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Ketogenic diet in cancer therapy

  • University Hospital Salzburg Paracelsus Medical University Salzburg
The Ketogenic Diet (KD), a high-fat/low-carbohydrate/
adequate-protein diet, has recently been proposed as an
adjuvant therapy in cancer treatment [1]. KDs target the
Warburg effect, a biochemical phenomenon in which
cancer cells predominantly utilize glycolysis instead of
oxidative phosphorylation to produce ATP. Further-
more, some cancers lack the ability to metabolize
ketone bodies, due to mitochondrial embarrassment and
down-regulation of enzymes necessary for ketone
utilization [2]. Thus, the rationale in providing a fat-
rich, low-carbohydrate diet in cancer therapy is to
reduce circulating glucose levels and induce ketosis
such that cancer cells are starved of energy while
normal cells adapt their metabolism to use ketone
bodies and survive. Furthermore, by reducing blood
glucose also levels of insulin and insulin-like growth
factor, which are important drivers of cancer cell
proliferation, drop.
Numerous preclinical studies have provided evidence
for an anti-tumor effect of KDs [1] (Figure 1). For
example, our laboratory intensively studied the anti-
tumor effect of KDs in combination with or without
low-dose chemotherapy on neuroblastoma. We found
that the growth of neuroblastoma xenografts was
significantly reduced by a KD consisting of a 2:1 ratio
of fat to carbohydrate + protein when combined with
caloric restriction [2]. However, caloric restriction,
despite its anti-tumor effect and potential to sensitize
cancer cells to chemotherapy, would be contraindicated
in a range of cancer patients, particularly those with
cachexia. Thus, we further focused on optimizing the
KD composition to address this issue. We found that an
ad libitum KD (8:1) with a fat content of 25% medium-
chain triglycerides and 75% long-chain triglycerides
produced a stronger anti-tumor effect compared to a KD
(8:1) with all long-chain triglycerides, and was as
efficacious against neuroblastoma as the above-
described KD (2:1) combined with caloric restriction
[3]. These results stress the importance of an optimized
KD composition to suppress tumor growth and to
sensitize tumors to chemotherapy without requiring
caloric restriction.
In addition to neuroblastoma, various researchers have
investigated the efficacy of KDs as an adjuvant therapy
for other types of cancer. The strongest evidence (> 3
studies) for a tumor-suppressing effect has been reported
for glioblastoma, whereas little or no benefit was found
for two other brain tumors (astrocytoma and medullo-
blastoma). Good evidence (2 - 3 studies) is available for
prostate, colon, pancreatic and lung cancer [1];
neuroblastoma also falls into this category (Figure 1).
Some of those studies report a tumor-suppressing effect
of KD alone and/or in combination with classic therapy
and/or caloric restriction. One study on prostate cancer
applied the KD in a preventive, instead of a therapeutic,
study setting. Only limited evidence (1 study) supports
the anti-tumor effect of an unrestricted KD on breast,
stomach, and liver cancer.
In contrast to the safe application of KDs reported in
various cancer models, our research group recently
reported that mice bearing renal cell carcinoma
xenografts and with signs of Stauffer’s syndrome
experienced dramatic weight loss and liver dysfunction
when treated with a KD [4]. Another study investigating
the effect of long-term KD treatment on kidney cancer
described a pro-tumor effect of the KD in a rat model of
tuberous sclerosis complex [5]. Most concerning is the
observation that, in a mouse model of BRAF V600E-
positive melanoma, tumor growth was significantly
increased under the KD [6]. Moreover, the study also
demonstrated that the ketone body acetoacetate
stimulated the oncogenic signaling of the BRAF
pathway. In contrast, the KD had no effect on the
progression of NRAS Q61K-positive or wild-type
melanoma xenografts [6]. Notwithstanding these obser-
vations, in a feasibility trial involving a limited number
of patients with advanced malignancies, a patient with
BRAF V600E-positive/BRAF-inhibitor resistant mela-
noma seemed to benefit from the KD [7].
