The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer

Poff, Angela M.; Ari, Csilla; Seyfried, Thomas N.; D’Agostino, Dominic P.

doi:10.1371/journal.pone.0065522

Cited by 165 publications

(163 citation statements)

References 88 publications

(118 reference statements)

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“…These data are consistent with published data demonstrating the antioxidative effect of ascorbic acid, inhibiting cross-linking of S100A4 (40). Given that reducing conditions predominate within the tumor microenvironment, protecting DAMPs such as HMGB1 and S100A4 from oxidation and inactivation, it seems reasonable to promote an oxidative environment within tumors to limit tumor cell growth, proliferation, and metastasis (41). Nevertheless, the moonlighting role of S100A4 in the nucleus has also been suggested (42), which may limit the ability of extracellular oxidation strategies to inhibit its activity (40).…”

Section: Discussionsupporting

confidence: 91%

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

Eisenbacher

Schrezenmeier

Jahrsdörfer

et al. 2014

The Journal of Immunology

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Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N-acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10– and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC-associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment.

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Section: Discussionsupporting

confidence: 91%

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

Eisenbacher

Schrezenmeier

Jahrsdörfer

et al. 2014

The Journal of Immunology

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“…Furthermore, KD improved rotarod performance in young (1-2 month) non-transgenic and APP +PS1 mice when fed on a KD for one month [35], while no effects on the soluble amyloid in brain or muscle could be detected by ELISA, in agreement with a previous study [36]. Additionally, it has been extensively reported that ketosis may be beneficial against cancer by decreasing blood glucose levels, the primary metabolic fuel for cancer cells [4,5]. In fact, previous work highlighted that blood ketone concentration was negatively correlated with tumor growth [37].…”

supporting

confidence: 88%

“…However, the brain is not capable to obtain significant energy from FFAs, thus hepatic ketogenesis converts them into ketone bodies: β-Hydroxybutyrate (BHB) and acetoacetate (AcAc), while a percentage of AcAc spontaneously decarboxylates to acetone [1]. To date, it has been broadly demonstrated how the metabolic state of mild ketosis, which can be induced through KD administration, calorie restriction or fasting, represents a valid tool for the metabolic management of epilepsy and a number neurodegenerative diseases [2], Amyotrophic Lateral Sclerosis (ALS) [3], and some types of cancer [4,5]. In addition, nutritional treatments represent an effective alternative where pharmaceutical approaches fail or produce unbearable side effects and costs for public health worldwide.…”

mentioning

confidence: 99%

The Ketogenic Diet Approach as Metabolic Treatment for a Variety of Diseases

Pilla¹

2016

J Epilepsy

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EditorialHuman brain derives over 60% of its energy from ketones when glucose availability is limited. After prolonged periods of fasting or Ketogenic Diet (KD), the whole body utilizes energy obtained from Free Fatty Acids (FFAs) released from adipose tissue. However, the brain is not capable to obtain significant energy from FFAs, thus hepatic ketogenesis converts them into ketone bodies: β-Hydroxybutyrate (BHB) and acetoacetate (AcAc), while a percentage of AcAc spontaneously decarboxylates to acetone [1]. To date, it has been broadly demonstrated how the metabolic state of mild ketosis, which can be induced through KD administration, calorie restriction or fasting, represents a valid tool for the metabolic management of epilepsy and a number neurodegenerative diseases [2], Amyotrophic Lateral Sclerosis (ALS) [3], and some types of cancer [4,5]. In addition, nutritional treatments represent an effective alternative where pharmaceutical approaches fail or produce unbearable side effects and costs for public health worldwide. However, before analyzing how benefits from therapeutic ketosis could be exploited, let us mention some pivotal concepts about metabolism. Under normal conditions and mostly in western societies, a healthy brain utilizes glucose as primary energy source, which unbalance can lead to a number of neurodegenerative disorders often associated with mitochondrial impairment and glucose transport-related dysfunctions, such as in epilepsy, Traumatic Brain Injury (TBI), Parkinson's and Alzheimer's diseases [6,7]. Ketone bodies and Krebs cycle intermediates represent the best fuels for brain and other organs. In fact, through their utilization, impaired glucose metabolism may be bypassed and their neuroprotective properties may be exploited [8]. However, neuroprotective mechanisms of ketosis are currently object of studies as mechanisms of action are still not sufficiently understood. It has been shown that ketone bodies are neuroprotective as they induce a consistent increase in mitochondrial biogenesis regulating the synaptic function, and also generate ATP increases, thus reducing the reactive oxygen species production in neurological tissues [9,10], and notably inhibit superoxide synthesis in primary rat neuronal cultures exposed to hyperoxia [11]. Moreover, the main reason why the KD has been proven so effective as an anticonvulsant aFpproach is because it significantly reduces the metabolism of glucose [12]. In addition, Ma and colleagues [13] demonstrated that, at physiological concentrations, BHB and AcAc reduce spontaneous discharges of GABAergic neurons in the rat substantia nigra, through ATP-sensitive potassium channels.Also, a reduction of total CNS aspartate levels in association with an increase of glutamate concentrations was found during ketosis, observing a significant increase of decarboxylated glutamate to GABA, the main inhibitory neurotransmitter [14,15]. Moreover, a remarkable increase in mitochondrial transcription enzymes and proteins was observed in rat hippocampus after the...

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“…Mouse on Keto diet showed lowered blood Glucose level, elevated blood Ketones and decreased Body Weight and declined tumor growth. Keto diet increased mean survival time in mice with systemic metastatic cancer [20]. Cancer Patients on keto diet showed tumor shrinkage [21].…”

Section: Keto Dietmentioning

confidence: 99%

Low Sugar Diet: A New Tool in War Against Tumorigenesis

Agarwal¹,

Maurya²

2018

Proc. Nat. Res. Soc.

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Cancer is a metabolic disease. Their typical characteristic is high consumption of glucose as these cells mostly have defective mitochondria. They primarily derive energy through aerobic glycolysis even in presence of abundant oxygen. Cancer cells thus are heavily dependent on ample and continuous availability of glucose for growth, proliferation and invasion. These cells adopt various strategies to satisfy their high demand for sugar which includes modification in signalling pathways and abnormally high expression of glucose transporters. Glucose uptake is favoured by alteration in PI3K-Akt-mTOR pathway. High glucose condition creates conducive environment for cancer cells to flourish. The H+ ion secreted as by-product of glycolysis helps in invasion and metastasis. Other by products of glycolysis which includes ATP, NADP and NADPH also aids in growth of cancer cells. Glucose restriction puts break on speedy multiplying tumor cells as unlike normal cells of the body they are unable to metabolize any other source of fuel. Lower glucose level induces changes in level of cleaved caspase 3, Bcl-2, p53 and p21 which prompts senescence and apoptosis in rapidly proliferating tumor cells. Various strategies can be employed to cut down glucose accessibility to cancer cells such as inhibition of glucose transporters, adoption of keto diet. Combining glucose restriction with either chemo or radiotherapy increases their effectiveness; lower CHO levels also provide protection to normal healthy cells of the body against toxic effect of anti-carcinogens. Carbohydrate restriction is a non-toxic, easily impeccable, economical and safe tactic which may be utilized as weapon in war against cancer.

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The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer

Cited by 165 publications

References 88 publications

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

The Ketogenic Diet Approach as Metabolic Treatment for a Variety of Diseases

Low Sugar Diet: A New Tool in War Against Tumorigenesis

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