Ketogenic diet in cancer therapy

Weber, Daniela D.; Aminazdeh-Gohari, Sepideh; Kofler, Barbara

doi:10.18632/aging.101382

Cited by 103 publications

(81 citation statements)

References 7 publications

(81 reference statements)

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“…The neuroprotective effect of the ketogenic diet has been hypothesized to be a result of the biochemical changes resulting from glycolytic inhibition, increased acetyl-CoA production, and formation of ketone bodies in the cell [71]. These biochemical changes have proven effective in targeting cancer cells, which primarily use glycolysis as their main source of ATP [72].…”

Section: Discussionmentioning

confidence: 99%

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Wert

Velez

Vijayalakshmi

et al. 2019

Preprint

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One Sentence Summary: The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina. Abstract: 244Main Text: 9,039References: 83 AbstractNeurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death.Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

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“…Several lines of evidence exist for the use of a ketogenic diet (KD) to treat brain tumors based on the idea that cancers are highly glycolytic and reducing the availability of blood glucose leaves the cells vulnerable to metabolic and chemotherapeutic insult. The first lies with the innate ability of the human body to efficiently adapt to ketosis 44 . For example, the KD has been successfully implemented to treat certain diseases such as refractory pediatric epilepsy with no clear sustained adverse health effects 45,46,47 .…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Sperry

Condro

Guo

et al. 2019

Preprint

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Glioblastoma (GBM) metabolism has traditionally been characterized by a dependence on aerobic glycolysis, prompting use of the ketogenic diet as a potential therapy. We observed growth-promoting effects on U87 GBM of both ketone body and fatty acid (FA) supplementation under physiological glucose conditions. An in vivo assessment of the unrestricted ketogenic diet surprisingly resulted in increased tumor growth and decreased animal survival. These effects are abrogated by FAO inhibition using knockdown of carnitine palmitoyltransferase 1 (CPT1).Primary patient GBM cultures revealed significant utilization of FAO regardless of tumorigenic mutational status and decreased proliferation, increased apoptosis, and elevated mitochondrial ROS production with CPT1 inhibition. Metabolomic tracing with 13 C-labeled fatty acids showed significant FA utilization within the TCA cycle, indicating that FAO is used for both bioenergetics and production of key intermediates. These data demonstrate important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.traditionally characterized by its reliance on the Warburg effect. Under normal physiological conditions the healthy adult brain meets most of its energy demand by complete oxidation of glucose. This produces pyruvate which is then converted into acetyl-CoA for entrance into the TCA cycle to support the electron transport chain 1 . Thus, glycolysis and respiration remain tightly connected and result in more efficient ATP production with little lactic acid production. In contrast, the Warburg effect dramatically increases the rate of aerobic glycolysis and lactic acid production in the cytosol. While the benefits of this phenomenon are not completely understood, it has been posited that its main advantages are increased biomass production and facilitated invasion due to acidification of the microenvironment 2 .GBMs have been identified as highly reliant on aerobic glycolysis to the point that they are sometimes referred to as being "glucose addicted". Several common signaling pathways found to be altered in GBM, such as PI3K-Akt-mTOR and Myc pathways, promote this phenotype by increasing expression of genes that allow cells to take up large amounts of glucose for increased glycolysis and lactate production 1, 3, 4 . Alterations to these pathways are often associated with mutations common to GBM such as EGFR and PTEN. EGFR, an activator of PI3K, is amplified in ~40% of GBMs with approximately half of those tumors expressing the constitutively active EGFRviii variant 5 . The tumor suppressor protein PTEN, a potent PI3K antagonist, is also altered in 30-40% of GBMs 6 . Similar to EGFR amplification, loss of PTEN function by either mutation or deletion results in hyperactivation of the PI3K/Akt signaling network. Despite these findings, little progress has been made therapeutically in targeting enzymes reported to regulate glucose metabolism in GBM.The interconnection between oncogenic signaling networks and metabolic pathways is complex in...

