Overcoming GBM Stem Cell Resistance with Resveratrol Analog E03

Overcoming GBM Stem Cell Resistance with Resveratrol Analog E03

Alvin Sherman Library

Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis, driven by GBM stem cells (GSCs) that promote growth, recurrence, and treatment resistance. The PI3K/AKT signaling pathway is frequently hyperactivated in GBM, contributing to cell survival and proliferation, making it a key therapeutic target. Resveratrol (RSV), a natural anticancer polyphenol downregulates AKT signaling but is limited by poor bioavailability and potency. We developed diaryl acrylonitrile analogs of RSV to improve potency, stability, and drug-like properties for targeting GSCs. This study aimed to synthesize, evaluate the anticancer activity of these analogs against GSCs, and elucidate their mechanism of action to guide future GBM therapy. We synthesized 80 diaryl acrylonitrile RSV analogs via Knoevenagel condensation and assessed their cytotoxicity against GSC lines. GSCs were treated with 0.1-10 μM concentrations, and viability was evaluated after 72 hours via MTS assay. Western blotting was performed to investigate the mechanism of action. Diaryl acrylonitrile RSV analog, E03 showed potent cytotoxicity against glioblastoma stem cells with an average IC50 of 0.19μM and was shown to be 10-fold more effective against GBM cells than non-tumor cells. Western blot analysis revealed E03 downregulated the PI3/AKT pathway and induced robust PARP cleavage and caspase activation, indicative of apoptosis. This study identifies E03 as a potent and selective diaryl acrylonitrile RSV analog which exhibits strong cytotoxic activity against GSCs. By inhibiting the PI3K/AKT pathway, E03 demonstrates significant potential as a lead compound for further novel GBM therapy development.