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Abstract

Abstract Cancer is considered one of the greatest killers in the developed world. Researchers are actively looking for treatments to better the prognosis of the disease. We present herein a dietary modification capable of modifying cancer growth and metabolism, the ketogenic diet (KD). The ketogenic diet is very low in carbohydrates, the main energy substrate for cancerous cells, which lose their ability to utilize alternative fuel sources and mainly use glycolytic fermentation as their main energy source. It has been demonstrated that by severely limiting glucose availability and lowering circulating insulin levels which also lowers IGF-1, TNF, MTR (known growth factors),cancer growth can be slowed down and mean survival time extended, both in animal and human studies, as well as improving the quality of life (QoL). The Ketogenic Diet is proving beneficial to limit malignant tumor growth, however when combined with other therapies such as Hyperbaric Oxygen Therapy (HBOT) and Intravenous Vitamin C (IVC) seems to further potentiate this action.
Archives of Oncology and Cancer Therapy V1 . I1 . 2018 48
Introduction
This literature review intends to state the severity of
the Cancer epidemic, give an overview of the changes
that occur within cancerous cells compare to healthy
cells and how these metabolic changes can be used
to target cancer cells while sparring healthy cells.
We also explainhow a Ketogenic Diet (KD) might be
therapeutic against cancer.
Cancer is amongst the top three causes of death in the
developed world,both in the US and in Puerto Rico. In
2014,591,699 people died of malignanttumors in the
US, only 25,000 (1) and in 2012 cancer killed more
people in Puerto Rico than heart disease, averaging
5,439 people per 100 thousand inhabitants; to 5,089
for heart disease (2).Even though earlier detection
of cancer has progressed the amount of deaths per
year of cancer has barely changed in the last 50 years,
while improvement in the treatment of Heart Disease
       
these 2 main killers (3). This could be considered a
treatmentsetback, due to lack of progress against
this degenerative disease, as the standard of care
        
options to improve the prognosis against cancer. For
this reason,recent studies have been directed into
the metabolic aspects of cancer. The idea of treating
cancer as a metabolic disease instead of a genetic one
is appealing. This is due to the fact that research has
 
      
cancerous and normal healthy cells(4):
A shift from respiratory (aerobic) pathways as a 1.
main ATP production mechanism to fermentative
(anaerobic) pathways (Oxidative phosphorylation
to Fermentation).
Mitochondrial dysfunction; both in structure 2.
and function, as mitochondrialose their cristae
and membrane potential, thus diminishing their
energy production potential. Creating what has
been named as ghost mitochondria.
Increased glycolysis, which raises lactic acid 3.
production thus lowering pH levels and oxygen

Archives of Oncology and Cancer Therapy
Volume 1, Issue 1, 2018, PP: 48-53
The Ketogenic Diet and Cancer
Yamil R. Torres Aponte1, Vilma Calderon2, Michael J Gonzalez1*
1Dept. Human Development, Nutrition Program, School of Public Health, Medical Sciences Campus
University of Puerto Rico, Puerto Rico.
2Las Americas Professional Center, Medical clinic in San Juan, PR.
michael.gonzalez5@upr.edu
*Corresponding Author: Dr. Michael J Gonzalez, Professor, Dept. Human Development, Nutrition Program,
Medical Sciences Campus, School of Public Health, University of Puerto Rico, San Juan, PR.
Abstract
Cancer is considered one of the greatest killers in the developed world. Researchers are actively looking for

cancer growth and metabolism, the ketogenic diet (KD). The ketogenic diet is very low in carbohydrates, the
main energy substrate for cancerous cells, which lose their ability to utilize alternative fuel sources and mainly
use glycolytic fermentation as their main energy source. It has been demonstrated that by severely limiting
glucose availability and lowering circulating insulin levels which also lowers IGF-1, TNF, MTR (known growth
factors),cancer growth can be slowed down and mean survival time extended, both in animal and human

tumor growth, however when combined with other therapies such as Hyperbaric Oxygen Therapy (HBOT) and
Intravenous Vitamin C (IVC) seems to further potentiate this action.
Keywords: Ketogenic Diet, Keto Diet, nutrition, cancer, cancer therapy
Archives of Oncology and Cancer Therapy V1 . I1 . 2018
49
F4.
ormation of coagulated proteins aroun
d
cancerous cells, which shield these from the host
immunological response (Cellular and humoral).
Augmented and uncontrolled cellular replication.5.
Loss of communication between cells.6.
Metastasis or colonization of other tissues by 7.
transformed cells.
These changes make cancer cells regress to resemble
simple single organisms which use fermentation
as their sole mechanism of ATP production. In the
    
