The efficacy of an unrestricted cycling ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma

Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1mut) or, less commonly, IDH2 (together called "IDHmut"). These mutations alter...

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Bibliographic Details
Published in:PloS one 2022-02, Vol.17 (2), p.e0257725-e0257725
Main Authors: Javier, Rodrigo, Wang, Wenxia, Drumm, Michael, McCortney, Kathleen, Sarkaria, Jann N, Horbinski, Craig
Format: Article
Language:English
Subjects:
3-Hydroxybutyric Acid - pharmacology
Animals
Biochemistry
Biology and Life Sciences
Blood Glucose - analysis
Brain cancer
Brain research
Cancer therapies
Carbohydrates
Cell culture
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Clinical trials
Complications and side effects
Cycles
Diet
Diet therapy
Diet, Ketogenic
Enzymes
Fibrosarcoma
Glioma
Glioma - diet therapy
Glioma - genetics
Glioma - mortality
Glioma - pathology
Glioma cells
Gliomas
Glucose
Glucose - pharmacology
Health aspects
High fat diet
Humans
Isocitrate dehydrogenase
Isocitrate Dehydrogenase - genetics
Kaplan-Meier Estimate
Ketogenesis
Ketogenic diet
Ketones
Laboratory animals
Low carbohydrate diet
Medical prognosis
Medicine
Medicine and Health Sciences
Metabolism
Mice
Mice, Nude
Mutation
Neoplasia
Neoplasms
Nutrient deficiency
Patient outcomes
Patients
Phosphorylation
Physical Sciences
Research and Analysis Methods
Surgery
Transplantation, Heterologous
Transposase
Tumors
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Summary:Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1mut) or, less commonly, IDH2 (together called "IDHmut"). These mutations alter cellular biochemistry, and IDHmut gliomas are generally less aggressive than IDH wild-type (IDHwt) gliomas. Some preclinical studies and clinical trials have suggested that various forms of a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, adherence to a strict KD is difficult, and not all studies have shown promising results. Furthermore, no study has yet addressed whether IDHmut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of a unrestricted, cycling KD (weekly alternating between KD and standard diet) in preclinical models of IDHwt versus IDHmut gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDHwt or IDHmut glioma cells, either in low or normal glucose conditions. Likewise, an unrestricted, cycling KD had no effect on the in vivo growth of patient-derived IDHwt or IDHmut gliomas, even though the cycling KD did result in persistently elevated circulating ketones. Furthermore, this KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDHmut or IDHwt glioma. These data suggest that neither IDHwt nor IDHmut gliomas are particularly responsive to an unrestricted, cycling form of KD.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0257725