TY - JOUR
T1 - The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma
AU - Stafford, Phillip
AU - Abdelwahab, Mohammed G.
AU - Kim, Do Young
AU - Preul, Mark C.
AU - Rho, Jong M.
AU - Scheck, Adrienne C.
N1 - Funding Information:
This work was supported by the Barrow Neurological Foundation, Students Supporting Brain Tumor Research and the Arizona Biomedical Research Commission. The authors gratefully acknowledge the assistance of Drs. Tejas Sankar, Nikolay Martirosyan and Sergey Kushchayev in establishing the cell implantation procedure and the technical assistance of Dr. Stan Iwai and Kathryn Fenton for cell culture and RNA isolation and Heather Milligan for advice on the use of the KD. We also thank Mahil Rao for invaluable advice regarding lentivirus production and Dr. Joshua B. Rubin for his generous gift of the FUW-GL plasmid. We thank the NIH Neuroscience Microarray consortium for their assistance. This paper is dedicated to the memory of Eleazar Rodriquez.
PY - 2010
Y1 - 2010
N2 - Background. Malignant brain tumors affect people of all ages and are the second leading cause of cancer deaths in children. While current treatments are effective and improve survival, there remains a substantial need for more efficacious therapeutic modalities. The ketogenic diet (KD) - a high-fat, low-carbohydrate treatment for medically refractory epilepsy - has been suggested as an alternative strategy to inhibit tumor growth by altering intrinsic metabolism, especially by inducing glycopenia. Methods. Here, we examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors vs. normal brain from animals fed either a KD or a standard diet. Results. Animals received intracranial injections of bioluminescent GL261-luc cells and tumor growth was followed in vivo. KD treatment significantly reduced the rate of tumor growth and prolonged survival. Further, the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens. Notably, genes involved in modulating ROS levels and oxidative stress were altered, including those encoding cyclooxygenase 2, glutathione peroxidases 3 and 7, and periredoxin 4. Conclusions. Our data demonstrate that the KD improves survivability in our mouse model of glioma, and suggests that the mechanisms accounting for this protective effect likely involve complex alterations in cellular metabolism beyond simply a reduction in glucose.
AB - Background. Malignant brain tumors affect people of all ages and are the second leading cause of cancer deaths in children. While current treatments are effective and improve survival, there remains a substantial need for more efficacious therapeutic modalities. The ketogenic diet (KD) - a high-fat, low-carbohydrate treatment for medically refractory epilepsy - has been suggested as an alternative strategy to inhibit tumor growth by altering intrinsic metabolism, especially by inducing glycopenia. Methods. Here, we examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors vs. normal brain from animals fed either a KD or a standard diet. Results. Animals received intracranial injections of bioluminescent GL261-luc cells and tumor growth was followed in vivo. KD treatment significantly reduced the rate of tumor growth and prolonged survival. Further, the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens. Notably, genes involved in modulating ROS levels and oxidative stress were altered, including those encoding cyclooxygenase 2, glutathione peroxidases 3 and 7, and periredoxin 4. Conclusions. Our data demonstrate that the KD improves survivability in our mouse model of glioma, and suggests that the mechanisms accounting for this protective effect likely involve complex alterations in cellular metabolism beyond simply a reduction in glucose.
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U2 - 10.1186/1743-7075-7-74
DO - 10.1186/1743-7075-7-74
M3 - Article
C2 - 20831808
AN - SCOPUS:77956465178
SN - 1743-7075
VL - 7
JO - Nutrition and Metabolism
JF - Nutrition and Metabolism
M1 - 74
ER -