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  • In glioma or glial derived primary brain tumors as

    2021-09-23

    In glioma, or glial-derived primary Tanespimycin tumors, as in other cancers, glutathione is an important survival mechanism. Glioma cells are dependent upon SXC-mediated cystine uptake for viability, as they require intracellular cystine/cysteine for GSH synthesis (Ogunrinu and Sontheimer, 2010, Sontheimer, 2008). Removal of cystine from the medium, as well as inhibition of GSH synthesis with the γ-glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) results in cell death. Similarly, treatment with Sulfasalazine to inhibit SXC depletes intracellular cystine and GSH, and inhibits glioma cell growth (Chung et al., 2005, Chung and Sontheimer, 2009). Additionally, as tumor cells outgrow their blood supply, areas of the tumor experience low oxygen tension, or hypoxia. Under hypoxic conditions, the dependence of glioma cells upon GSH increases, and they increase xCT cell-surface expression and SXC-mediated cystine uptake to meet this higher demand for GSH (Ogunrinu and Sontheimer, 2010, Scatena, 2012). Expression of SLC7A11, the gene that encodes xCT, negatively correlates with chemotherapeutic resistance in glioma cells and inhibition of SXC activity or GSH synthesis increases sensitivity (Guan et al., 2009, Huang et al., 2005). Chemotherapy resistance in glioma is associated with elevated GSH levels (Ali-Osman et al., 1990, Friedman et al., 1992). GSH is able to bind xenobiotics, such as chemotherapy drugs, and export them out of cells through a family of proteins called Multidrug resistance proteins (MRP) (Singh et al., 2012). Expression of MRP1, one of the MRPs that mediate cellular export of GSH, is elevated in glioma (Benyahia et al., 2004), and has also been found to be higher in higher-grade gliomas versus lower-grade gliomas (de Faria et al., 2008). Administration of Indomethacin, an MRP inhibitor, is able to increase the cytotoxic effect of etoposide in glioma cell lines (Benyahia et al., 2004). The higher expression of these proteins may be at least one cause of multidrug resistance in human gliomas. Radiation resistance in glioma also involves increased GSH. One study found that by depleting nuclear GSH before irradiation, nuclear fragmentation and apoptosis was increased (Morales et al., 1998). A radioresistant clone of U251, a commonly used glioma cell line, has a 5-fold increase in antioxidant enzymes, including glutathione peroxidase and glutathione reductase. This resistant cell line showed cross-resistance to the commonly used chemotherapeutic cisplatin as well (Lee et al., 2004). Similar findings are seen in other cancer cells. Sertoli cells demonstrate an increase in GSH after irradiation that is dose dependent (Brouazin-Jousseaume et al., 2002), and decreasing intracellular thiols in a lymphoma cell line increases radiation-induced apoptosis (Mirkovic et al., 1997). Even photodynamic therapy (PDT), which works in a similar manner to radiation therapy by producing ROS to kill cancer cells, is enhanced through GSH inhibition using BSO. PDT plus BSO enhances the ability of this treatment modality to kill tumor cells and decrease their migration (Jiang et al., 2003). Taken together, much of the research today on cancer biology and therapy suggests GSH is an important therapeutic target. Many current treatment strategies are focused on GSH inhibition as a way to sensitize glioma and other cancer cells to current chemo- and radiotherapy [see (Singh et al., 2012) for an overview of some of these therapies]. Surprisingly however, little has been published regarding SXC inhibition in the context of sensitizing glioma cells to treatment. Recent studies have found that SXC inhibition using Sulfasalazine decreases chemotherapy and radiation resistance in pancreatic cancer (Lo et al., 2008) and many in vitro and in vivo studies showing GSH dependence on SXC activity strongly suggest that SXC inhibition may be a viable mechanism to enhance current treatment of glioma (Sontheimer, 2008, Chung et al., 2005, Ye et al., 1999, Sato et al., 2005). In this study, we have investigated the consequences of SXC expression on radiation resistance in human derived glioma tissue. Using a xenograft model of glioma, where patient-derived glioblastoma tissue is propagated in the flank of nude mice, we were able to study tumors with high and low SXC expression and function. We found that high SXC expressing tumors are more radiation resistant than low SXC expressing tumors, and SXC inhibition with Sulfasalazine increases the sensitivity of high SXC expressing tumors. These results are presented and discussed in the following Section 6.