Calorie
restriction (CR) and a ketogenic diet (KD) target the same molecular
pathways that are also targeted individually by drugs to improve cancer
treatment outcomes. Arrows indicate activation, truncated lines
inhibition. Carbohydrate (CHO) restriction up-regulates fatty acid
oxidation and ketogenesis (beneficial for normal tissues) and impairs
glycolysis and glutaminolysis (detrimental to tumor cells). Full study here.
One of the truly exciting new frontiers in nutrition therapy is the study of the high-fat low-carb ketogenic diet, especially in relation to preventing and curing cancer. The ketogenic diet as a therapeutic diet is not new. It has been around at least since the 1920s, when researchers at John Hopkins discovered that the diet could cure some children from epileptic seizures where drugs had failed.
In 2013 we published a few stories highlighting new research showing the ketogenic diet’s value to cancer patients:
Study: Ketogenic Diet and Hyperbaric Oxygen Therapy Stops Cancer
Ketogenic Diet in Combination with Calorie Restriction and Hyperbaric Treatment Offer New Hope in Quest for Non-Toxic Cancer Treatment
The Benefits of a Ketogenic Diet and its Role in Cancer Treatment
Using the Ketogenic Diet to Heal Brain Tumors
Starving Cancer: The High-fat Ketogenic Diet
Many of these studies are looking at not only the ketogenic diet, but also the concept of intermittent fasting or calorie restriction. These are beneficial aspects to study, as generally they cannot be mimicked by drugs.There are indications that the way the ketogenic diet produces “ketones”, or the “ketogenic effect”, is being studied in order to produce pharmaceutical products (drugs or vaccines) that can mimic the same effect. With years of experience now documented in using the ketogenic diet with children suffering from seizures, one of the most common complaints is that the diet is difficult to adhere to, as the child has to abstain from refined carbohydrates and typical childhood sweets such as cakes and candies. The reasoning is that a drug would make life more bearable instead of following such a strict diet.
I am very encouraged by this recent study, published in January 2014, looking at the ketogenic diet and intermittent fasting as an adjunct nutritional therapy to be administered to cancer patients undergoing standard radiation therapy in cancer treatment. The study provides “dietary interventions” to be used along side “radiotherapy”. Therefore, this is not really a study that lends itself to developing more pharmaceutical drugs. However, will physicians in the allopathic medical field seriously consider rigorous diet therapy?
Of course, there are plenty of cancer therapies that are effective and non-toxic, but they are not covered by insurance companies in the U.S., and most of them are not approved by the FDA, so one must go south of the border into Mexico or travel to another country to receive the best non-toxic cancer therapies. (See: Cancer – The Forbidden Cures and Why Medicine Won’t Allow Cancer to Be Cured)
Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation
Cancer and Metastasis ReviewsJanuary 2014
Abstract
Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R’s of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K–Akt–mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K–Akt–mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.http://coconutoil.com/study-intermittent-fasting-and-ketogenic-diet-effective-in-cancer-therapy/
Cancer and Metastasis Reviews
© The Author(s) 2014
10.1007/s10555-014-9495-3
NON-THEMATIC REVIEW
Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation
(1)
Department
of Radiotherapy and Radiation Oncology, Leopoldina Hospital
Schweinfurt, Gustav-Adolf-Straße 8, 97422 Schweinfurt, Germany
(2)
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Published online: 17 January 2014
Abstract
Aggressive tumors typically
demonstrate a high glycolytic rate, which results in resistance to
radiation therapy and cancer progression via
several molecular and physiologic mechanisms. Intriguingly, many of
these mechanisms utilize the same molecular pathways that are altered
through calorie and/or carbohydrate restriction. Furthermore, poorer
prognosis in cancer patients who display a glycolytic phenotype
characterized by metabolic alterations, such as obesity and diabetes, is
now well established, providing another link between metabolic pathways
and cancer progression. We review the possible roles for calorie
restriction (CR) and very low carbohydrate ketogenic diets (KDs) in
modulating the five R’s of radiotherapy to improve the therapeutic
window between tumor control and normal tissue complication probability.
Important mechanisms we discuss include (1) improved DNA repair in
normal, but not tumor cells; (2) inhibition of tumor cell repopulation
through modulation of the PI3K–Akt–mTORC1 pathway downstream of insulin
and IGF1; (3) redistribution of normal cells into more radioresistant
phases of the cell cycle; (4) normalization of the tumor vasculature by
targeting hypoxia-inducible factor-1α downstream of the PI3K–Akt–mTOR
pathway; (5) increasing the intrinsic radioresistance of normal cells
through ketone bodies but decreasing that of tumor cells by targeting
glycolysis. These mechanisms are discussed in the framework of animal
and human studies, taking into account the commonalities and differences
between CR and KDs. We conclude that CR and KDs may act synergistically
with radiation therapy for the treatment of cancer patients and provide
some guidelines for implementing these dietary interventions into
clinical practice.