Taken together, results from preclinical studies, albeit
sometimes contradictory, tend to support an anti-tumor
effect rather than a pro-tumor effect of the KD for most
solid cancers. However, even though pro-tumor effects
are rare, they cannot be ruled out per se. Most impor-
tantly, available preclinical evidence implies that the
feasibility of a KD as an adjuvant cancer therapy
strongly depends on the type of tumor and its genetic
To date, evidence from randomized controlled clinical
trials is lacking, but needed, to answer the question of
whether an adjuvant KD would benefit specific cancer
patients. Human data pertaining to KDs and cancer are
DanielaDWeber,SepidehAminazdehGohari,BarbaraKofler   AG IING2018,Vol.10,No. 2    164AGING
mostly based on single case reports and a smattering of
preliminary clinical studies with small study cohorts,
heterogenous study designs, poor compliance to the
diet, noncomparable regimens, or without standardized
dietary guidance. Even so, results of the first clinical
studies support the hypothesis of an anti-tumor effect of
KDs. For example, 10 of the 24 (42%) clinical studies
included in a recent review [1] provide evidence for the
anti-tumor effect of KDs, whereas seven (29%) showed
no effect and only one study reported a pro-tumor effect
of the KD. The currently available medical literature
presents strong scientific evidence for the safe
application of a KD only in patients with glioblastoma.
However, a clear recommendation for adjuvant use of
the KD in glioblastoma patients still requires results
from ongoing randomized controlled clinical trials.
In conclusion, clinical application of KDs as an
adjuvant therapy for cancer patients first requires that
the KD be evaluated for its anti-tumor effect for each
single type/genetic subtype of cancer in a preclinical
setting, as the safety and efficacy of the KD strongly
depend on the tumor entity and its genotype. Based on
the results of rigorous preclinical and clinical studies
performed thus far, the KD would appear to be a
promising and powerful option for adjuvant therapy for
a range of cancers. Cancer-specific recommendations
await the findings of randomized controlled clinical
Published:February11,2018    165AGING
... KDs lower blood glucose and provide KBs to tissues, thereby reducing cancer cell proliferation, and enhancing survival. KD alone or in combination with CR has been successful in the treatment of malignant gliomas in animal models [126,152,158] and in patients with brain tumors [159][160][161][162][163]. Tumor-suppressive effect and anti-cancer progression by the KD has also been shown in many other cancer models including colon, lung, neuroblastoma, breast, pancreas, prostate, and stomach cancer [148,[164][165][166][167][168][169][170][171]. ...
... This suggests that the KD induces anti-tumor effects toward melanoma regardless of genetic background and metabolic plasticity. Therefore, it is suggested that numerous factors control the ability of cells to utilize KBs in vitro and in vivo, and their sensitivity to KD's or KBs' action may vary with cancer type, grade and stage, and genetic mutations [5,148,171]. ...
... Potential mechanisms for KBs and KDs in cancer therapy are schematically shown in Figure 5. KD can affect tumor cell growth by lowering insulin and IGF-1 levels, thereby reducing receptor tyrosine kinase-dependent signaling pathways such as PI3K-Akt-mTOR for tumor cell proliferation and tumor growth ( Figure 5A) [154,158,171,176]. A recent study showed that a KD, BHB, or ketone supplementation exhibited a strong tumorsuppressive effect in an animal model of colorectal cancer [25]. ...