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“…The process typically comprises supplementation with eicosapentaenoic acid and branched chain amino acids that promote anabolism and suppress cellular catabolism, associated with an enhanced lean body mass (Holecek, ). The beneficial impact of KD on tumor growth and proliferation as well as longevity has been observed to be greater under calorie‐restricted regimens, rather than ad libitum treatment that blocked circulating glucose reduction (Weber, Aminazdeh‐Gohari, & Kofler, ). A combination of KD, calorie‐restricted diet, and a glycolysis inhibitor, glucose analogue 2‐deoxy‐d‐glucose, caused a synergistic reduction in tumor progression; however, with increased mortality, owing to significant reduction in glycolysis (Singh et al, ).…”

Section: Kd and Cancermentioning

confidence: 99%

“…A combination of KD, calorie‐restricted diet, and a glycolysis inhibitor, glucose analogue 2‐deoxy‐d‐glucose, caused a synergistic reduction in tumor progression; however, with increased mortality, owing to significant reduction in glycolysis (Singh et al, ). The probable mechanism governing this reduced tumor proliferation could be an inactivation of insulin/IGF‐1‐dependent phosphatidylinositol 3‐kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) and activation of the AMP‐activated protein kinase (AMPK) system of autophagy that stimulate tumorogenesis (Weber et al, ). Additionally, treatment with PUFA and MCTs or lard‐rich diets caused significant necrosis and limited glucose supply to tumors (Connor et al, ).…”

Section: Kd and Cancermentioning

confidence: 99%

“…The probable mechanism governing this reduced tumor proliferation could be an inactivation of insulin/IGF-1-dependent phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) and activation of the AMP-activated protein kinase (AMPK) system of autophagy that stimulate tumorogenesis (Weber et al, 2018). Additionally, treatment with PUFA and MCTs or lard-rich diets caused significant necrosis and limited glucose supply to tumors (Connor et al, 2007).…”

Section: K D and C An Cermentioning

confidence: 99%

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Ketogenic diets and protective mechanisms in epilepsy, metabolic disorders, cancer, neuronal loss, and muscle and nerve degeneration

Liu

et al. 2020

J Food Biochem

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Ketogenic diet (KD), the “High‐fat, low‐carbohydrate, adequate‐protein” diet strategy, replacing glucose with ketone bodies, is effective against several diseases, from intractable epileptic seizures, metabolic disorders, tumors, autosomal dominant polycystic kidney disease, and neurodegeneration to skeletal muscle atrophy and peripheral neuropathy. Key mechanisms include augmented mitochondrial efficiency, reduced oxidative stress, and regulated phospho‐AMP‐activated protein kinase, gamma‐aminobutyric acid‐glutamate, Na+/K+ pump, leptin and adiponectin levels, ghrelin levels, lipogenesis, ketogenesis, lipolysis, and gluconeogenesis. In cancer cells, KD targets glucose metabolism, suppresses insulin‐like growth factor‐1 and PI3K/AKT/mTOR pathways, and reduces cancer cachexia and muscle waste and fatigue. An associated increased skeletal proliferator‐activated receptor‐γ coactivator‐1α activity alters systemic ketone body homeostasis, contributing toward attenuated diabetic hyperketonemia. Antioxidative and anti‐inflammatory properties enable KD enhance endurance and sports performances while preventing exercise‐induced muscle and organ debility. KD reduces metabolic syndromes‐associated allodynia and promotes peripheral axonal and sensory regeneration. This review enlightens effects of KD on various disease conditions. Practical applications It is increasingly being realized that diet plays a very important role in our fight against several diseases. This can range from neurological disorders to diabetes and cancer. In this context, the potential of KD, the “High‐fat, low‐carbohydrate, adequate‐protein” diet strategy, is increasingly being realized. In this article, we provide a comprehensive analysis of the benefits of KD against many diseases and discuss the underlying biochemical mechanisms. We hope that our write‐up will stimulate further research on KD and help generate an interest for the populations to adopt this healthy diet. It can help overcome the problems associated with weight and dysregulated metabolism.

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Ketogenic diet in cancer therapy

Cited by 103 publications

References 7 publications

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Ketogenic diets and protective mechanisms in epilepsy, metabolic disorders, cancer, neuronal loss, and muscle and nerve degeneration

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