ET-11 * RESVERATROL REGULATES GLIOBLASTOMA AND GLIOBLASTOMA STEM-LIKE CELLS VIA ANTI-TUMORIGENIC AKT DEPHOSPHORYLATION AND p53 ACTIVATION

Abstract

Resveratrol (RES), a natural non-toxic plant product, exerts broad anti-cancer effects. RES was investigated for efficacy against glioblastoma (GBM) and therapeutically resistant GBM stem-like cells (GSC) hypothesized to drive tumor recurrence. Patient-derived GSC lines (12.1, 22, 33, 44) isolated via marker-neutral sphere cultures in stem cell medium, and U87 glioma were treated with RES. Low RES (25 µM) achieved significant inhibition of U87 cell proliferation after 4 days compared to control vehicle (DMSO) treatment. RES also inhibited GSC sphere-forming ability, with 50% inhibitory concentrations (IC50) from 5-25 µM. Interestingly, both 12.1 and 22 GSC lines highly express stem cell markers and initiate focal orthotopic GBM xenografts in brains of immunodeficient mice, and were most sensitive to RES compared to 33 and 44 GSC lines that cause highly infiltrative xenografts. This suggests differential RES response by various GBM/GSC subtypes. In a Matrigel transwell assay, 50 µM RES significantly inhibited invasion (>50%) of both U87 and 44 GSCs. RES also altered GSC progenitor marker expression, with 50 µM RES inducing increased expression of neural differentiation markers GFAP (astrocyte) and βIII-tubulin (neuron) after 3 days on western immunoblotting. We observed the broad anti-tumorigenic RES effects against GBM/GSC by dephosphorylating oncogenic AKT and activating tumor suppressor p53. Quantitative PCR revealed RES activates a large p53 tumor suppressive gene network (PIGG8, CD95, TP53, and NOXA). In U87 flank xenografts, oral RES (50 mg/kg daily) significantly inhibited xenograft growth, and single intra-tumoral 1mg injections reduced tumor volume by >60% compared to injection of vehicle control. In conclusion, RES causes broad anti-GBM and anti-GSC effects via AKT dephosphorylation and p53 activation, and warrants further study as a non-toxic adjuvant GBM therapy.