Keywords
Calorie restriction
Ketogenic diet
Metabolism
Radiotherapy
1 Background
Soon after the discovery of X-rays
by Wilhelm Conrad Röntgen in 1895, ionizing radiation was utilized for
cancer treatment. Today, it constitutes the standard of care for many
cancer patients, along with surgery and chemotherapy. Recently,
treatment outcomes have been improved in conjunction with a reduction in
toxicity through technological innovations such as intensity modulated
radiotherapy or stereotactic body radiotherapy. Despite these
advancements, several cancer types continue to elude modern treatment
techniques with radiation therapy (RT). Radioresistance of these tumors
can be ascribed to two factors: environmental and intrinsic. The former
include hypoxia, high lactate levels or the abundance of growth factors
within the cellular microenvironment. Intrinsic factors include
chronically activated proliferative, invasive, and antiapoptotic
signaling pathways. A commonality between all of these factors appears
to be the upregulation of glycolysis in cancer cells, resulting in the
increased influx of glucose and excessive production of lactate
regardless of partial oxygen pressure [1–3]. This phenomena was described nearly a century ago [4, 5], known as the Warburg effect, which affords cells both a high ATP generation and biomass synthesis [6]. It is the basic principle behind positron emission tomography (PET) with the glucose analog 2-(18F)fluoro-2-deoxy-d-glucose (FDG). PET studies have revealed that FDG uptake is inversely correlated with tumor control probability [7, 8] and overall survival [9], and areas with high FDG-PET have been suggested as targets for dose escalation with dose-painting RT [10].
The Warburg phenotype provides
tumors an enhanced resistance against cytotoxic insults. In fact, work
as early as 1933 has revealed that tumor cells have increased ability to
resist radiation damage in the presence of elevated glucose [11].
However, this may come at the expense of metabolic flexibility. Hypoxia
and genetic defects that chronically drive proliferation leave such
tumors dependent on a steady supply of nutrients, especially glucose.
Additionally, such tumors appear to benefit from pathological metabolic
conditions of their host, in particular hyperglycemia, hyperinsulinemia,
and elevated insulin-like growth factor (IGF)-1 levels [12, 13].
As a result, there has been recent enthusiasm towards metabolism-based
therapies targeting whole-body metabolism, cellular kinases and
glycolytic enzymes in order to sensitize these tumors to cytotoxic
insults like RT [14–16].
As nutrition is a major modulator of global and cellular metabolism, it
becomes apparent that nutritional interventions may impact cancer
progression. In this context, metabolic targeting via calorie restriction (CR) has been described as a promising synergistic treatment option [17–19].
CR has consistently been shown to extend life span in organisms from
yeast and worms to mice; furthermore, CR protects against age-related
diseases like cancer [20].
While the beneficial effects of CR on whole-body metabolism, including
improved insulin and glucose profiles, have been described for decades,
recent research has revealed that, on a cellular level, CR affects the
same molecular pathways as current biological agents proposed for
targeting cancer metabolism. Recent data from our group [21]
has revealed that caloric restriction in mice works synergistically
with RT to target and downregulate several of these pathways and to slow
tumor growth (Fig. 1).
In humans, as discussed below, these molecular effects seem to be
mediated mainly by the restriction of carbohydrates (CHOs) rather than
total energy, which provides a rationale for the application of a very
low carbohydrate, high-fat ketogenic diet (KD) in clinical practice [22].
Yet, the discussion of either CR or the KD as a low-cost and non-toxic
treatment with multiple molecular targets is lacking in most discussions
regarding metabolic targeting strategies.
Fig. 1
Nutrient deprivation via alternate day fasting (a) or overall caloric restriction (b) synergistically work with radiation therapy to significantly slow tumor growth and downregulate several key pathways (c). AL ad libitum feeding, CR calorie restriction (taken with permission from Saleh et al. [21])
The goal of this review is to
therefore enhance the awareness for the potential benefits of CR and a
KD as an adjunct to treatment for cancer patients during RT, and the
strong preclinical data revealing that these modalities may enhance the
efficacy of RT. Such benefits range from the cellular level to global
metabolism, and underline the link between tumor cell metabolism and
that of its host. Focus also lies on the commonalities and differences
between these dietary modifications that should be considered when
developing supplemental dietary treatment strategies.
2 Calories or carbohydrates? Similar metabolic effects of calorie restriction and the ketogenic diet
CR is usually defined as a 30–50 % reduction in energy intake without malnutrition compared to ad libitum
feeding. The caloric deficit can be induced either by intermittent
fasting (IF), the extreme form of which is water-only short term fasting
(STF), or chronic daily energy restriction (DER). However, as
preclinical data is extrapolated to humans for clinical research design,
it is important to point out that DER in mice corresponds to
therapeutic STF in humans. Along these lines, fasting for 1 day in the
mouse is roughly comparable to a 1-week water-only fast in a human [23].
Protein restriction leading to a negative nitrogen balance has been shown to mediate the decrease of IGF-1 during CR [24, 25], explaining the significant decrease in IGF-1 after STF or the initiation phase of a KD [26], but not after several weeks of a KD [27] or long-term CR with adequate protein intake [25]. However, most other metabolic effects of CR appear to result from the accompanying restriction of CHOs [28].
