Abstract
To investigate the anticancer activity of ellagic acid (EA) in U251 human glioblastoma cells and its possible molecular mechanism. 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. 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. 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.
Highlights
MethodsGliomas account for more than 50% of primary malignant tumors of the central nervous system with high mortality rates and high incidence rates[1]
In order to investigate whether ellagic acid (EA) treatment affects cell viability, U251 cells treated with various concentrations (0200μM) of EA were tested using CCK-8 at several different time points
We investigated whether the activation of MAP kinasesERK1/2, p38 and JNK exert their roles in EA-induced apoptosis
Summary
Gliomas account for more than 50% of primary malignant tumors of the central nervous system with high mortality rates and high incidence rates[1]. World Health Organization (WHO) classifies gliomas to four grades (I-IV) with increasing degree of malignancy[2]. Grade IV, glioma-glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumors with the median survival time of patients less than 14 months even with multimodal therapy comprising the combination of surgery, radiation therapy and chemotherapy[3,4]. The major reason is that the diffuse invasion of tumor cells invading the surrounding brain shelters themselves from surgery and radiation. The malignant glioma seems to proliferate indefinitely. Development of novel biologicals in brain tumor therapy is crucial
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