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Ketogenic diet in cancer therapy

Authors:
  • 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
Editorial
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
alterations.
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
Ketogenicdietincancertherapy
DanielaDWeber,SepidehAminazdehGohari,BarbaraKofler
www.agingus.com   AG IING2018,Vol.10,No. 2
www.agingus.com    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
trials.
REFERENCES
1.KlementRJ.MedOncol.2017;34:132.
https://doi:10.1007/s1203201709915
2.MorscherRJ,etal.PLoSOne.2015;10:e0129802.
https://doi:10.1371/journal.pone.0129802
3.AminzadehGohariS,etal.Oncotarget.2017;
8:6472844.https://doi:10.18632/oncotarget.20041
4.VidaliS,etal.Oncotarget.2017;8:5720115.
https://doi.org/10.18632/oncotarget.19306
5.LiskiewiczAD,etal.SciRep.2016;6:21807.
https://doi:10.1038/srep21807
6.XiaS,etal.CellMetab.2017;25:35873.
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7.TanShalabyJL,etal.NutrMetab(Lond).2016;13:52.
https://doi:10.1186/s129860160113y
BarbaraKofler:ResearchProgramforReceptor
BiochemistryandTumorMetabolism,UniversityHospital
forPediatricsoftheParacelsusMedicalUniversity,5020
Salzburg,Austria
Correspondence:BarbaraKofler
Email:b.kofler@salk.at
Keywords:tumormetabolism,ketogenicdiet,adjuvant
therapy
Copyright:Weberetal.Thisisanopenaccessarticle
distributedunderthetermsoftheCreativeCommons
AttributionLicense(CCBY3.0),whichpermitsunrestricted
use,distribution,andreproductioninanymedium,
providedtheoriginalauthorandsourcearecredited
Received:January31,2018
Published:February11,2018
www.agingus.com    165AGING
Figure1.PreclinicalevidenceindicatingtheeffectofaKD
ontumorgrowthandprogression.Thebarchartshowsthe
numberofpreclinicalstudies,whichinvestigatedtheeffectofa
KDondifferenttypesofcancer.Colorsofthebarsrepresentthe
resultofeachstudyasindicatedinthecolorkey.StudiesonKD
andcancerwerecollectedbyaliteraturesearchcovering
throughtheendof2017.Rindicatesstudieswithacalorie
restrictedKD;TindicatesuseofaKDasanadjuvanttherapyto
classictherapy.
... 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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... 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. ...
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... 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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... 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. ...
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... 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 . ...
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... 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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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 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 registrationClinicaltrials.gov NCT01716468. Registered on September 18, 2012
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