KDs were actually developed in the 1920s as a method of mimicking
fasting while avoiding malnourishment in the treatment of epilepsy [29]. The notion that KDs mimic the beneficial response to long-term fasting [30, 31] suggests the possibility to apply this dietary method to the oncological setting when weight loss must be avoided [22]. As displayed in Fig. 2,
CHO restriction, whether through CR or a KD, decreases serum glucose
and insulin levels, which increases lipolysis and leads to fatty
acid-mediated activation of peroxisome proliferator-activated receptor α
(PPARα). PPARα inhibits glycolysis and fatty acid synthesis, while
promoting the transcription of enzymes that increase ketogenesis and
mitochondrial and peroxisomal fatty acid oxidation [32].
The drop in insulin levels that accompanies the reduction in CHOs
lowers the bioavailability of IGF-1 through increased transcription of
IGF binding protein (IGFBP)-1 [33].
When insulin and free IGF-1 bind to their specific tyrosine kinase
receptors they activate the phosphatidylinositol-3 kinase
(PI3K)–Akt–mammalian target of rapamycin complex 1 (mTORC1) signaling
pathway to promote many of the hallmarks of cancer including sustained
proliferative signaling, resisting cell death and altered cellular
metabolism including increased fermentation of glucose and glutamine [34]. mTORC1 downregulates ketogenesis through its inhibitory action on PPARα [35].
This action is counteracted during metabolic stress induced by CR or
glucose withdrawal which decreases the intracellular ATP/AMP ratio and
activates liver kinase B1 (LKB1)–adenosine monophosphate-activated
protein kinase (AMPK) signaling. AMPK inhibits mTORC1 either directly
through phosphorylation of the regulatory-associated protein of mTOR
(Raptor) or indirectly by phosphorylating the mTOR inhibitor tuberous
sclerosis complex protein-2 (TSC2). Increased lipid oxidation resulting
from AMPK activation also increases the NAD+/NADH ratio thus amplifying the activity of the NAD+-dependent deacetylase silent mating type information regulation 2 homologue 1 (SIRT1) [36].
SIRT1 influences cellular lifespan and metabolism through epigenetic
regulation of gene transcription and posttranslational protein
modifications. Molecular targets of SIRT1 include LKB1 and peroxisome
proliferator-activated receptor γ co-activator α (PGC1α), which is also
activated through AMPK-mediated phosphorylation at Ser538 and Thr177 and
cooperates with PPARα to induce mitochondrial biogenesis. This was
demonstrated recently by Kitada et al. [37]
in human skeletal muscle cells treated with serum obtained from four
healthy obese subjects after a 25 % DER intervention lasting 7 weeks.
Compared to treatment with serum obtained at baseline, there was a
significant increase in AMPK, SIRT1, and PGC1α-mediated mitochondrial
biogenesis. In addition, significantly higher levels of phospho-AMPK and
phospho-SIRT1 were measured in peripheral blood mononuclear cells
compared to baseline. Thus, CR and CHO withdrawal activate an energy
sensing network consisting of AMPK, SIRT1, PPARα and PGC1α that promotes
mitochondrial function and counteracts the
insulin/IGF-1–PI3K–Akt–mTORC1 pathway. Studies by Draznin et al. [38] and Bergouignan et al. [39]
suggest that CHO restriction alone, and even in the presence of caloric
overconsumption, is sufficient for the activation of this network in
human muscle cells, in line with the finding that AMPK is sensitive not
only to the intracellular ATP/AMP ratio, but also to glycogen stores [40]. Studies have revealed increased phospho-AMPK levels in the liver, but not brain of rats fed a KD [41] and in the liver, but not epidermis or prostate of mice fed a 30 % CR diet [42],
which implies tissue-dependent effects of CHO restriction on AMPK
activation. Nonetheless, Akt and mTOR signaling were decreased by either
the KD or CR in all of these tissue sites, again indicating the common
effects of calorie and CHO restriction at the cellular level. Thus, CR
and likely KDs target the same molecular pathways that are also targeted
individually by drugs to improve cancer treatment outcomes, including
Akt, mTOR, and AMPK (Fig. 2).
Fig. 2
Calorie restriction (CR) and a ketogenic diet (KD) target the same molecular pathways that are also targeted individually by drugs to improve cancer treatment outcomes. Arrows indicate activation, truncated lines inhibition. Carbohydrate (CHO)
restriction up-regulates fatty acid oxidation and ketogenesis
(beneficial for normal tissues) and impairs glycolysis and
glutaminolysis (detrimental to tumor cells). See Section 2 for more details
3 How calorie and carbohydrate restriction may influence the response to radiotherapy
Most often, RT is applied in a
fractionated fashion with typical doses per fraction in the range of
1.8–3 Gy. The biological rationale behind fractionated RT is based on
exploiting the different responses between fast proliferating tumors and
slowly proliferating normal tissue (Fig. 3). The factors underlying these responses are known as the “five R’s of radiobiology” (Fig. 4):
Repair of sublethal DNA damage; Repopulation of the tumor;
Redistribution of cells to different phases of the cell cycle;
Reoxygenation of hypoxic tumor areas; and finally, intrinsic
Radioresistance as suggested by Steel et al. [43].