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The ketone bodies (KBs) β-hydroxybutyrate and acetoacetate are important alternative energy sources for glucose during nutrient deprivation. KBs synthesized by hepatic ketogenesis are catabolized to acetyl-CoA through ketolysis in extrahepatic tissues, followed by the tricarboxylic acid cycle and electron transport chain for ATP production. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. KBs participate in various cellular processes as signaling molecules. KBs bind to G protein-coupled receptors. The most abundant KB, β-hydroxybutyrate, regulates gene expression and other cellular functions by inducing post-translational modifications. KBs protect tissues by regulating inflammation and oxidative stress. Recently, interest in KBs has been increasing due to their potential for treatment of various diseases such as neurological and cardiovascular diseases and cancer. Cancer cells reprogram their metabolism to maintain rapid cell growth and proliferation. Dysregulation of KB metabolism also plays a role in tumorigenesis in various types of cancer. Targeting metabolic changes through dietary interventions, including fasting and ketogenic diets, has shown beneficial effects in cancer therapy. Here, we review current knowledge of the molecular mechanisms involved in the regulation of KB metabolism and cellular signaling functions, and the therapeutic potential of KBs and ketogenic diets in cancer.
... Currently, it is still widely used in the treatment of epilepsy; not infrequently, its efficacy exceeds that of pharmacotherapy [2][3][4]. The extraordinary therapeutic effects seen in drug-resistant epilepsy gave a motive for the development of research into the effect of the ketogenic diet in many other domains [5][6][7]. One very interesting and forward-looking approach, from the perspective of progress in medicine, concerns the effectiveness of the ketogenic diet in treating diabetes mellitus. ...
... The remaining 24 trials underwent further screening of the titles and abstracts. As a result, 17 articles were excluded for the following reasons: other co-morbidities (5), no RCT (4), an animal-based study (1), and unrelated topics (7). Full-text examination by two independent reviewers narrowed down the number of articles to 7. The available data from randomized controlled trials (RCT) shows a positive prognosis for the ketogenic diet's application in diabetes. ...
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The exponentially growing frequency of diagnosing diabetes mellitus means that a verification of the previous dietetic approach to treating the disease seems justified. The simultaneous growth of interest in the ketogenic diet and the development of knowledge in this field have contributed to the increasingly frequent application of the ketogenic diet in diabetes treatment. This paper also deals with that issue; its aim includes an extensive analysis of the influence of the ketogenic diet on the prophylaxis and treatment of diabetes. The paper has been prepared based on a wide, meticulous analysis of the available literature on the subject. Among other findings, a favorable effect of that nutrition model has been demonstrated on the values of glycated hemoglobin, glucose, insulin, or other metabolic parameters in diabetes patients. The effect of the ketogenic diet on the pharmacotherapy of type 1 and type 2 diabetes has been presented and compared with the standard nutritional management plan recommended for that disease. Further research is needed in this field, especially studies with a long follow-up period. The discussed articles report interesting therapeutic advantages to the ketogenic diet in comparison with standard diets.
... Cancer cells are unable to metabolize ketone bodies (KB) due to the mitochondrial altered morphology and dysfunction. LCKD can decrease glucose levels, deprive cancer cells of energy and create metabolic stress, while normal cells adapt and utilize KB for energy production and survival [39]. Nutritional ketosis reduces insulin and IGF-1 and thus downregulates the cancer cells' mitogenic activity, the proliferation and generation of inflammatory molecules, increases DNA repair mechanisms, autophagy and mitophagy, telomerase length, inhibits NF-kB, promotes apoptosis, and prevents tumorigenesis [40]. ...
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The correlation between pancreatic ductal adenocarcinoma (PDAC) and diabetes-related mechanisms support the hypothesis that early therapeutic strategies targeting diabetes can contribute to PDAC risk reduction and treatment improvement. A systematic review was conducted, using PubMed, Embase and Cochrane Library databases, to evaluate the current evidence from clinical studies qualitatively examining the efficacy of four natural products: Curcumin—Curcuma longa L.; Thymoquinone—Nigella sativa L.; Genistein—Glycine max L.; Ginkgo biloba L.; and a low-carbohydrate ketogenic diet in type 2 diabetes (T2D) and PDAC treatment. A total of 28 clinical studies were included, showing strong evidence of inter-study heterogeneity. Used as a monotherapy or in combination with chemo-radiotherapy, the studied substances did not significantly improve the treatment response of PDAC patients. However, pronounced therapeutic efficacy was confirmed in T2D. The natural products and low-carbohydrate ketogenic diet, combined with the standard drugs, have the potential to improve T2D treatment and thus potentially reduce the risk of cancer development and improve multiple biological parameters in PDAC patients.
