Taxodione Inhibits Glioblastoma Proliferation and Potentiates the Cytotoxicity of Paclitaxel.

Abstract

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 a 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 U87MG 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 associated with FDPS inhibition and the transcriptional downregulation of other mevalonate pathway genes. Consistent with this putative mechanism of action, taxodione sensitized glioblastoma cells to subnanomolar concentrations of paclitaxel.