The goal of RT is to utilize these factors in order to maximize the
therapeutic window under the constraints of sufficiently large tumor
control probability (TCP) and acceptable normal tissue complication
probability (NTCP). Any additional intervention that increases TCP for a
given dose while keeping NTCP constant, decreases NTCP at a given dose
while keeping TCP constant, or both, will likely enhance treatment
efficacy (Fig. 3).
However, many pharmaceutical interventions do not increase the
therapeutic window as they are often exceedingly unspecific and increase
both TCP and NTCP at a given prescribed dose. In contrast, favorable
treatment outcomes through a combination of CR [21, 44] or the KD [45, 46]
with RT have been described in the literature. Data has demonstrated
that CR or its pharmaceutical mimetic protects normal cells and
sensitizes cancer cells to various common chemotherapeutic drugs;
remarkably, this so-called differential stress resistance was observed
across a wide range of normal and tumor cell lines, mouse strains and
even humans [44, 47–51].
Apart from their direct relevance for patients undergoing simultaneous
chemoradiation, these findings also suggest that CR or the KD may
influence the five R’s of radiobiology (Fig. 4) in a manner that increases the therapeutic window.
Fig. 3
Illustration of a typical tumor control probability (solid blue line) and normal tissue complication probability (red solid line)
curve as a function of total dose delivered to the tumor. We argue that
CR and possibly a KD may increase the therapeutic window by favorably
affecting both curves, i.e. a differential response between tumor and normal tissue
Fig. 4
The five R’s of radiobiology
3.1 DNA damage repair
The interaction of ionizing
radiation with molecules in tissue leads to the production of free
electrons, leaving behind charged molecules with unpaired valence
electrons called radicals. Radiolysis of water is the most frequent
ionization event outside of the DNA and leads to the formation of
reactive oxygen species (ROS) including the hydroxyl radical (OH•) and its reaction product with oxygen, hydrogen peroxide (H2O2).
ROS are able to diffuse to and oxidize DNA at various sites including
the sugar-phosphate backbone leading to single (SSBs) and double strand
breaks (DSBs). While a single lesion can usually be repaired and is
considered sublethal, accumulation of sublethal lesions with increasing
dose can lead to their interaction and conversion to lethal lesions.
Differences between tumors and normal tissues in the ability to repair
sublethal damage are therefore an important rationale for fractionated
RT.
Numerous studies suggest that CR enhances DNA repair of sublethal damage in normal tissues (reviewed in Ref. [52]),
implying a role for CR in limiting toxicity to normal tissues during
RT. Along these lines, CR may impact DSB repair, which is vital for cell
survival between fractions [53].
The repair of DSBs is achieved by two different mechanisms known as
non-homologous end joining (NHEJ) and homologous recombination repair
(HRR). During NHEJ, the DSB ends are quickly recognized and bound by the
Ku protein which subsequently recruits the catalytic subunit of the
DNA-dependent protein kinase (DNA-PKcs) to form the DNA-PK holoenzyme.
Binding to DNA triggers the kinase activity of DNA-PK which recruits and
activates other proteins in order to clean and rejoin the DNA ends.
Final ligation is carried out by the interaction of the XRCC4, ligase IV
and XLF proteins. Although it can utilize short homologous sequences of
up to 4 bp when possible, NHEJ does not necessarily conserve DNA
sequences and is considered error-prone. In contrast, HRR is an
error-free repair mechanism which requires DNA homology. It is therefore
mostly efficient during and shortly after DNA replication in late S and
G2 phases of the cell cycle when sister chromatids are available. It
follows that HRR is an important pathway against DSB-induced lethality
in fast proliferating tumors.
A dose of 1 Gy photon irradiation yields approximately 1.000 SSBs and 40 DSBs in a cell’s nucleus [54],
a number that can be greatly enhanced through the combination with
chemotherapeutic drugs. As noted previously, differential stress
resistance between normal tissue and tumor cells has been observed when
STF was combined with chemotherapy [44, 47–51].
STF likely selectively improves DSB repair in normal but not cancer
cells. In the lung, liver, spleen, and kidney of aging rats, CR
attenuated the decline of NHEJ activity [55];
this coincided with increased levels of XRCC4 in these tissues. Other
NHEJ proteins like XLF and Ku may be upregulated by CR in a
tissue-dependent manner [55, 56]. Like other DNA stress response genes, XRCC4 appears to be a target of the forkhead box O (FOXO) transcription factor family [55], which has been implicated with the antitumoral effects of CR [57].
FOXO-mediated transcription of stress response proteins is positively
regulated by deacetylation through SIRT1, while phosphorylation through
Akt leads to its nuclear exclusion and degradation. Furthermore, upon
radiation-induced DNA damage SIRT1 binds to and deacetylates the repair
protein Ku70, which enhances the efficacy of DSB repair [58].
Thus, CR and possibly a KD may positively affect NHEJ in normal tissue
by increasing SIRT1 activity and decreasing insulin/IGF-1–PI3K–Akt
signaling (Fig. 2).
These protection mechanisms are likely defective in tumor cells with
self-sufficiency in growth signals and constitutively activated PI3K–Akt
pathway [50, 59].
Contrary to this, it is possible that CR impairs DSB repair in tumor cells and thus contributes to increased cell death. Chen et al.
showed that mTOR inhibition through rapamycin or everolimus impairs
both HRR and NHEJ in MCF7 breast cancer cells, without significant
alterations in several important DNA repair proteins [60].