are basically anaerobic and utilize the sugar of the
ova for its ATP production needs. Embryonic cells
repl
    
me
studies have tried with to reactivate the function of
the mitochondria using dichloroacetate (DCA), which
by inhibits PDK (pyruvate dehydrogenase kinase),
decreasing the conversion of pyruvate to lactate,
thus mobilizing pyruvate into the mitochondria
and promoting respiration over fermentation(5).
This mechanism may also reverse the suppressed
mitochondrial apoptosis (programed cell death)
in cancer cells, by increasing certain signaling ROS
(Reactive Oxygen Species) and pro-apoptotic factors
from the mitochondria.This has shown to reduce
cancer growth in vivo in animal models.In addition,
large doses of Vitamin Cmay assist in the transport
of oxidation potential to the mitochondria therefore
encouraging the utilization of the mitochondrial
    
with all of its’ anti-carcinogenic mechanisms and
implications (increase H2O2, collagen, humoral
and cellular immune response) (6). Asascorbate’s
transport into the cell is facilitated by ascorbate’s
similar molecular structure to glucose and malignant
cells have anincreased need for glucose; this could

Discussion
The increased dependency of cancer cells for glucosehas
been used as a diagnostic way of scanning for cancer

a positive positron emission tomographic (PET) result
for areas consuming excess glucose.As a therapeutic
option the limitation of glucose by consuming a diet
very low in carbohydrates makes sense. This approach
should limit the availability of energy substrate for
   
energy for normal healthy cells. Normal cells maintain

as ketones as energy while malignant cells lose this
ability (7). This strategy should theoretically not only
reduce the speed of replication of malignant cells by
reducing available substrate, but also downregulate
some of the growth factors associated with cancer
       
TNF(Tumor Necrosis Factor) and MTOR (Mammalian
Target of Rapamycin) as all of these decrease as insulin
levels do; as well as activate apoptotic mechanisms
that might eradicate these malignant cells(8). To

low in order to elevate ketone bodies for optimal
       
with a ketogenic diet (KD).
AKD is one which raises the level of Beta-Hydroxy
butyrate (BHB) to over 0.5 Mmol/L, but for this to
happen levels of insulin have to be suppressed for
extended periods of time to allow for the body to utilize
fatty acids as energy source and the liver to produce
ketone bodies (9). This metabolic action is suppressed
by the presence of insulin. When dietary carbohydrates
are consumed the body releases insulin to lower blood
glucose level and make it available to the cell, but the
insulin surge needed to accomplish this inhibits fat
utilization as energy. For this reason, a ketogenic diet
must be high in fat (3:1 to 4:1, fat calories to protein
and carbohydrates), moderate in protein and very
low in carbohydrates. Most people think of the Atkins
diet when they think of a low carbohydrate diet but
the Atkins diet is not ketogenic due to its’ unrestricted
protein intake, which would raise blood glucose levels
by gluconeogenesis, primarily by means of glutamine
and produce an insulin spike non-conducive to ketosis.
For this reason a ketogenic diet should have no more
than 20% of its calories coming from protein making
a good starting point for most people a macronutrient
breakdown of approximately 75% fats, 20% protein
and 5% carbs (3:1); some highly insulin resistant
individuals may need to bring down their protein level
to 15% and their fats to 80% (4:1) to attain therapeutic
levels of ketones (>2Mmol) (7). Historically this diet
has been used therapeutically used since 1921 for the
management of epileptic seizures with great success,
as it provides an alternative fuel source for the brain

and other issues not allowing glucose to pass the
blood brain barrier; as ketones are independent of
these mechanisms(10).
The Ketogenic Diet and Cancer
Archives of Oncology and Cancer Therapy V1 . I1 . 2018 50
There are a considerable amount of studies exploring
the use of ketogenic diets in cancer (mostly in animal
models) looking for possiblemechanisms in which
    
