Ellagic acid inhibits proliferation and induces apoptosis in human glioblastoma cells

Abstract

PURPOSE:To investigate the anticancer activity of ellagic acid (EA) in U251 human glioblastoma cells and its possible molecular mechanism. METHODS:The cells were treated with EA at various concentrations for different time periods. Cell viability and cell proliferation were detected by cell counting kit-8(CCK-8) assay and live/dead assay respectively. Cell apoptosis were measured with Annexin V-FITC/PI double staining method by flow cytometry and Mitochondrial membrane potential assay separately. Cell cycle was measured with PI staining method by flow cytometry. The expressions of Bcl-2, Survivin, XIAP, Caspase-3, Bax, JNK, p-JNK, ERK1/2, p-ERK1/2, p38, p-p38, DR4, DR5, CHOP and GRP78-related proteins were detected by western blot after EA treatment. RESULTS:Cell viability and proliferation of glioblastoma cells treated with EA were significantly lower than the control group. EA caused robust apoptosis of the glioblastoma cells compared to the control group. EA significantly decreased the proportion at G0/ G1 phases of cell cycling accompanied by increased populations at S phase in U251 cell lines. And the expressions of anti-apoptotic proteins were dramatically down-regulated. CONCLUSION:Ellagic acid potentially up-regulated DR4, DR5 and MAP kinases (JNK, ERK1/2 and p38). EA also caused significant increase in the expressions of CHOP and GRP78. Our findings suggest that EA would be beneficial for the treatment of glioblastoma.

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins

“…EA could induce apoptosis and G0/G1 arrest via upregulation of p21 and p53 and downregulation of CDK2 gene expression in human bladder cancer T24 cells . Additionally, in U251 human glioblastoma cells, EA was able to arrest cell cycle in G0/G1 phases accompanied by increasing population in S phase and significantly increase the expression levels of CHOP and GRP78 in accordance with upregulation of DR4, DR5, and mitogen‐activated protein kinase (MAPK) kinases, which resulted in apoptotic and antiproliferative effect . Meanwhile, dietary EA exhibited chemoprevention via reversing gene expression signature relative to carcinogenesis in the DMBA‐induced hamster buccal pouch carcinogenesis model, such as the downregulation of TGF‐βRI, TGF‐βRII, Smad‐7, NF‐κB p50, and NF‐κB p65, indicating that EA may be a promising candidates for cancer prevention and therapy .…”

“…Both ETs and EA are metabolized to urolithins via the action of microbiota in the distal section of small intestine and colon, which are converted to a variety of derivatives of urolithin‐3‐ O ‐glucuronide through the action of phase II enzymes after absorption . In previous studies, EA exerted potential anticancer effect via induction of apoptosis and inhibition of proliferation in various cancers, such as oral carcinoma, glioblastoma, colorectal cancer, and bladder cancer . EA could induce apoptosis and G0/G1 arrest via upregulation of p21 and p53 and downregulation of CDK2 gene expression in human bladder cancer T24 cells .…”

The Neuroprotective Effects of Phenolic Acids: Molecular Mechanism of Action

“…decrease of cell proliferation, cell viability, decrease of the proportion at G0/G1 phase of the cell cycle together with increased cell population at S phase; upregulation of Death receptor 4, Death receptor 5, and MAP kinases (JNK, ERK1/2, and p38), as well as CCAAT-enhancer-binding homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) expressions leading to the severe apoptosis in U251 human glioblastoma cells [104]. …”

Cell type-dependent effects of ellagic acid on cellular metabolism

“…Ellagic acid has been shown to specifically induce apoptosis in cancer cells [13, 14, 18, 30–34] while having cytoprotective activity in non-transformed cells [2, 4, 10, 12, 19, 35]. To determine whether EA activated apoptotic pathways, we measured caspase-3 catalytic activities in cells treated with EA for 24 hours.…”