... On the contrary, other studies have provided evidence for BMI not being an independent predictor of disease and is likely to be part of all the risk factors contributing to EC [9••, 17••, 44]. Although BMI is a common tool used to estimate obesity state, it is influenced by many factors that are not accounted for (e.g., muscle mass, bone, water content, fat distribution) [45][46][47]. Studies that utilize BMI as a primary measure should be either re-assessed or incorporate more reliable measures (e.g., waist-to-hip ratio, waist circumference) to support and verify their results. ...
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Purpose of Review Endometrial cancer is the most common gynecological malignancy and represents a notorious threat to women’s health worldwide. Endometrial cancer predominantly affects post-menopausal women; yet the prevalence of this disease has been rising also among pre-menopausal women. Poor nutritional habits, inflammation, and obesity may be associated with endometrial cancer (EC) among both pre-menopausal and post-menopausal women and should be further assessed among a wide spectrum of age groups. Recent Findings This scoping review explores and reports on primary research studies conducted to investigate the impact of nutrition, inflammation, and/or obesity on endometrial cancer risk among both pre-menopausal and post-menopausal women. Using a predefined protocol in compliance with the PRISMA guidelines, a search was conducted on four separate databases including PubMed, Cochrane Library, ProQuest, and Google Scholar to investigate the association between nutrition, inflammation, obesity, and endometrial cancer. A total of 4862 articles were identified. Following a full article analysis, 27 articles met the full inclusion criteria and were included in the current review. Findings from the literature support a role of nutrition, obesity, and inflammation in the development of EC. The studies included in the current review supported that plant-based, Mediterranean, or ketogenic diets are associated with a lower risk of EC while there is no association between glycemic index and EC risk. On the other hand, increased BMI is associated with a higher risk of EC and there is a positive association between obesity-related pro-inflammatory biomarkers and increased risk for EC development. Summary Further research needs to be conducted to gain more insight into the complex interactions between nutrition, obesity, and inflammation and their association with EC development among pre-, peri-, and post- menopausal women with the ultimate goal to improve management and preventive strategies and achieve reduced prevalence of endometrial cancer.
... This characteristic explains the great need that the cancer cells have for sugar, in order to rapidly duplicate and use mainly glucose as an energy source. Precisely for this reason, in PET, a diagnostic technique used to visualize the tumor mass, a glucose analogue is used as a tracer [1][2][3][4][5]. A diet that allows keeping low blood sugar level could therefore be useful in limiting the nourishment of cancer cells as much as possible. ...
Cancer cells have a particular metabolism, which differs from normal cells; according to the so called “Warburg effect”, cancer cells have a predominant use of anaerobic glycolysis, i.e. they are able to use the sugar (glucose) present in the blood in any condition, both in the presence and absence of oxygen.
... For instance, the ketogenic diet (also known as the very-low-carbohydrate diet) has been shown to elicit anti-tumoral effects in several types of cancers 130 . Interestingly, the ketogenic diet targets the Warburg effect in tumour cells by reducing the amount of glucose 131 . In response to an increase of ketone bodies under ketogenic diet feeding, CD8 + T cells are metabolically reprogrammed to rely on OXPHOS 129 . ...
The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour–immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses.