aggressive cancers, whether life expectancy can be
lengthened, quality of life improved or even remission
attained. Since most still consider cancer a genetic
disease instead of a metabolic disease some of these
studies have examined how gene expression can
      
expression (epigenetics). One study analyzed a mouse
model of glioma’s (an aggressive form of brain cancer)
reaction to a KD and compared the gene expression
of 4 groups: (1) Standard Diet (SD), no cancer; (2) SD
+ cancer; (3) Ketogenic Diet (KD), no cancer; (4) KD +
     
      
showed that rats with glioma on a KD reversed
their gene expression to a pattern that more closely
resembles the gene patterning of the rats without
cancer, than the one of the cancer rats on the standard
       
oxygen species(ROS) and oxidative stress were
also down regulated on the glioma plus KD group,
compared to the glioma SD group as well as lower
signaling of growth factors known to augment tumor
size and metastasis. Even though the rat’s tumors did
not go into remission the average survival period of
the glioma plus KD went up to 25 days past tumor
implantation comparedto 19 days for the SD group,
a 32% increase in survival time. In a similar study,
CT-2A (Malignant mouse astrocytoma) and a human
   
and observed for 45 days, the mice were divided in
3 groups: a Standard Diet unrestricted (SD-UR), a
Ketogenic Diet unrestricted (KD-UR) and a restricted
Ketogenic diet (KD-R) (12). The mice in the (KD-R) had
a 65% smaller mouse tumor and 35% smaller human
glioma compared to the SD-UR group, as well as their
survival time was almost doubled. When comparing
both unrestricted groups the KD group had smaller
tumor size and increased survival time, as well as lower
blood glucose levels and higher b-hydroxybutyrate
levels, however the biggest improvements were seen
when calorie restriction and KD were combined, which
is very common when following a strict KD. The study
also looked at genes for ketone body metabolism on
healthy brain cells compared to the malignant tumor,
as these are severely downregulated it would make
sense to utilize this genetic testing to measure how
sensitive a cancer might be to this type of therapy.
At this stage, human research into this type of dietary
intervention is still in the pilot trial stage to test
      
before moving to larger sample sizes and longer
interventions. In a pilot trial of 10 patients with
advanced metastatic cancer investigators measured
and compared: macro-nutrient intake, body weight,
b-hydroxybutyrate, insulin, and insulin-like growth

and end of a 4 week intervention with a ketogenic diet
(13). Adherence to the diet was highly associated to
the level of b-hydroxybutyrate measured at the end
of the study and was compared to the level of the
same individual at the beginning of the study. At the
end of the study 4 of the 10 subjects had achieved a
stable disease status plus one partial remission; it
was observed that their levels of ketones were triple
compared to those of the subjects whose disease was
still progr
essing. Another worthy observatio
n was that
all participants spontaneously reduced their caloric
intake by an average of 35% even though they were
encouraged to increase their food consumption. This
natural appetite suppression related to KD(14) may
be an added bonus as some studies have proposed
calorie reduction to prevent cancer, delay onset or
as treatment(15). A small study of 5 patients with
Tuberous Sclerosis Complex (TSC), which develop
tumors along multiple organs (and between 80-90%
also develop epilepsy),who were being treated with
a KD for their drug resistant epilepsy was followed
for 5 years to observe if the diet seemed to have a
 
researchers hypothesized that the progression of their
tumo
rs might be slowed down since they were a
lready
adhering to a strict KD for seizure control and mTORC1
(mammalian target of rapamycin complex-1) pathway
is reduced as well as thelevels of insulin are. Although
3 out of 5 patients’ condition remained stable, tumor
growth was observed in 2 of the 5 patients; new renal
      
ependymal giant cell tumors) in the brain while on
the KD diet. Another human pilot trial with 16 adult
patients with advanced metastatic tumors (most were
at end stage) and no clear conventional treatment
options left, were instructed how to follow a KD
(less than 70g carbs/day) for 90 days and they were
given ingredients to make a lipid/protein shake for
The Ketogenic Diet and Cancer
Archives of Oncology and Cancer Therapy V1 . I1 . 2018
51
convenience during the intervention (17). During the
3 months, every 2 weeks’ blood was drawn, a Quality

