Ellagic acid inhibits human glioblastoma growth in vitro and in vivo

Ellagic acid (EA) is present in various fruits and plants and has recently been found to possess anticarcinogenic effects. The objective of this study was to investigate the anti-glioblastoma effect of EA and its mechanisms in vitro and in vivo. We first studied the anticancer activity of EA in U87 and U118 human glioblastoma cell lines. The cell viability and cell proliferation were examined by Cell Counting Kit-8 (CCK-8) assay and 5-ethyny1-2'-deoxyuridine staining respectively. The cell cycle was detected with propidium iodide staining method by flow cytometry and the DNA damage of the cells caused by EA exposure was evaluated by detection of gamma-H2AX foci. Then we examined the effect of EA on tumor growth in glioblastoma xenografted mice, and expression of Akt and Notch signaling and their target gene products were detected by immunohistochemistry and western blot analysis. As a result, we found that the cell viability and proliferation of glioblastoma cells treated with EA were significantly suppressed compared with the control; EA significantly increased the proportion of cells in the S phase accompanied by a decrease in the population in the G1 and G2/M phase in both cell lines. Meanwhile, the level of DNA damage in the EA-treated group was significantly higher than that of the control. Treatment of glioblastoma in xenografted mice by EA led to a significant suppression in tumor growth. EA upregulated the expression of E-cadherin and inhibited the expression of Snail, matrix metalloproteinase (MMP)-2 and MMP-9. EA also inhibited the expression of Bcl-2, cyclin Dl, cyclin-dependent kinase (CDK)2 and CDK6 in U87 xenograft tissues. In addition, significant suppression of Akt and Notch was found in the xenografts of the tumor-bearing mice treated with EA. These data indicate that EA can suppress glioblastoma proliferation and invasion by inhibiting the Akt and Notch signaling pathways, which suggests that EA may be beneficial for the treatment of glioblastoma.