Importantly, a dose-dependent effect of CR on mTOR inhibition mediated
by AMPK was also observed in a rat model of breast cancer [61], suggesting that fasting might have similarly negative effects on DNA repair capacity in mammary tumors as rapamycin. Song et al. incubated mouse fibrosarcoma cells with 5 mM metformin for 24 h before and after irradiation [62].
The treated cells exhibited a steeper survival curve with a narrower
shoulder, indicating increased accumulation of sublethal lesions at a
given dose and suggesting impaired DNA repair.
In summary, CR has been shown to
enhance various DNA repair mechanisms in normal tissues including HRR
and NHEJ, which are essential for RT-induced DSB repair. In contrast,
repair capacity in cancer cells may be left unaffected or even
attenuated through CR. The differential stress resistance between normal
and cancerous cells to chemotherapeutic drugs seems to be mediated at
least in part by decreased glucose and free IGF-1 levels [47, 50];
it could therefore be speculated that the KD might achieve similar
effects, although this would have to be investigated in future studies.
3.2 Repopulation of the tumor cells
Repopulation, i.e.,
the cell proliferation occurring during the course of fractionated RT,
occurs in both tumors and normal tissue, and provides the biological
rationale behind altered fractionation schedules in certain cancer types
such as accelerated fractionation in head and neck squamous cell
carcinoma or hypofractionation in non-small cell lung cancer [63].
Such cancers respond to RT with an increase in tumor doubling times and
hence accelerated proliferation during extended treatment times,
therefore decreasing the TCP. Radiobiological modeling suggests that any
strategy that delays the onset and/or decreases the rate of tumor
repopulation could increase TCP at a given NTCP or decrease the late
responding NTCP through the application of smaller doses in the presence
of a larger number of fractions without impairing TCP [64]. Figure 3
demonstrates this effect qualitatively if one assumes the solid blue
curve to be the TCP with accelerated repopulation starting within the
treatment period. The dashed blue curve would indicate the lack of this
effect, i.e., a delay in the
onset of accelerated repopulation to a time point after finishing the
treatment. A quantitative calculation for non-small cell lung cancer
based on the linear-quadratic formalism was performed by Fowler et al. [65],
demonstrating that the TCP would be roughly doubled for a typical dose
of 70 Gy given in 2-Gy fractions if accelerated repopulation of the
tumor could be delayed long enough.
CR in rodents reduces
IGF-1/insulin–PI3K–Akt–mTor signaling which has been shown to be
correlated with significant tumor growth delay [21]. CHO restriction in patients with advanced cancer has also revealed downregulation of this pathway [66].
The causal and important role of this pathway in promoting tumor
progression is exemplified by the fact that CR combined with IGF-1
administration [67] or constitutive PI3K activation through genetic mutations [59]
rescues tumors from growth inhibition induced by CR. We recently
reviewed the large number of animal studies showing the potential of CR [19] and KDs [22]
to delay and retard tumor growth and even metastasis, often without
additional treatment. CR in mice is able to slow tumor growth by 50–80 %
though it is important to note that the majority of these studies
reduced CHO within the diet and replaced it with fat. It still remains
unclear if and to what extend these findings translate to humans, the
more so as available data suffer from small sample sizes. A
retrospective analysis of five patients with tuberous sclerosis complex
yielded mixed results concerning tumor progression during a KD and in no
case tumor regression was achieved [68]. Other data are more supportive for targeting tumor cell proliferation through CHO restriction. Rossi-Fanelli et al. [69]
showed that a high-fat diet (80 % non-nitrogenous calories from fat)
inhibited tumor cell proliferation while a high-dextrose diet (100 %
non-nitrogenous calories from dextrose) increased proliferation over
14 days in patients with gastrointestinal cancers, though patient
numbers were too small to reach statistical significance. Diets were
administered parenterally and cell proliferation was assessed using
thymidine labeling index on tumor samples, which measures the fraction
of cells in the S phase as a proxy for de novo DNA synthesis. Zuccoli et al.
reported on a female patient with GBM undergoing two therapeutic fasts
followed by a KD restricted to 600 kcal/day and concomitant RT and
temozolomide treatment [70].
This intervention stopped tumor growth completely as judged by MRI and
PET imaging, but tumor recurrence occurred 10 weeks after suspension of
this diet.
Fast proliferating cancer cells
rely on a high glycolytic rate in order to shuffle phosphometabolites
into the pentose phosphate pathway for biosynthesis of nucleic acids and
lipids. Activation of PPARα by KD or CR promotes ketosis and inhibits
glycolysis, therefore abating proliferation in tumor cells. In normal
cells, abundant acetyl-CoA from the breakdown of ketone bodies and fatty
acids inhibits glycolysis to ensure stable ATP levels; tumor cells
which often have dysfunction mitochondria lack this flexibility and
quickly die when confronted with glucose withdrawal [71–76]. This was exemplified in a study by Fine and colleagues [77],
revealing that overexpression of uncoupling protein (UCP) 2, a common
defect in tumor mitochondria, rendered these cells vulnerable to
treatment with the ketone body acetoacetate [77].