new nutrition packet was sent out. During the process
of the intervention all but 5 dropped out for various
reasons (2 died, others because of progression of the
disease and others because they felt unable to follow
the diet), the 5 that completed the intervention had
a stable disease at the end and felt that an improved
emotional state and less insomnia along as other
positive aspects of life, but not without some of
aspects worsening, as is to be expected because of

were associated with the KD (temporary constipation
and fatigue were the most common). Though the diet
was well tolerated by 5 of 16 patients for 3 months
and 7 for at least 5 weeks’ adherence is feasible but

such a drastic dietary change. Most blood parameters
measured improved (blood glucose, cholesterol, LDL &
LDL/HDL) as well as most perceptions of their quality
of life. Among the limitations observed in this study is
that 70g of carbohydrate is too high to produce ketosis
in every patient, as lower levels are needed for more
insulin insensitive individuals (this can be appreciated
in table 4 where you can see that 4 out of the 10
evaluated for blood ketones did not even maintain the
minimum required to be in mild ketosis, for half of the
study). As it seems that no large human studies have

diet in cancer treatment further studies with a larger
sample and of longer duration are needed to be able
   
studies, this type of dietary manipulation may be a
viable non-toxic therapeutic option.
       
       

the standard of care is partial removal of the tumor
followed by chemotherapy, radiation or both. A study
looked at an intracranial bioluminescent mouse
model of malignant glioma and implementation of
a KD based on the consumption of KetoCal (KC), a
nutritionally complete 4:1 (fat: protein+carbs) ready
to drink ketogenic formula(18). The mice were divided
in 4 groups: acontrol group consisting of 19 mice fed
their standard diet chow (SD), the KetoCal group (19),
standard diet plus radiation (11) and 11 who received
radiation plus Keto Cal. The KC only grouped survived
5 extra days compared to the SD group (28 vs. 23), the
group that received radiation with a SD survived 41
days in average and the KC plus radiation group went
into complete remission. The KC plus radiation group
stayed on KC for 101 days after tumor implantation
and afterwards were switched to their standard
chow and observed for 200 extra days and no signs of
gliomas were observed. This study seems to point that
for very aggressive tumors such as gliomas it may not
be advisable to forgo radiation as the radiation and
SD group outlived the KD without radiation group,
however the real value seems to be in combining a
KD regimen with radiation to help their chances of
survival, as all in this combined therapy group had no
sign of gliomas, even 200 days after discontinuing the
diet.
Tumors often exhibit abnormal vasculature which
creates hypoxic (low oxygen) pockets which increase
the glycolytic dependency of these cancers, promote
faster proliferation and provide chemotherapy and
radiation resistance. Hyperbaric Oxygen Therapy
(HBO2T) uses 100% oxygen at higher than normal
atmospheric pressures (>1At) this can saturatethese
pockets with oxygen, diminishing their hypoxic
       
previous studies (by these same researchers) utilizing
     
in a rat model they performed a study in which they
divided their mice in 4 groups: A Standard Diet (SD)
control, a SD plus HBO2T group, KD alone and KD
combined with HBO2T. They compared their survival
times and the SD mean survival time was 31 days,
the SD + HBO2T= 39; KD alone = 49 and KD + HBO2T
55.5 days, showing a 56.7% and 77.9% increase
in survival time for the KD only and KD + HBO2T
group respectively. The increase in survival time also
correlated with the lowest levels of blood glucose and
highest ketone levels which were observed in the KD
groups with the KD +HBO2T being the biggest change
     
the ketogenic diet can be a synergistic player when
     
cancer. In addition, Intravenous Vitamin C may also
be a synergistic cofactor in this suggested therapeutic
protocol, since Vitamin C competes with glucose and
its anticancer action is enhanced by oxygen (20).
The Ketogenic Diet and Cancer
Archives of Oncology and Cancer Therapy V1 . I1 . 2018 52
Conclusion
Cancer is the second largest killer in the US and Puerto
Rico as well as many developed countries but once the
disease spreads the chances of survival are very small
for which better treatment options are being actively
searched. Per the data analyzed in this literature
review, results in animal models utilizing the KD by
itself brought increased survival time of 32%, to
77.9% and when combined with Hyperbaric Oxygen
Therapy and radiation led to a complete remission.
This seems to point to the usefulness of the diet by
itself but even more so to the value of combining it
with othernon-toxic treatments (HBOT, IV Vit C). Even
though human trials have shown promise at this stage
no large cancerstudies have been performed using
the KD. We believe that future research will prove
       
treatment of human cancers.
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
      

