Glioblastoma (GBM) is a deadly disease with a need for deeper understanding and new therapeutic approaches. The microenvironment of glioblastoma has previously been shown to guide glioblastoma progression. In this study, astrocytes were investigated with regard to their effect on glioblastoma proliferation through correlative analyses of clinical samples and experimental in vitro and in vivo studies. Co‐culture techniques were used to investigate the GBM growth enhancing potential of astrocytes. Cell sorting and RNA sequencing were used to generate a GBM‐associated astrocyte signature and to investigate astrocyte‐induced GBM genes. A NOD scid GBM mouse model was used for in vivo studies. A gene signature reflecting GBM‐activated astrocytes was associated with poor prognosis in the TCGA GBM dataset. Two genes, periostin and serglycin, induced in GBM cells upon exposure to astrocytes were expressed at higher levels in cases with high “astrocyte signature score”. Astrocytes were shown to enhance glioblastoma cell growth in cell lines and in a patient‐derived culture, in a manner dependent on cell–cell contact and involving increased cell proliferation. Furthermore, co‐injection of astrocytes with glioblastoma cells reduced survival in an orthotopic GBM model in NOD scid mice. In conclusion, this study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies.
Cocrystallized acetonitrile solvent molecules located inside 5.2 A channels in the crystal structure of L-leucyl-L-serine have been replaced by I2 molecules with full retention of the peptide scaffold.
Metastatic tumors with moderate radiosensitivity account for most cancer-related deaths, highlighting the limitations of current radiotherapy regimens. The xCT-inhibitor sulfasalazine (SAS) sensitizes cancer cells to radiotherapy by blocking cystine uptake via the xCT membrane antiporter, and thereby glutathione (GSH) synthesis protecting against radiation-induced oxidative stress. The expression of xCT in multiple tumor types implies it as a target generic to cancer rather than confined to few subtypes. However, SAS has limited clinical potential as a radiosensitizer due to side effects and low bioavailability. Using SAS as a starting point, we previously developed synthetic xCT-inhibitors through scaffold hopping and structure optimization aided by structure-activity relationship analysis (SAR). Notably, the compound DC10 exhibited inhibition of GSH synthesis. In this study, we validated DC10 as a radiosensitizer in the xCT-expressing cancer cell lines A172, A375 and MCF7, and mice harboring melanoma xenografts. After DC10 treatment, we measured 14C-cystine uptake in the cancer cells using liquid scintillation counting, and intracellular GSH levels and reactive oxygen species (ROS) using luminescence assays. We performed immunoblotting of H2AX and ATM to assess DNA damage after treatment with DC10 and radiotherapy. We then assessed the effect of adding DC10 to radiation upon cancer cell colony formation. Blood samples from mice treated with DC10 underwent biochemical analysis to assess toxicity. Finally, mice with A375 melanomas in the flank, received DC10 and radiotherapy in combination, as monotherapies or no treatment. Notably, DC10 reduced cystine uptake and GSH synthesis and increased ROS levels in a dose-dependent manner. Furthermore, DC10 interacted synergistically with radiation to increase DNA damage and reduce tumor cell colony formation. Mice receiving DC10 were clinically unaffected, whereas blood samples analysis to assess bone marrow suppression, liver or kidney toxicity revealed no significant differences between treated mice and untreated controls. Importantly, DC10 potentiated the anti-tumor efficacy of radiation in mice with melanoma xenografts. We conclude that DC10 is well tolerated and acts as a radiosensitizer by inhibiting cystine uptake, leading to GSH depletion and increased oxidative stress. Our findings demonstrate the feasibility of using synthetic xCT-inhibitors to overcome radioresistance.
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