EXTH-48. THE KETONE BODY β-HYDROXYBUTYRATE CHEMO- AND RADIO-SENSITIZES MALIGNANT GLIOMA CELLS BY INHIBITING HISTONE DEACETYLASE ACTIVITY AND DOWNREGULATING EXPRESSION OF RAD51

Abstract

Mounting evidence suggests that raising blood ketones and reducing blood glucose may be an effect anti-glioma strategy. We have demonstrated that this approach not only impacts multiple hubs of glioma growth but also greatly increases survival in a mouse model of malignant glioma when administered in combination with temozolomide or radiation. However, the underlying mechanisms have not been fully elucidated. To examine these mechanisms we explored the anti-tumor properties of the ketone body β-hydroxybutyrate (BHB). We demonstrated that BHB treatment alone radiosensitizes mouse glioma, human glioblastoma and human glioma stem-like cells in vitro. Furthermore, BHB resensitized resistant cells to radiation and TMZ. We also showed that BHB inhibits the activity of histone deacetylases (HDACs) and increases the expression of microRNAs that regulate DNA repair genes. Evidence suggests that HDAC inhibition can impact DNA damage repair in cancer cells. We therefore assessed the impact of BHB on DNA damage repair pathways. In mouse malignant glioma cells BHB treatment lead to decreased expression of proteins involved in DNA repair and increased radiation-induced expression of the double stranded DNA break marker γ-H2AX. Specifically, BHB treatment led to decreased expression of RAD51, a crucial regulator of homologous repair. This was validated in mouse malignant glioma cells and several human glioblastoma (GBM) cell lines. RAD51 expression has also been linked to temozolomide (TMZ) resistance. We therefore tested the impact of BHB on response to TMZ in vitro. BHB sensitized human GBM cells to TMZ¸ possibly through modulation of O(6)-methylguanine DNA methyltransferase (MGMT) expression. As clinical interest in ketogenic therapies and exogenous ketone supplementation increases it is paramount that the precise mechanisms underlying this approach are elucidated, particularly as they impact standard of care. These data shed light on these mechanisms and bring us closer to understanding how to best implement it for clinical use.