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from: http://journals.plos.org/plosone/article/
asset?id=10.1371/journal.pone.0065522.PDF
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intravenous Vitamin C as an anticancer agent. J
Orthomolec Med 2015, 30(1):45-50.
The Ketogenic Diet and Cancer
Citation: Yamil R. Torres Aponte, Vilma Calderon, Michael J Gonzalez. The Ketogenic Diet and Cancer.
Archives of Oncology and Cancer Therapy. 2018; 1(1): 48-53.
Copyright: © 2018 Yamil R. Torres Aponte, Vilma Calderon, Michael J Gonzalez. This is an open access
article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.
... The classic ketogenic diet is called the 4:1 diet, i.e., 80% of the energy is provided by fats and 20% by proteins and glucose (but there are many variations). The Atkins diet is therefore not ketogenic due to the unlimited protein intake [14]. In practice, KD-R means a glucose restriction of a maximum of 50 g per day. ...
... Because you have to eat about 5 g of omega-3 fatty acids per day, I have supplemented this with capsules [9]. It appears that adherence to therapy is related to the level of ketones that are formed: the higher the ketone level, the better one feels [14]. ...
Research
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A personal experience with the ketogenic diet.
... [6] Recent studies showed that limiting glucose availability and lowering circulating insulin levels also lowers the insulin-like growth factor 1 (IGF-1) and tumor necrosis factor (TNF), decreases progression rate, extends the mean survival time, as well as improves the quality of life, both in animal and human studies. [7] Hence, the study aims at evaluating the effect of high-dose IV ascorbic acid in cancer patients as monotherapy following ketogenic diet and improvement in the quality of life. ...
... Twice a week is feasible and potentially beneficial for patients with inflammation and anemia during the end stage (third and fourth) of cancer disease. [7] It is essential to maintain the quality of life in cancer patients during IV Ascorbic acid therapy when compared to highly toxic chemotherapeutic regimen, hence the safe dose of IV Ascorbic acid should be considered. ...
Article
Background: The role of ascorbic acid in cancer therapy is mainly due to its structural similarity with glucose. When supplemented intravenously in high dose, ascorbic acid can get into the cancer cells and induce apoptosis by causing mitochondrial damage. Aim: The aim was to study the efficacy of high-dose intravenous (IV) ascorbic acid as monotherapy in cancer patients following ketogenic diet and its role in improving the quality of life. Results: C-reactive protein (CRP) and erythrocyte sedimentation rates (ESRs) were considered as parameters to determine the efficacy of the treatment, and substantial decrease in both the levels was observed within 1-week treatment. CRP levels declined from 3.1946 ± 3.2508 mg/L to 1.0606 ± 0.6706 mg/L (P = 2.27E-10), whereas ESR levels declined from 64.1333 ± 38.8253 mm/h to 31.6 ± 16.5520 mm/h (P = 0.0041). A decline in these parameters shows the association of ascorbic acid in reducing the inflammatory response in cancer. The renal effect of ascorbic acid was also studied by analyzing the creatinine level pre- and postascorbic acid treatment sessions, and it raised from 0.8526 ± 0.22904 to 1.1666 ± 0.2894 mg/dL (P = 1.18E-14). This showed the renal impact of ascorbic acid. Conclusion: The study highlighted the clinical benefit of IV ascorbic acid in the reduction of inflammatory response in cancer patients. The renal adverse events associated with ascorbic acid alarm the use with caution and therapeutic drug monitoring for ascorbic acid.
... As for the calorie-restricted diet, KD was shown to lead to the downregulation of growth factors such as IGF-1 and insulin [60,61] and to influence gene expression [41], probably through inhibition of histone deacetylases [62]. A role of reactive oxygen species (ROS) has also been documented but both reduction and increase in oxidative stress were reported according to the models [39,63,64]. As discussed above, the most relevant sets of data related to the efficacy of KD in vitro are related to the ability of cancer cells to enzymatically process ketone bodies or not. ...
Article
