Abstract 1670: Radiosensitization of glioma cells by the ketone body β-hydroxybutyrate is associated with enhanced cell cycle arrest in the G2/M phase

Abstract

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with a 5 year survival rate of 25% in children and less than 10% in adults. Improvement in the prognosis of GBM patients requires the development of new therapeutic approaches. One emerging strategy is to target aberrant cell metabolism, a trait shared by virtually all tumor cells. The ketogenic diet (KD), a high fat, low carbohydrate and protein metabolic therapy has been shown to prolong survival in animal glioma models, and when used in conjunction with radiation cured 9 of 11 mice of their implanted tumors. We have also shown that the KD alters hypoxia, angiogenesis, and other hallmarks of glioma progression. To elucidate the underlying mechanisms through which ketones exert their effects on glioma, we are doing analyses of the effect of β-hydroxybutyrate (βHB), the most prevalent ketone body synthesized during ketosis, on glioma cells in vitro. We found that βHB both alone and in conjunction with radiation significantly inhibits proliferation of human and mouse glioma cells and human glioma stem cells (GSC). Alterations in passage through the cell cycle may affect proliferation, and cells are also more sensitive to radiation in the G2/M cell cycle phase. We therefore analyzed the effect of βHB on cell cycle distribution of cells treated with βHB and/or radiation. An analysis of cell cycle status by flow cytometry demonstrated that treating the GSC line L0 with 5mM βHB in combination with 4 Gy of radiation significantly increased the number of cells in G2/M cell cycle arrest. In GL261-Luc2 mouse glioma cells, 5mM βHB alone significantly enhanced G2/M cell cycle arrest, which could lead to radiosensitization. Currently we are analyzing proteins involved in cell cycle progression and apoptosis to better understand βHB mediated changes in growth and radioresistance. In summary, these data provide insight to the radiosensitization and anti-proliferative mechanisms of βHB and may hold implications for the use of the KD in the treatment of GBM. Citation Format: Helena B. Silva-Nichols, Alex P. Rossi, Eric C. Woolf, Marshall J. Fairres, Loic P. Deleyrolle, Brent A. Reynolds, Adrienne C. Scheck. Radiosensitization of glioma cells by the ketone body β-hydroxybutyrate is associated with enhanced cell cycle arrest in the G2/M phase. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1670.