RALOXIFENE SENSITIZES GLIOBLASTOMA CELLS TO HYPOXIA -INDUCED DEATH THROUGH INHIBITION OF STRESS GRANULE DISSOLUTION

Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumour and carries a uniformly poor prognosis. Despite aggressive therapy, median survival is only 14 months. Death typically results from treatment failure and local recurrence. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cells residing in hypoxic regions resist treatment. Hypoxia can trigger formation of stress granules (SGs), sites of mRNA triage that promote multiple cell survival mechanisms. We hypothesize that SGs play a role in hypoxia-induced resistance to therapy. A screen of 1120 FDA-approved drugs (the Prestwick Drug Library) was conducted, and 98 candidates were identified that inhibited hypoxia-induced SG formation whereas 127 candidates inhibited SG dissolution following return to normoxia. The screen identified the selective estrogen receptor modulator raloxifene as a potent inhibitor of SG dissolution in a dose-dependent manner. When raloxifene was administered to U251 astrocytoma cells prior to hypoxia, the combination achieved synergistic killing of tumour cells that correlated with the activation of apoptosis and autophagy pathways. Taken together, this data suggests that raloxifene induces apoptotic and autophagic death in GBM cells by disrupting normal SG dynamics. As raloxifene is a currently approved drug already used in the treatment of estrogen receptor-positive breast cancer and osteoporosis, promising pre-clinical data could inform the development of a phase III clinical trial in GBM patients.