The Effect of Sodium Valproate on the Glioblastoma U87 Cell Line Tumor Development on the Chicken Embryo Chorioallantoic Membrane and on EZH2 and p53 Expression.

Dovilė Kavaliauskaitė,Donatas Stakišaitis,Justė Martinkutė,Ingrida Balnytė,Arūnas Kazlauskas,Lina Šlekienė,Angelija Valančiūtė,Vaiva Lesauskaitė

doi:10.1155/2017/6326053

Dovilė Kavaliauskaitė, Donatas Stakišaitis + Show 6 more

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https://doi.org/10.1155/2017/6326053

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Abstract

Literature data support evidences that glioblastoma (GBM) patients experience prolonged survival due to sodium valproate (NaVP) treatment. The study assessed the human GBM cell U87 xenograft studied in the chicken embryo chorioallantoic membrane (CAM) model evaluating NaVP effect on tumor. Three groups of tumors (each n = 10) were studied: nontreated, treated with 4 mM, and treated with 8 mM of NaVP. The majority of tumors without NaVP treatment during tumor growth destroyed the chorionic epithelium, invaded the mesenchyme, and induced angiogenesis. Incidence of tumor formation on CAM without invasion into the mesenchyme was higher when U87 cells were treated with NaVP; the effect significantly increased with NaVP concentration. Treatment with 8 mM of NaVP did not show clear dynamics of tumor growth during 5 days; at the same time, the angiogenesis failed. With a strong staining of EZH2, p53 in tumors without NaVP treatment was found, and NaVP significantly decreased the expression of EZH2- and p53-positive cells; the effect was significantly higher at its 8 mM concentration. NaVP has a function in blocking the growth, invasion, and angiogenesis of tumor in the CAM model; tumor growth interferes with EZH2 and p53 molecular pathways, supporting the NaVP potential in GBM therapy.

Highlights

Glioblastoma multiforme (GBM) is the most frequent, highly recurrent, and rapidly progressing type of astrocytic brain tumor in adults [1]
The tumors that developed from 8 mM of NaVP-treated U87 cells did not show clear dynamics during 5 days of development: the in vivo biomicroscopy tumor images are very similar during days 2–5 (Figure 1(c), EDD9–12), and tumors failed to attract blood vessels
Our study revealed a high expression of p53 in U87 cell tumors which were not treated with NaVP, and this expression was accompanied with pronounced angiogenesis in tumors in the chorioallantoic membrane (CAM) model

Summary

Introduction

Glioblastoma multiforme (GBM) is the most frequent, highly recurrent, and rapidly progressing type of astrocytic brain tumor in adults [1]. Sodium valproate (NaVP) is an authorized medicinal product for the treatment of epileptic seizure, migraine, neuralgia, and bipolar disorder [4, 5]. The meta-analysis of studies data supports the evidence that glioblastoma patients experience prolonged survival due to NaVP treatment [6, 7]. The mechanisms of NaVP without an antiepileptic activity are the known inhibitor of histone deacetylase [4]. It has an anticancer effect in several human GBM cell lines [8]. NaVP shows antineoplastic activity based on its gene-regulation functions [11,12,13]; it has an effect on chloride, sodium ions transport in vivo [14], induces cell cycle arrest, and enhances

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