Numerous studies show that dietary energy restriction is a general metabolic therapy that naturally lowers circulating glucose levels and significantly reduces the growth and progression of numerous tumor types, including cancers of the breast, brain, colon, pancreas, lung, and prostate. (245-251) An impressive body of evidence indicates that dietary energy restriction can retard the growth rate of many tumors regardless of the specific genetic defects expressed within the tumor. (245-251) Hyperglycemia with high insulin levels is associated with tumor recurrence. (58, 252) Sugar sweetened beverages are associated with an increased risk of cancer. (253-255) Both experimental and clinical data suggest that fructose, particularly fructose-corn syrup, to be more carcinogenic than glucose. (229, 256, 257)

As demonstrated by Dr. Otto Warburg, almost all cancer cells are dependent on glucose as a metabolic fuel via aerobic glycolysis, (21, 22) with hyperglycemia being a potent promotor of tumor cell proliferation and associated with poor survival. (258) Although the mechanisms responsible for the caloric-restriction-mediated reduction in tumorigenesis have not been unequivocally identified, they may involve caloric-restriction-induced epigenetic changes as well as changes in growth signals and in the sirtuin pathway. (259)

Insulin resistance plays a major role in the initiation and propagation of cancer. (260) Reversing insulin resistance is therefore a major goal in patients with cancer. Dietary energy restriction specifically targets the IGF-1/PI3K/Akt/HIF-1α signaling pathway, which underlies several cancer hallmarks including cell proliferation, evasion of apoptosis, and angiogenesis. IGF-1 production is stimulated by growth hormone (GH) and can be inhibited by calorie restriction, suggesting it could play a central role in the protective effect of calorie restriction. In this regard, humans with mutations in the GH receptor (known as Laron syndrome) have low serum IGF-1 levels, and have a remarkably low risk of developing cancer. (259) Glucose reduction not only reduces insulin but also reduces circulating levels of IGF-1, which is necessary for driving tumor cell metabolism and growth. In diabetics, those on insulin or insulin secretagogues were demonstrated to be more likely to develop solid cancers than those on metformin. (261)

Dietary energy restriction targets inflammation and the signaling pathways involved with driving tumor angiogenesis. Indeed, calorie restriction is considered a simple and effective therapy for targeting tumor angiogenesis and inflammation. Calorie restriction results in the downregulation of multiple genes and metabolic pathways regulating glycolysis. Besides lowering circulating glucose levels, dietary energy restriction elevates circulating levels of fatty acids and ketone bodies (β-hydroxybutyrate and acetoacetate). Fats, and especially ketones, can replace glucose as a primary metabolic fuel under calorie restriction. This is a conserved physiological adaptation that evolved to spare protein during periods of starvation. Many tumors, however, have abnormalities in the genes and enzymes needed to metabolize ketone bodies for energy. Elevation in ketone bodies is well known to be able to suppress blood glucose levels and glycolysis, which are major drivers of tumor growth. A transition from carbohydrates to ketones for energy is a simple way to target energy metabolism in glycolysisdependent tumor cells while enhancing the metabolic efficiency of normal cells. 

Metabolism of ketone bodies and fatty acids for energy requires inner mitochondrial membrane integrity and efficient respiration, which tumor cells largely lack. Under fasting conditions, ketone bodies are produced in the liver from fatty acids as the main source of brain energy. Ketone bodies bypass the glycolytic pathway in the cytoplasm and are metabolized directly to acetyl CoA in the mitochondria.

The ketogenic diet is a high-fat, low-carbohydrate diet with adequate protein and calories originally developed in the 1920s as a treatment for intractable epilepsy.(262) The traditional ketogenic diet is a 4:1 formulation of fat content to carbohydrate plus protein. (262) A classic 4:1 ketogenic diet delivers 90% of its calories from fat, 8% from protein and only 2% from carbohydrate. Ketogenic diets of the 1920s and 1930s were extremely bland and restrictive diets and, therefore, prone to noncompliance. In recent years, alternative keto-genic protocols have emerged, making adherence to the diet much easier.(263) Alternatives to the traditional keto-genic diet include a medium-chain triglyceride (MCT)-based ketogenic diet and the Atkins diet. Compared to long-chain triglycerides, MCTs are more rapidly absorbed into the bloodstream and oxidized for energy because of their ability to passively diffuse through membranes. Another characteristic of MCTs is their unique ability to promote ketone body synthesis in the liver. Thus, adding MCTs to a ketogenic diet would allow significantly more carbohydrates to be included. (263)

