P.042 Raloxifene sensitizes glioblastoma cells to hypoxia-induced death through inhibition of stress granule dissolution

Abstract

Background: Glioblastoma (GBM) is the most common primary malignant brain tumour. Despite aggressive therapy, median survival is only 14 months. Death typically results from treatment failure and local recurrence. The GBM microenvironment is highly hypoxic, which correlates with treatment resistance. Cytoplasmic RNA stress granules (SGs) form in response to hypoxic stress and act as sights of mRNA triage, allowing preferential translation of pro-survival mRNA during stress. We hypothesize that SGs may play a role in hypoxia-induced resistance to therapy, and may be targetable by chemotherapeutics to improve outcomes. Methods: We screened 1280 approved compounds to identify drugs that inhibited formation or dissolution of SGs in U251 glioma cells. Raloxifene inhibited SG dissolution in a dose dependent manner. We treated cells with raloxifene and incubated them in hypoxia, and then measured rates of cell death using cell counting and Presto blue. Results: Cell death rates were synergistically higher in cells treated with the combination of raloxifene and hypoxia compared to either treatment alone. Conclusions: Raloxifene inhibits the dissolution of SGs in glioma cells, and combination treatment results in synergistic tumour cell death. Taken together, this provides evidence that inhibition of SG dissolution may be a viable target for future GBM chemotherapeutics.