug that was not previously reported in the literature.These findings provide potential molecular and cellular evidence that gigantol may be a promising antitumor agent.

Topics: Bibenzyls; Carcinoma, Hepatocellular; Cell Proliferation; Guaiacol; Humans; Liver Neoplasms; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases

Gigantol is a phenolic substance extracted from plants in the genus Dendrobium and used in traditional Chinese medicine. In the present study, we aimed to investigate the growth inhibition and apoptotic effects of gigantol on human liver cancer cells through the PI3K/Akt/NF-κB signaling pathway. HepG2 cells were treated with different concentrations of gigantol (0-150 µM) for 12, 24 and 48 h. It was found that gigantol significantly inhibited the proliferation and induced apoptosis of the HepG2 cells. The results of fluorescence micrographs showed that a 48-h treatment with gigantol induced typical apoptotic morphological features, which were consistent with the flow cytometric analysis where 20% of apoptotic cells were detected in response to gigantol treatment. In addition, western blot analysis indicated that gigantol enhanced the activities of caspase-3, PARP and p53 and downregulated the expression of p-Akt/Akt. Collectively, the present data suggest that gigantol induces growth inhibition and apoptosis of HepG2 cells via the PI3K/Akt/NF-κB signaling pathway.

Topics: Apoptosis; Bibenzyls; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Flow Cytometry; Guaiacol; Humans; Immunoenzyme Techniques; Liver Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured