Abstract 3346: The ketone body β-hydroxybutyrate increases radiosensitivity in glioma cell lines in vitro

Abstract

Abstract Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor. Despite aggressive treatment, including maximum surgical resection followed by both chemotherapy and radiotherapy, median survival for patients remains at approximately 1.5 years after diagnosis. Recent preclinical studies examining the potential of the ketogenic diet (KD) as an adjuvant therapy for the treatment of malignant gliomas demonstrated that animals fed a KD and treated with chemotherapy or radiation survived significantly longer than those treated with chemotherapy or radiation and fed a standard diet. One of the key results of the KD is an increase in the blood level of the ketone body β-hydroxybutyrate (BHB). To more fully examine the mechanism through which the KD potentiates radiation, we examined the potential of BHB to increase radiosensitivity in mouse glioma cells in vitro. Plating cells in 10mM BHB followed by treatment for 2 weeks following radiation prevented colony formation in both the control and the radiation groups. We therefore assessed the effect of pretreatment with 5mM or 10mM BHB alone prior to radiation with 4 Gy. A statistically significant change in survival was observed when cultures were pre-treated with 10mM BHB for 24 hours prior to irradiation but not with 5mM BHB. However, significant changes in clonogenic survival were observed with a dose of 5mM BHB when cells were treated for 7 days post irradiation, starting 24 hours after irradiation. The effect of BHB on cell growth was then assessed using live cell counts. Both 5mM and 10mM BHB were effective in significantly reducing the cell number by 192 hours post plating. Growth was similarly affected by 10mM BHB or 2 Gy of radiation alone; however, when 10mM BHB was added to 2 Gy of radiation there was a very strong potentiating effect. These data suggest that BHB is an effective radiosensitizer for mouse glioma cells when used alone. In addition, they provide evidence that the extended survival seen in our in vivo mouse model of glioma when radiation is used in addition to the ketogenic diet may be modulated, to a large extent, by blood ketone levels. Whether this is due to differences in radiation-induced DNA damage, DNA repair or changes in the growth rate of the tumor cells is currently under investigation. Citation Format: Alex P. Rossi, Eric C. Woolf, Kenneth S. Brooks, Marshall J. Fairres, Adrienne C. Scheck. The ketone body β-hydroxybutyrate increases radiosensitivity in glioma cell lines in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3346. doi:10.1158/1538-7445.AM2015-3346