Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
cancer is predicted to overtake heart disease as the leading cause of death in Western societies
cancer can also be recognized as a metabolic disease.
glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
Otto Warburg first proposed that all cancers arise from damage to cellular respiration
The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
Glucose and glutamine act synergistically for driving rapid tumor cell growth
Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
reason to eliminate glutamine in cancer patients and even GSH with cancer patients
It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
Ketone bodies and fats are non-fermentable fuels
Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
Apoptosis under energy stress is greater in tumor cells than in normal cells
A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
. This energy stress acts as a press disturbance
Drugs that target availability of glucose and glutamine would act as pulse disturbances
Hyperbaric oxygen therapy can also be considered another pulse disturbance
The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
Protein amino acids can be metabolized to glucose through the Cori cycle
The fats in KDs used clinically also contain more medium chain triglycerides
Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
GKI values of 1.0 or below are considered therapeutic
The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
Ketones are much more than energy adaptabilit, but actually are therapeutic.
ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
Ketone supplementation has also been shown to reduce anxiety behavior in animal models
This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
oxaloacetate is a glycolytic inhibitor, as is doxycycline, and IVC.
A synergistic interaction of the KD diet plus radiation was seen
It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
GBM and use glutamine as a major fuel
Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
radiation from mammograms shown to increase cancer risk in those with BRCA mutations. IN this cohort, the risk was found in those under 30 years of age. In this study, they suggested MRI as a safer alternative. But, what about thermograms?
Androgen deprivation therapy increases fatal heart attack risk in those with prostate cancer. Also of note, the ADT therapy group did not provide a survival benefit over that of radiation alone.