The ketogenic diet for the treatment of malignant glioma

Woolf, Eric C.; Scheck, Adrienne C.

doi:10.1194/jlr.r046797

Cited by 77 publications

(73 citation statements)

References 78 publications

(83 reference statements)

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“…The KD mimics these biologic effects and has been proposed as a treatment for GB and other cancers (5). This was first explored in two pediatric patients with advanced-stage astrocytomas, following SOC treatments, and was able to produce long-term (>5 years) tumor maintenance, employing a KD supplemented with MCT oil (16).…”

Section: Discussionmentioning

confidence: 99%

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A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Martuscello

Vedam‐Mai

McCarthy

et al. 2016

Clinical Cancer Research

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Purpose: Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations. Experimental Design: The dietary paradigm was tested in vitro and in vivo, utilizing multiple patient-derived gliomasphere lines. Cellular proliferation, clonogenic frequency, and tumor stem cell population effects were determined in vitro using the neurosphere assay (NSA). Antitumor efficacy was tested in vivo in preclinical xenograft models and mechanistic regulation via the mTOR pathway was explored. Results: Reducing glucose in vitro to physiologic levels, coupled with ketone supplementation, inhibits proliferation of GB cells and reduces tumor stem cell expansion. In vivo, while maintaining animal health, the sHFLC diet significantly reduces the growth of tumor cells in a subcutaneous model of tumor progression and increases survival in an orthotopic xenograft model. Dietary-mediated anticancer effects correlate with the reduction of mTOR effector expression. Conclusions: We demonstrate that the sHFLC diet is a viable treatment alternative to the KD, and should be considered for clinical testing. Clin Cancer Res; 22(10); 2482–95. ©2015 AACR.

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Section: Discussionmentioning

confidence: 99%

“…GB has been proposed to be a promising candidate for dietary intervention due to its substantial reliance and utilization of glucose (4,5). At the forefront of dietary anticancer therapy is the ketogenic diet (KD), which is a highfat, low-carbohydrate, low-protein diet, used for decades to treat refractory epileptic seizures.…”

Section: Introductionmentioning

confidence: 99%

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Martuscello

Vedam‐Mai

McCarthy

et al. 2016

Clinical Cancer Research

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“…KG diet with extremely high fat composition has been used worldwide for refractory childhood epilepsy (40). The KG diet recently has also been reported to improve diabetes and malignant glioma (41,42), although the long term compliance of the KG diet is problematic. The present work provides another mechanism to explain these different impacts of Western diet and KG diet on healthy outcomes based upon their converse contribution to HNE catabolism.…”

Section: Discussionmentioning

confidence: 99%

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

Jin

Berthiaume

et al. 2014

Journal of Biological Chemistry

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Background: (2E)-4-hydroxy-2-nonenal (HNE) catabolism and its regulation remain to be fully investigated. Results: New catabolic pathways of HNE via -/-1-oxidation are elucidated and up-regulated in a ketogenic diet. Conclusion: HNE catabolism plays a major role in HNE disposal in certain organs. Significance: This work will further enhance our understanding of the metabolic fate of HNE and the roles of -and -1-oxidations in HNE disposal.

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“…The ketogenic diet and its calorie restricted variant that augments fasting responses, have been proposed to support anti-glioma therapy [190,191]. Indeed, bHB and acetoacetate exerted cytotoxic and growth inhibitory action on various cancer cells including lymphoma, melanoma, neuroblastoma, kidney and thyroid cancer cells [192,193].…”

Section: Ketogenesis and Ketolysis In Cancer Cellsmentioning

confidence: 99%

Regulation of Ketone Body Metabolism and the Role of PPARα

Grabacka

Pierzchalska

Dean

et al. 2016

IJMS

231

193

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Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions.

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The ketogenic diet for the treatment of malignant glioma

Cited by 77 publications

References 78 publications

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

Regulation of Ketone Body Metabolism and the Role of PPARα

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