Taxodione Inhibits Glioblastoma Proliferation and Potentiates the Cytotoxicity of Paclitaxel

Glioblastoma rapidly acquires resistance to conventional genotoxic therapy. This behavior is closely associated with the enhancement of stem-cell-like character during disease progression. Farnesyl diphosphate synthase (FDPS) plays an important role in maintaining such stem-cell-like features. This finding has stimulated interest in FDPS as neuro-oncology drug target; however, the lack of CNS-permeable inhibitors has hampered further development. In this study, we explored the utility of taxodione, a diterpenoid described as an FDPS inhibitor and predicted to penetrate the blood-brain-barrier. The effects of taxodione were compared to its congener 7-(2-oxohexyl)-taxodione and a known FDPS inhibitor in glioblastoma cells. Taxodione was the only treatment that significantly reduced the size of tumor spheroids in a temporal and dose-dependent manner. This activity was linked to FDPS inhibition and transcriptional downregulation of other Mevalonate Pathway genes. Consistent with this putative mechanism-of-action, taxodione sensitized glioblastoma cells to nanomolar concentrations of paclitaxel.