In these cells, the decrease in glycolytic ATP production cannot be
compensated by oxidative phosphorylation, leading to ATP depletion and
cell growth inhibition. FDG-PET studies in cancer patients on a KD
confirmed that CHO restriction with subsequent insulin inhibition and
ketosis inhibits tumor glycolysis in vivo [66, 70, 78]. The importance of ketone bodies was thereby demonstrated by Fine and co-workers [66]
who found a statistically significant correlation between the level of
ketosis and partial remission or stable disease on PET scans after a
4-week KD in nine patients with prior rapid disease progression.
In conclusion, CR and KDs have
shown significant inhibitory effects on tumor growth in animal studies
which would predict a left-shift of the TCP curve (Fig. 3).
Based on mechanistic insights that the IGF-1/insulin–PI3K–Akt–mTORC1
pathway and glycolysis play a key role for tumor cell proliferation and
supported by positive evidence from small patient studies we hypothesize
that CR and KDs could be used as supportive strategies to target tumor
cell repopulation during RT.
3.3 Redistribution in the cell cycle
Normal cells interrupt typical
cell cycling after exposure to ionizing radiation in order to allow for
enough time for DNA repair, or in case of extreme or irreparable damage,
prepare for cell death or senescence. Transition from one phase of the
cycle into the other is regulated by a family of kinases known as
cyclin-dependent kinases (CDKs), whose activity is regulated through
three mechanisms: (1) association with phase-dependent proteins called
cyclins; (2) phosphorylation and de-phosphorylation; (3) inhibition by
CDK inhibitors such as p21. Cells are most sensitive to DNA damage
during replication and mitosis, i.e.,
the S and M phases of the cycle, respectively. Therefore, phases
preceding mitosis utilize a variety of molecular pathways known as
checkpoints to ensure that necessary steps for a phase have been
completed and no severe DNA damage has gone unrepaired. In tumor cells,
checkpoints are often overridden by oncogenic activation of
proliferative signaling via PI3K-Akt [79, 80] and/or loss-of-function of gatekeeper genes like TP53.
It follows that with increasing RT fraction number, ionizing radiation
leads to a decreasing fraction of normal cells in sensitive S and M
phases while tumor cells are mostly unaffected by redistribution.
With a mutation rate of more
than 50 %, the transcription factor p53 is the most frequently mutated
gene in tumors. Important transcriptional targets of p53 include p21 and
the growth arrest and DNA-damage-inducible protein Gadd45a, two CDK
inhibitors that promote G1 and G2 arrest, respectively. p53 is strongly
connected to the Warburg phenotype [81] and provides a rationale for the use of cycle-dependent chemotherapy. p53 mutations disrupt cytochrome c
function, thus decreasing respiration. This leads to compensatory
fermentation or the Warburg effect which can be targeted by glucose
restriction. Apontes et al. [82]
showed that rapamycin and metformin acted synergistically to induce
G1/G2 arrest and protect normal cells under both normal and low glucose
conditions against the mitotic inhibitor nocodazole, a drug causing
lethal mitotic arrest; in contrast, the same treatment did not protect
MDA-MB-231 breast cancer cells expressing mutant p53, and even was toxic
under low glucose conditions. In addition to p53, other frequent
mutations in cancer cells are responsible for constitutive activation of
the PI3K–Akt pathway. These cells are able to overcome both the G1/S
and G2/M checkpoints normally induced by DNA damage, and continue to
divide [79, 80]. However, such cells may selectively be targeted by glucose withdrawal. Shim et al. [72]
showed that c-Myc transformed cells underwent apoptosis upon glucose
restriction, while normal cells remained intact in G0/G1 cell cycle
arrest. Glucose restriction was also shown to exert opposite epigenetic
effects upon human telomerase reverse transcriptase and the cell cycle
regulator p16 between immortalized and normal fetal lung fibroblasts,
such that the former underwent apoptosis while the latter responded with
an extension of lifespan [74]. The same authors later identified SIRT1 as a key regulator of this mitigation of p16 in normal cells [83].
Paradoxically, fasting seems to stimulate the translation of genes
involved in growth and proliferation and to further increase
phosphorylation of Akt in oncogene-activated cells [51].
However, though this may appear to be “adding fuel to the fire” and
driving tumor growth, it also demands increased energy production which
eventually leads to an increase in ROS and cell death under low nutrient
and growth factor conditions [51, 73, 76].
Conversely, in normal cells, the
decrease of mitogenic stimuli induced by CR and perhaps to a lesser
extent, the KD favors redistribution into a non-dividing state in order
to preserve and redistribute energy for cellular protection mechanisms [50]. This finding can be exploited clinically by having patients fast prior to each RT session and/or chemotherapy cycle [48, 49]. Safdie et al.
reported that fasting before and/or after chemotherapy decreased
symptoms of weakness and fatigue, while reducing gastrointestinal side
effects when compared to a normal diet in six cancer patients undergoing
a median of four cycles of chemotherapy [48]. In C57BL/6J mice, CR upregulated Gadd45a and p21 in a FOXO1-dependent manner [57].
