diospyros and Carcinoma--Hepatocellular

Persimmon (Diospyros kaki L.f.) trees are widely cultivated for their edible fruits in Asia. D. kaki leaves are abundant in phytochemicals that have numerous medicinal properties. Hepatocyte growth factor (HGF) and its receptor Met lead to poor prognosis via the promotion of metastasis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, inhibitors targeting the HGF/Met pathway are regarded as promising drugs against HCC. Here, we investigated the effects of D. kaki leaves on HGF-induced epithelial-to-mesenchymal transition (EMT) and stemness traits in HCC. The ethanol extract of D. kaki leaves (EEDK) markedly suppressed HGF-mediated cell migration and invasion through upregulation of CDH1 and downregulation of SNAI1, VIM, MMP1, MMP2, and MMP9. Moreover, EEDK increased the cytotoxicity of sorafenib, which was reduced by HGF, and decreased the expression of the stemness markers KRT19 and CD44. Additionally, we found a clear correlation between stemness and EMT markers in HCC patients. Importantly, EEDK reduced Met activity and attenuated HGF-mediated activation of JNK/c-Jun. Our findings provide new evidence that EEDK can ameliorate HCC with poor prognosis and aggressive phenotype by blocking HGF/Met signaling.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Diospyros; Epithelial-Mesenchymal Transition; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Neoplastic Stem Cells; Plant Extracts; Plant Leaves; Proto-Oncogene Proteins c-met; Signal Transduction

Persimmon leaves are known to have some beneficial effects, including ROS elimination, lipid circulation, and neuronal protection. However, their anti-cancer properties and the underlying mechanisms remain unclear. Herein, we show that treatment with the ethanol extract of persimmon, Diospyros kaki, leaves (EEDK) induces cancer cell death and inhibits cell proliferation. Using fluorescence resonance energy transfer (FRET) technology with genetically-encoded biosensors, we first found that EEDK stimulates a PDGFR-Rac signaling cascade in live cells. Moreover, we found that downstream of the PDGFR-Rac pathway, JNKs are activated by EEDK. In contrast, JNK-downstream inhibitors, such as CoCl2, T-5224, and pepstatin A, attenuated EEDK-induced cell death. Thus, we illustrate that the PDGFR-Rac-JNK signaling axis is triggered by EEDK, leading to cancer cell death, suggesting the extract of persimmon leaves may be a promising anti-cancer agent.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Diospyros; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; MAP Kinase Kinase 4; Plant Extracts; Plant Leaves; rac GTP-Binding Proteins; Receptor, Platelet-Derived Growth Factor beta; Receptors, Platelet-Derived Growth Factor

Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cyclophosphamide; Diospyros; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Flavonoids; Humans; Killer Cells, Natural; Liver Neoplasms; Macrophages; Male; Mice; Phagocytosis; Plant Extracts; Plant Leaves

In this experiment, we examine the functional property of carotenoids; beta-cryptoxanthin (Cry), zeaxanthin (Zea), beta-carotene (Car)) and ascorbic acid (AsA). The accumulation amounts of Cry, Zea and Car in HepG2 cells cultured in the high concentration medium were larger than that in a low concentration. Further those accumulation amounts in long incubation time within 24 hours were greater than that in a shorter time. When the added carotenoid concentration, with or without hydrogen peroxide, increased from 0 to 5 microM in the culture medium, the thiobarbituric acid reaction substance (TBARS) values in the HepG2 cells decreased significantly (p < 0.05). The decrease of TBARS values shows the antioxidative property of the carotenoids. When AsA and Tocopherol(Toc) were added to the medium from 0 to 20 microM, the TBARS values, with or without hydrogen peroxide, decreased significantly with increasing concentrations of AsA and Toc respectively (p < 0.05). The decreased amount of TBARS in 5 microM Cry compared with control(0 microM) was the largest among 6 antioxidants (Cry, Car, Zea, Retinol(Ret), AsA, Toc) used in this experiment.

Topics: alpha-Tocopherol; Antioxidants; Ascorbic Acid; Biological Transport; Carcinoma, Hepatocellular; Carotenoids; Cell Line, Tumor; Diospyros; Humans; Japan; Lipid Peroxidation; Liver Neoplasms; Plant Extracts; Thiobarbituric Acid Reactive Substances; Vitamin A