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Specific diets for cancer patients have the potential to offer an adjuvant modality to conventional anticancer therapy. If the concept of starving cancer cells from nutrients to inhibit tumor growth is quite simple, the translation into the clinics is not straightforward. Several diets have been described including the Calorie-restricted diet based on a reduction in carbohydrate intake and the Ketogenic diet wherein the low carbohydrate content is compensated by a high fat intake. As for other diets that deviate from normal composition only by one or two amino acids, these diets most often revealed a reduction in tumor growth in mice, in particular when associated with chemo- or radiotherapy. By contrast, in cancer patients, the interest of these diets is almost exclusively supported by case reports precluding any conclusions on their real capacity to influence disease outcome. In parallel, the field of tumor lipid metabolism has emerged in the last decade offering a better understanding of how fatty acids are captured, synthesized or stored as lipid droplets in cancers. Fatty acids participate to cancer cell survival in the hypoxic and acidic tumor microenvironment and also support proliferation and invasiveness. Interestingly, while such addiction for fatty acids may account for cancer progression associated with high fat diet, it could also represent an Achilles heel for tumors. In particular n-3 polyunsaturated fatty acids represent a class of lipids that can exert potent cytotoxic effects in tumors and therefore represent an attractive diet supplementation to improve cancer patient outcomes.
... Therefore, KD is becoming a promising adjuvant support therapy for cancer treatment in recent years [14]. Indeed, it has reported that KD has been used in the adjuvant treatment of many different tumors, such as gastric cancer, prostate cancer or glioma, and had a positive therapeutic effect while no obvious adverse effects were observed [15][16][17][18]. Further studies showed that KD can limit the growth of tumor, enhance the effects of chemotherapy to tumor cells while reducing the toxicity of chemotherapy to normal cells [19], and attenuate the in ammatory level of tumor [20]. ...
Preprint
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Background: High-fat, low-carbohydrate and adequate-protein ketogenic diets (KD) are expected to become an effective adjunct therapy for cancer patients. However, the direct effects of KD on tumor cells and the underlying mechanisms are elusive. In this study, the nude mouse models of subcutaneous transplanted human colon cancer cells were established and applied to study the effects and mechanisms of KD on the growth of subcutaneous tumors in nude mice. Methods: Male nude mice were injected subcutaneously with human colon cancer HCT-116 cell line to construct a subcutaneous tumor model of human colon cancer. The successfully constructed subcutaneous tumor mice were divided into normal diet group and KD group. The mice were anesthetized and euthanized after 30 days of feeding, the subcutaneous tumor tissues were collected, and the size of tumors was measured and weighed. HE staining was used to observe the pathological changes of subcutaneous tumor tissues in normal feeding group and KD group. TUNEL staining was used to detect the level of apoptosis in tumor tissue. Immunohistochemistry of subcutaneous tumor tissues was used to detect the expression levels of Wnt-1 and β-catenin. In addition, RT-qPCR and western blotting were applied to detect the expression levels of Wnt1/β-catenin signaling pathway-related proteins. Results: After 30 days of normal diet and KD feeding, the subcutaneous tumor tissues of human colon cancer mice were taken out for various assays. The results of tumor size measurement showed that the tumor size and weight of KD group were significantly smaller than that of the normal diet group. HE staining showed that the pathological characteristics of colon tumor tissue in the KD group were significantly improved, and the infiltration of inflammatory cells was reduced. TUNEL staining showed that the apoptosis level of tumor cells in the KD group was significantly increased compared to the normal diet group. RT-qPCR and western blotting revealed that the expression of pro-apoptotic proteins such as caspase 3,caspase 9 and Bax were increased(P < 0.01), while the expression of anti-apoptotic protein such as Bcl-2 or survivin was decreased (P < 0.01). Furthermore, the expression of Wnt1/β-catenin signaling pathway-related proteins including Wnt1 and β-catenin were largely reduced after 30 days of KD feeding compared to normal feeding group (P < 0.01). Conclusions: Ketogenic diets (KD) promotes apoptosis of human colon cancer subcutaneous tumor cells and inhibits the growth of tumor by inhibiting Wnt1/β-catenin signaling pathway in mouse subcutaneous tumor models of human colon cancer.
... Many patients try to adapt their diets in order to fight cancer, reduce side effects and improve their prognosis [1]. While many physicians will not recommend extreme diets such as the total cure by Breuss (42 days drinking only veg- etable juice), the ketogenic diet (KD) seems to remain attractive from the professional point of view [2][3][4]. ...
Article
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