Analysis of the oxidative stress induced by sulfasalazine associated with temozolomide in human and rat glioma cells

Abstract

Gliomas are the most common adult brain tumors. High-grade astrocytomas are astrocyte-derived gliomas, which pathogenesis includes overexpression of the epidermal growth factor receptor (EGFR) and loss of p53 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein function. Such proteins regulate cell cycle and DNA stability. Additionally, it has been described that gliomas show increased concentration of the antioxidant glutathione(GSH), which would protect cells from redox stress. Astrocytes - the neoplastic ones mainly - express a cytoplasmic membrane transporter (system Xc-) that imports cystine for GSH synthesis and releases glutamate. The latter event would induce excitotoxicity and death in peritumoral cells, thus favoring tumor invasion. Neoplastic invasion also involves degradation of extracellular matrix by metalloproteinases 2 and 9 (MMP-2 and 9). The DNA alkylating agent temozolomide (TMZ) has been used in the treatment of patients with high-grade gliomas. However, their clinical outcome has invariably been fatal. In the present study, we aim to study the viability of glioma cell lines (U87-MG, T98G, A172 and C6) treated with TMZ and/or sulfasalazine (SAS), an inhibitor of the system Xc-. Moreover, we will evaluate EGFR, PTEN, TP53, MMP-2 and MMP-9 gene expression in and invasive capacity of treated cells. Our intention is to contribute to the understanding of gliomagenesis and investigate new therapeutic approaches to glioma treatment. (AU)