However, tumors with FOXO inactivation due to hyperactive PI3K–Akt
signaling would be unable to benefit from CR-induced cell cycle arrest
under irradiation, providing a further opportunity to widen the
therapeutic window.
In summary, CR arranges a
redistribution of normal cells in the cell cycle, potentially protecting
them from subsequent DNA damaging insults like RT. The situation in
tumor cells seems quite contrary. Here, fasting seems to promote cell
cycle progression, M phase accumulation and energy expenditure, in this
way rendering such cells synthetically vulnerable to the combination of
nutrient restriction with RT or chemotherapy.
3.4 Reoxygenation
A major challenge for RT is the
presence of hypoxic areas within solid tumors. The lack of oxygen
molecules within these regions inhibits the formation of H2O2 from OH•,
thus lessening the frequency and severity of DNA damage. A single
fraction of irradiation preferentially kills the well-oxygenated cells,
but reoxygenation of hypoxic areas occurs during fractionated treatment
in part due to tumor shrinkage. Hypoxia facilitates DNA repair and leads
to stabilization of the α-subunit of hypoxia-inducible factor (HIF)-1, a
transcription factor that lies downstream of mTOR and upregulates
glycolysis [84].
The Akt–mTOR pathway upregulates the translation of HIF-1α mRNA in a
glucose- and reoxygenation-dependent manner after irradiation [85].
Tumors possess a heterogeneous
network of abnormal blood vessels characterized by chaotic anatomical
arrangement, dead ends, and increased leakiness which leads to increased
interstitial fluid pressure [86].
This results in areas with both chronic and acute hypoxia, the former
occurring where oxygen supply is limited by diffusion from proximal
blood vessels, and the latter where perfusion is transiently
constricted. The abnormal vasculature is caused by an excess of
pro-angiogenic signaling mainly due to vascular endothelial growth
factor 2 (VEGF). VEGF is another target of HIF-1α, but its transcription
is also increased through epigenetic modulation by inflammatory
cytokines, growth factors, and sex hormones. Contrary to what may be
expected from inhibiting VEGF and therefore new blood vessel formation,
evidence has accumulated supporting the hypothesis that anti-VEGF
therapy actually decreases hypoxia and facilitates the delivery of
chemotherapeutic drugs to cancer cells by normalizing the vasculature
which in turn normalizes the microenvironment [86].
Since VEGF is upregulated as a
consequence of Akt–mTOR–HIF-1α signaling, any strategy that inhibits
this pathway can be hypothesized to lower VEGF expression and tumor
progression. Mukherjee, Seyfried, and colleagues have reported that CR
downregulates VEGF and normalizes vascularization across a range of
several rodent and human prostate and brain tumors [87–89].
In the CT-2A mouse astrocytoma, CR increased the perivascular cell
coverage of blood vessels, insinuating decreased leakiness, less
interstitial fluid pressure, and better drug delivery to the tumor [89].
Hyperbaric oxygen therapy (HBOT)
is another approach to overcome hypoxia. The principle of HBOT
encompasses breathing hyperbaric oxygen during irradiation in order to
oxygenate and radiosensitize hypoxic cancer cells. A recent Cochrane
review concluded that HBOT combined with RT may improve local control in
head and neck and cervical cancers, but at the expense of significant
adverse effects [90]. Recently, Poff et al.
evaluated the combination of HBOT with a KD in the murine VM-M3 model
of metastatic cancer which closely mimics several aggressive human
cancers [91]. Interestingly, despite ad libitum
feeding, mice on the KD lost about 10 % body weight, suggesting
involuntary under-eating. While the KD alone increased mean survival
time by 57 %, the combination of HBOT + KD increased survival time by
78 % compared to a standard diet. The translation of these results into
clinical practice remains an open question. It can at least be
hypothesized that ketone bodies might attenuate additional oxidative
stress to normal tissues [92–94] but not cancer cells, which are unable to metabolize them [95–98].
3.5 Intrinsic radiosensitivity
The Warburg effect seems to be a
hallmark of radioresistant cancer cells. FDG uptake by tumors is a
negative predictor of local control [7, 8] and survival [9], and is employed to guide the contouring of particularly radioresistant areas for dose escalation [10].
The high glycolytic rate appears to protect cancer cells from
ROS-induced DNA damage by supplying large amounts of reducing
equivalents like pyruvate, lactate, gluthatione, and NAD(P)H that
scavenge ROS molecules [1]. Quantifying lactate via
bioluminescence imaging in more than 1,000 individual xenografts of
human HNSCC, Sattler and colleagues demonstrated that intra-tumoral
lactate concentrations were significantly inversely correlated with
tumor control after a 6-week RT schedule [99].
However, no such correlation was found for pyruvate, which can be
explained by the fact that its concentration in tumors is much lower
than that of lactate.
Ketone bodies and fatty acids inhibit glycolysis [32],
which is why both fasting and the KD have the potential to target the
antioxidative defense mechanisms outlined above. There is also evidence
that due to dysfunctional mitochondrial electron transport chains, many
cancer cells possess high steady state levels of ROS that quickly lead
to cell death once glycolysis is impaired [46, 73]. On the other hand, oxidation of ketone bodies in peripheral tissue decreases the NADP+/NADPH ratio, which increases the amount of reduced gluthatione available for scavenging H2O2 [93].
