Resveratrol Affects Ganglioside Remodeling and Inflammatory Markers in Glioblastoma Multiforme

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most aggressive form of brain cancer with a 15 - 18 month survival rate. Challenges to its successful treatment include the invasive growth of tumor cells into surrounding healthy tissue. Studies have attributed GBM progression partly to inflammation created through communication with tumor-invading microglia cells. Studies have also shown that gangliosides, a family of glycolipids known for their involvement in specific neuropathologies, play a role in tumorigenesis, metastasis, angiogenesis, and the immune response. GBM stem cells are known to over-express ganglioside GD3 and its synthetic enzyme, GD3 synthase. Targeting of GD3 synthase has therefore become a focus of GBM intervention. Resveratrol (RSV) is a natural polyphenol known for its potent anti-oxidant and anti-inflammatory properties. RSV has also demonstrated ganglioside-altering effects, as well as powerful antitumor effects on GBM including inhibition of tumor growth, invasiveness and the sphere-forming ability of GBM stem cells, and activation of p53. This study sought to examine the influence of RSV on ganglioside remodeling and tumor cell immune response in GBM and evaluate its potential as a co-therapeutic in GBM intervention. GBM and Adult Pigmented Retinal Epithelial cells (ARPE-19) were treated with RSV for 24h and assayed for viability and ganglioside profiles by HPTLC. Expression of ganglioside synthetic enzymes was evaluated by qPCR using gene specific primers and RT2 Profiler Arrays were used to evaluate inflammatory response and cancer markers. Expression of selected genes was validated by qPCR. RSV had a significant effect in reducing cell viability in GBM without negatively affecting ARPE control cells. RSV also significantly down-regulated expression of all four ganglioside synthetic enzymes. HPTLC analysis showed an effect of RSV treatment on ganglioside profiles however this was less robust. qPCR Arrays yielded more than forty immuno-regulating factors that were either up- or down-regulated by RSV and more than twenty genes involved in cell proliferation and cell death pathways were also affected by RSV treatment. An important consideration in oncology is to maximize efficacy while minimizing toxicity. These data suggest that RSV is effective in reducing viability of GBM cells, without adversely effecting normal cells. Down-regulation of ganglioside synthetic enzymes, specifically GD3 synthase suggests it may be an effective complementary intervention in GBM treatment. Co-recruitment of immune factors may provide both additional anti-tumor assistance and cytoprotective support for healthy cells.