... The molecular and biochemical results of this study showed that the consumption of the KD, curcumin, and ODE alone or in combination could improve gastric cancer by inhibiting inflammation, angiogenesis, and oxidative damage and inducing apoptosis. In agreement with our findings, preclinical and clinical studies have suggested that KD alone or in combination with caloric restriction significantly reduced tumor weight and volume as well as prolonged survival time (Weber et al., 2018(Weber et al., , 2020. Moreover, KD could increase the sensitivity of tumor cells to chemotherapy and radiotherapy Allen et al., 2013;Zahra et al., 2017). ...
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The pathogenesis of gastric cancer is a multistage process that involves glucose metabolism, inflammation, oxidative damage, angiogenesis, autophagy, and apoptosis. Moreover, microRNA‐340 (miR340) also plays a vital role in tumorigenesis and the biology of gastric cancer as an epigenetic factor. It seems that the use of ketogenic diets (KDs) and plant extracts that have antitumor, anti‐inflammatory, and antioxidant properties can be good treatment options to cure gastric cancer. The aim of this study was to investigate the role of miR‐340 on pathways involved in the pathogenesis of gastric cancer and the improving effects of the KD, Oldenlandia diffusa extract (ODE), and curcumin in the animal model of gastric cancer. One hundred and ten male Wistar rats were divided into control and treatment groups. The expression of miR‐340 along with genes involved in inflammation, oxidative damage, angiogenesis, and apoptosis were assessed. The results showed that the KD and different doses of curcumin and ODE in a dose‐dependent behavior could induce apoptosis and the expression of the Akt/mTORC1 pathway and inhibit inflammation, oxidative damage, and angiogenesis in the gastric tissue of rats with cancer. In addition, there was no significant difference between cancer groups receiving ODE and curcumin. These results also showed that consumption of KD could significantly increase the efficacy of ODE and curcumin which may be due to increasing miR‐340 expression. The results of this study suggested well that the KD along with conventional therapies in traditional medicine can be a useful solution for the prevention and treatment of gastric cancer. Practical applications Gastric cancer is the third leading cause of cancer death, and genetic and epigenetic factors, including miR‐340, are involved in its pathogenesis. However, the use of ketogenic diets (KDs) and plant products such as curcumin and Oldenlandia diffusa extract (ODE) can play an effective role in inhibiting tumorigenesis in some cancers. Our results showed that the KD and different doses of curcumin and ODE could induce apoptosis and the expression of the Akt/mTORC1 pathway and inhibit inflammation, oxidative damage, and angiogenesis in the gastric tissue. Moreover, the KD could significantly increase the efficacy of ODE and curcumin which may be due to an increase in miR‐340 expression. These findings provide novel perceptions about the mechanisms of the KD, curcumin, and ODE to cure gastric cancer. It suggested that the KD as adjunctive therapy along with conventional therapies in traditional medicine could be considered a useful solution to prevent and treat gastric cancer.
... It was found that LCKD during chemotherapy for three months was suitable, and there were no severe side effects and even some improvements in quality of life [91]. It has additionally been reported that KD was safe and effective in patients with high-grade glioma during treatment [92]. An animal study of neuroblastoma cases revealed that KD plus chemotherapy exerted anti-tumor effects, suppressing growth and causing a significant reduction of tumor blood-vessel density and intra-tumoral hemorrhage, accompanied by activation of AMP-activated protein kinase in neuroblastoma cells [93]. ...
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Cardiovascular disease (CVD) and cancer are the first and second leading causes of death worldwide, respectively. Epidemiological evidence has demonstrated that the incidence of cancer is elevated in patients with CVD and vice versa. However, these conditions are usually regarded as separate events despite the presence of shared risk factors between both conditions, such as metabolic abnormalities and lifestyle. Cohort studies suggested that controlling for CVD risk factors may have an impact on cancer incidence. Therefore, it could be concluded that interventions that improve CVD and cancer shared risk factors may potentially be effective in preventing and treating both diseases. The ketogenic diet (KD), a low-carbohydrate and high-fat diet, has been widely prescribed in weight loss programs for metabolic abnormalities. Furthermore, recent research has investigated the effects of KD on the treatment of numerous diseases, including CVD and cancer, due to its role in promoting ketolysis, ketogenesis, and modifying many other metabolic pathways with potential favorable health effects. However, there is still great debate regarding prescribing KD in patients either with CVD or cancer. Considering the number of studies on this topic, there is a clear need to summarize potential mechanisms through which KD can improve cardiovascular health and control cell proliferation. In this review, we explained the history of KD, its types, and physiological effects and discussed how it could play a role in CVD and cancer treatment and prevention.
Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.
The gut microbiome is critical for overall human health. Many factors can disturb the gut microbiome and create dysbiosis. Both the mucous layer and the gut epithelial lining, which collectively serve as the gastrointestinal mucosal border, can be structurally degraded by gut dysbiosis. Increased intestinal permeability and compromised host resistance can ensue. Since all mucosal tissues in the body participate in cross-talk, other organ systems can be affected according to genetic predispositions and an increase in systemic chronic inflammation. The manifestation of named chronic diseases is the ultimate outcome. In this case, symptoms of various chronic diseases must be addressed. Specifically, periodontal disease, which is a chronic disease, must be understood and treated appropriately because it can become a second nidus of infection along with the primary nidus emanating from gut dysbiosis. However, the mystery of treatment does not only require medical intervention, although medical treatment for acute disease is critical. Essential treatment for this scenario usually includes a dietary and lifestyle solution to restore healthy gastrointestinal tract function. Unraveling the mystery of treatment involves introducing viable probiotics and prebiotics; removing elements of an inflammatory diet; providing necessary nutrients and nourishment for cellular function, eliminating toxic elements and chemicals; and creating a healthy lifestyle of stress reduction, restorative sleep, and efficient exercise.
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Abstract Neuroblastoma (NB) is a pediatric malignancy characterized by a marked reduction in aerobic energy metabolism. Recent preclinical data indicate that targeting this metabolic phenotype by a ketogenic diet (KD), especially in combination with calorie restriction, slows tumor growth and enhances metronomic cyclophosphamide (CP) therapy of NB xenografts. Because calorie restriction would be contraindicated in most cancer patients, the aim of the present study was to optimize the KD such that the tumors are sensitized to CP without the need of calorie restriction. In a NB xenograft model, metronomic CP was combined with KDs of different triglyceride compositions and fed to CD1-nu mice ad libitum. Metronomic CP in combination with a KD containing 8-carbon medium-chain triglycerides exerted a robust anti-tumor effect, suppressing growth and causing a significant reduction of tumor blood-vessel density and intratumoral hemorrhage, accompanied by activation of AMP-activated protein kinase in NB cells. Furthermore, the KDs caused a significant reduction in the serum levels of essential amino acids, but increased those of serine, glutamine and glycine. Our data suggest that targeting energy metabolism by a modified KD may be considered as part of a multimodal treatment regimen to improve the efficacy of classic anti-NB therapy.
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The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFα) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFα, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome, because they potentially worsen the associated hepatic dysfunction.