This antioxidative property of ketone bodies would not benefit tumor
cells which lack the necessary enzymes to metabolize them [95–98].
Furthermore, Shimazu and colleagues showed that beta-hydroxybutyrate
(BHB) levels achievable after a several days fast or KD potently
protected the kidneys of mice from oxidative stress measured by both
protein carbonylation and lipid peroxidation [94].
The action of BHB and, to a lesser extent acetoacetate, was thereby
related to their roles as class I and II histone deacetylase inhibitors,
leading to histone acetylation with subsequent transcriptional
activation of antioxidant genes like metallothionein and Foxo3a. Finally, the activation of the histone deacetylase SIRT1, which in humans occurs after CR [37], or more generally, CHO restriction [38, 39], has been shown to prevent H2O2-induced hyperacetylation of p53 in skeletal muscle cells, therefore protecting against oxidative stress in these tissues [37].
Cancer stem cells possess the
highest intrinsic radiosensitivity and have been implicated in the
failure to achieve local control, yet studies characterizing their
metabolic phenotype are scarce. A recent study by Vlashi et al.
suggests that such cells possess high metabolic flexibility and readily
switch between glycolysis and oxidative phosphorylation if only one of
these pathways is targeted [100].
This might indicate that—at least in the case of certain gliomas—CR or a
KD alone is not sufficient to decrease ATP content and radioresistance
in cancer stem cells.
4 Clinical implementation
Dietary strategies that involve
reducing food intake during cancer treatment leave the treating
physician with trepidation as data has revealed that weight loss during
treatment leads to poorer outcomes [101].
While significant weight loss from CR is a concern, fat loss in
overweight patients during and after treatment may lead to an improved
outcome as excessive adipose tissue in breast cancer patients may help
fuel tumor cells [102].
However, recent data reveals that a CHO-restricted or KD may have a
greater effect on attenuating metabolic factors associated with
increased failure rates of RT, while avoiding the concern of both
physician and patient in regards to severely restricting calories [103].
Most CR studies in animals employ a
reduction in calories by 30 % or greater, and as discussed previously,
such a restriction in mice is roughly comparable to a 1 week water-only
fast in humans [23],
both options that may not be reasonable for the cancer patient. This
issue may be minimized through IF around RT treatments, as it results in
less weight loss when used for periods of 2–3 months [51],
similar to RT treatment times. Other pertinent issues include possible
toxicity from CR, as chronic CR may decrease immune function [104] and impair wound healing [105],
both issues for the post-operative and immunocompromised patient.
Patients on a KD must also be closely monitored to ensure sufficient
vitamins and nutrients are consumed for immunoprotection and adequate
healing.
One of the first CR studies fasted
conscientious objectors to WWII to 1,500 kcal/day while increasing
their activity, leading to severe cachexia, malnourishment, and
psychological detriment [106].
Such limits would be similar to those recommendations of 30 % or
greater reduction in calories to achieve CR. While these patients were
engaging in activity to increase their metabolic rate, this may not be
dissimilar from the physiologic state resulting from a metabolically
active tumor. The GBM patient on a KD reported by Zuccoli et al. was calorically restricted to 600 kcal/day [70].
Such limits on calories are not feasible in most oncologic settings,
and more reasonable methods to achieve the metabolic effects of CR,
without the potential of severe malnourishment and toxicity, include IF
and CHO restriction [107]. Along these lines, preclinical data have revealed that the replacement of CHOs with fat may actually reduce cachexia [108], and clinical data have shown weight gain in pancreatic [109] and gastrointestinal [110]
cancer patients with fat supplementation. However, patients must be
assessed to ensure they can adequately tolerate a diet exceedingly high
in fat (Fig. 5).
We recently found that 5 weeks of a self-prescribed KD in healthy
volunteers significantly increased bioelectrical phase angle [111], which is a proxy for muscle mass and a strong predictor of survival in cancer patients [112, 113].
Furthermore, randomized dietary studies in noncancer patients have
revealed a significant decrease in blood glucose and the insulin pathway
with a non-calorically but CHO-restricted diet versus a low-fat, calorically restricted diet [reviewed in Ref. 114].
Even caloric excess by 40 % in conjunction with CHO restriction appears
to result in AMPK upregulation, pointing towards CHO and not calories
as the prime target of dietary intervention [38].
Fig. 5
Proposed workflow of implementing dietary manipulation for cancer patients based on the results from an initial assessment
5 Conclusions
Dietary manipulation through CHO
restriction, CR, and a KD may enhance the efficacy of radiation therapy
by exploiting the five R’s of radiotherapy, while simultaneously
reducing treatment-related toxicity. The treating physician, however,
must weigh the benefits and risks of each dietary intervention, as each
may be suitable in varying situations. While there is an ample amount of
preclinical data, and clinical data continues to accumulate, further
studies must take place comparing the different methods of dietary
manipulation during radiation treatment and assessing their impact on
tumor progression.
Conflicts of interest statement
No conflicts of interest exist.
Open Access
This article is distributed under the terms of the Creative Commons
Attribution License which permits any use, distribution, and
reproduction in any medium, provided the original author(s) and the
source are credited.
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