The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma

Mohammed G Abdelwahab, Kathryn E Fenton, Mark C Preul, Jong M Rho, Andrew Lynch, Phillip Stafford, Adrienne C Scheck, Mohammed G Abdelwahab, Kathryn E Fenton, Mark C Preul, Jong M Rho, Andrew Lynch, Phillip Stafford, Adrienne C Scheck

Abstract

Introduction: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4:1 (fat:carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas.

Methods: We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging.

Results: Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days.

Conclusions: KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

Conflict of interest statement

Competing Interests: This work was supported by a grant from Nutricia Advanced Medical Nutrition through Nutricia North America, the company that distributes KetoCal® in the USA. Dr. Andrew Lynch is employed by Nutricia Advanced Medical Nutrition in the UK. Dr. Lynch did provide input to the study design. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. KetoCal® enhances survival of glioma-bearing…
Figure 1. KetoCal® enhances survival of glioma-bearing mice.
Kaplan-Meier plot of survival in KC versus SD (A), radiation versus KC plus radiation (B). Animals on KC survived significantly longer when treated with KC alone (p

Figure 2. KetoCal® plus radiation treated animals…

Figure 2. KetoCal® plus radiation treated animals experienced a loss of bioluminescence.

(A) Radiation and…

Figure 2. KetoCal® plus radiation treated animals experienced a loss of bioluminescence.
(A) Radiation and KetoCal® plus radiation animal imaged every three days. Color scheme represents signal intensity with red representing the highest intensity photon count. (B) (C) Bioluminescent signal plotted as in vivo photon count versus days post-implantation.

Figure 3. Blood ketone and glucose levels.

Figure 3. Blood ketone and glucose levels.

Measurements of animal ketone and glucose levels show…

Figure 3. Blood ketone and glucose levels.
Measurements of animal ketone and glucose levels show higher βHB blood levels in animals treated with KetoCal®. (A) βHB levels (B) Blood glucose measurements. ** = p

Figure 4. Animal weights.

Weight measurements were…

Figure 4. Animal weights.

Weight measurements were taken every 3 days. Graph shows animals weights…

Figure 4. Animal weights.
Weight measurements were taken every 3 days. Graph shows animals weights normalized to the average starting weight of each group on day zero. (B) Arrow denotes a long-term survivor 60 days following tumor implantation in the SD plus radiation group.
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Figure 2. KetoCal® plus radiation treated animals…
Figure 2. KetoCal® plus radiation treated animals experienced a loss of bioluminescence.
(A) Radiation and KetoCal® plus radiation animal imaged every three days. Color scheme represents signal intensity with red representing the highest intensity photon count. (B) (C) Bioluminescent signal plotted as in vivo photon count versus days post-implantation.
Figure 3. Blood ketone and glucose levels.
Figure 3. Blood ketone and glucose levels.
Measurements of animal ketone and glucose levels show higher βHB blood levels in animals treated with KetoCal®. (A) βHB levels (B) Blood glucose measurements. ** = p

Figure 4. Animal weights.

Weight measurements were…

Figure 4. Animal weights.

Weight measurements were taken every 3 days. Graph shows animals weights…

Figure 4. Animal weights.
Weight measurements were taken every 3 days. Graph shows animals weights normalized to the average starting weight of each group on day zero. (B) Arrow denotes a long-term survivor 60 days following tumor implantation in the SD plus radiation group.
Figure 4. Animal weights.
Figure 4. Animal weights.
Weight measurements were taken every 3 days. Graph shows animals weights normalized to the average starting weight of each group on day zero. (B) Arrow denotes a long-term survivor 60 days following tumor implantation in the SD plus radiation group.

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