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Background: Ketogenic diets (KDs) have gained popularity among patients and researchers alike due to their putative anti-tumor mechanisms. However, the question remains which conclusions can be drawn from the available human data thus far concerning the safety and efficacy of KDs for cancer patients. Methods: A realist review utilizing a matrix-analytical approach was conducted according the RAMESES publication standards. All available human studies were systematically analyzed and supplemented with results from animal studies. Evidence and confirmation were treated as separate concepts. Results: 29 animal and 24 human studies were included in the analysis. The majority of animal studies (72%) yielded evidence for an anti-tumor effect of KDs. Evidential support for such effects in humans was weak and limited to individual cases, but a probabilistic argument shows that the available data strengthen the belief in the anti-tumor effect hypothesis at least for some individuals. Evidence for pro-tumor effects was lacking completely. Conclusions: Feasibility of KDs for cancer patients has been shown in various contexts. The probability of achieving an anti-tumor effect seems greater than that of causing serious side effects when offering KDs to cancer patients. Future controlled trials would provide stronger evidence for or against the anti-tumor effect hypothesis
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Background Dysfunctional mitochondrial processes limit malignant cells ability to use energy from fatty acids and ketones. Animal studies using ketogenic diets for cancer show encouraging results. We tested the diet’s safety and feasibility in cancer patients across a broad variety of solid tumors. Methods We recruited 17 advanced cancer patients who were not on chemotherapy. They consumed 20 to 40 g of carbohydrates daily with evaluations performed weekly until week 4, then every 4 weeks until 16 weeks. Quality of life questionnaires monitored for tolerability and compliance. Positron emission/computerized tomography was ordered at baseline, 4,8 and 16 weeks. Student t-testing evaluated differences between baseline and last visit scores for quality of life, weight, body mass index, and serum parameters. Correlations between weight loss and serum ketones, glucose, lipids and creatinine were done. Two-tailed unpaired t-testing of the mean weight loss compared responders against non-responders. ResultsEleven out of seventeen enrolled patients were evaluable. Mean age was 65+/- 11.7 years, weight 203 +/- 4.98 lbs. (92 ± 2.3 kgs.) and previous treatment failures was 1.7, +/- 0.97. All lost significant weight with hematologic, biochemical and lipid tests remaining stable. Quality of life scores slightly improved. At 4,8 and 16 weeks, six (54.5 %), five (45.4 %) and four (36 %) patients were stable or improved. We observed no correlations between serum glucose, ketones or lipids. Clinical response did not correlate with ketosis or glycemia. Responders (stable disease or partial responders) lost statistically more weight than non-responders. Dietary compliance was difficult. Only three patients continued dieting past 16 weeks. Out of these, two patients developed brain metastases and were on steroids. They survived 80 and 116 weeks respectively. The third patient underwent residual tumor resection and has no disease at 131 weeks. Conclusions Modified Atkins diets are safe and feasible in advanced cancer. Quality of life was preserved. Patients who lost at least 10 % of their body weight responded the best. Steroid intake affected optimal ketone and glucose levels. Despite this, survival improved in some melanoma and lung cancer patients. Further studies are recommended. Trial NCT01716468. Registered on September 18, 2012
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Nutritional imbalance underlies many disease processes but can be very beneficial in certain cases; for instance, the antiepileptic action of a high fat and low carbohydrate ketogenic diet. Besides this therapeutic feature it is not clear how this abundant fat supply may affect homeostasis, leading to side effects. A ketogenic diet is used as anti-seizure therapy i.a. in tuberous sclerosis patients, but its impact on concomitant tumor growth is not known. To examine this we have evaluated the growth of renal lesions in Eker rats (Tsc2+/−) subjected to a ketogenic diet for 4, 6 and 8 months. In spite of existing opinions about the anticancer actions of a ketogenic diet, we have shown that this anti-seizure therapy, especially in its long term usage, leads to excessive tumor growth. Prolonged feeding of a ketogenic diet promotes the growth of renal tumors by recruiting ERK1/2 and mTOR which are associated with the accumulation of oleic acid and the overproduction of growth hormone. Simultaneously, we observed that Nrf2, p53 and 8-oxoguanine glycosylase α dependent antitumor mechanisms were launched by the ketogenic diet. However, the pro-cancerous mechanisms finally took the ascendency by boosting tumor growth.
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Introduction Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer’s oxidative phosphorylation system. Methods Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content). Results Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention. Conclusions Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose that a ketogenic diet and/or calorie restriction should be further evaluated as a possible adjuvant therapy for patients undergoing treatment for neuroblastoma.
Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized “precision diets” that may prevent or delay tumor progression based on an individual’s specific oncogenic mutation profile.