A ketogenic diet KD has tumor growth-limiting effects, protects healthy cells from damage by chemotherapy or radiation, accelerates chemotherapeutic toxicity toward cancer cells, and lowers inflammation. (263) Altered availability of glucose and induction of ketosis influence all the classically defined hallmarks of cancer.(264) Weber et al demonstrated that ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity. (265) Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation. In glioma cancer models a ketogenic diet has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. (266) Similarly, a ketogenic diet altered the hypoxic response and affects expression of proteins associated with angiogenesis, invasive potential and vascular permeability in a mouse glioma model. (267) The ketogenic diet may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression.(268) A meta-analysis on the use of ketogenic diet in animal models demonstrated significantly prolonged survival time and reduced tumor weight and tumor volume. (269) The ketogenic diet was effective across a broad range of cancers. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma.(270)

Ketone bodies have been shown to inhibit histone deacetylases and may decrease tumor growth. In addition, the ketone bodyβ-hydroxybutyrate acts as an endogenous histone deacetylase inhibitor, resulting in downstream signaling that protects against oxidative stress. (271-274) Calorie restriction, which lowers blood glucose and elevates blood betahydroxybutyrate, reduces nuclear expression of phosphorylated NF-kB (p65), cytosolic expression of phosphorylated IkB, total IkB, and DNA promoter binding activity of activated NFkB. (275) NF-kB is a major driver of inflammation in the tumor microenvironment. 

The randomized controlled trial by Chi et al describes how adhering to a caloric-restricted diet for 6 months can have therapeutic benefits in slowing the growth of prostate cancer. (276) The men in the control group were instructed to avoid any dietary changes, whereas the men in the calorie-restricted group were coached by a dietician to restrict dietary carbohydrates to <20 grams/day. The authors found that elevated levels of serum ketone bodies (3- hydroxy-2- methylbutyric acid) at both 3 and 6 months were associated with significantly longer prostate cancer antigen doubling time (p < 0.0001), which is a marker of prostate cancer growth rate. Similarly, in a post hoc exploratory analysis of the CAPS2 randomized study the PSA doubling time was significantly longer in the low carbohydrate diet versus control diet (28 vs. 13 months, P = 0.021) arms.(277) These findings support the concept that elevations in ketone bodies are associated with reduced tumor growth. In a randomized trial in women with endometrial or ovarian a ketogenic diet was associated with a significant improvement in physical function scores with less fatigue.(278) In this study the ketogenic diet resulted in the selective loss of fat mass, retention of lean mass with lower fasting serum insulin levels. (279) In a randomized controlled trial Khodabakshi et al determined the feasibility, safety, and beneficial effects of an MCT-based Ketogenic diet in patients with locally advanced or metastatic breast cancer and planned chemotherapy. (280) Compared to the control group, fasting blood glucose, BMI, body weight, and fat% were significantly decreased in intervention group (P < 0.001). Overall survival in neoadjuvant patients was higher in the ketogenic group compared to the control (P = 0.04). 

A ketogenic diet following completed courses of chemotherapy and radiotherapy was further reported to be associated with long-term survival in a patient with metastatic non-small cell lung cancer. (281) “Long-term” survival has been reported in patients with glioblastoma on a ketogenic diet. (281, 282) Furthermore, evidence shows that therapeutic ketosis can act synergistically with conventional chemotherapeutic drugs, irradiation, and surgery to enhance cancer management, thus improving both progression-free and overall survival. (282) In addition, it is highly likely that therapeutic ketosis acts synergistically with the repurposed anticancer drugs reviewed in this document. Therapeutic ketosis requires a blood glucose < 90 mg/dl and a blood ketone > 2 mmol/l, aiming for a Glucose-Ketone Index < 2. (283) See the Glucose-Ketone Index Calculator in the section on caloric restriction. There are no known drugs that can simultaneously target as many tumor-associated signaling pathways as can calorie restriction. Hence, energy restriction can be a cost-effective adjuvant therapy to traditional chemo- or radiation therapies, which are more toxic, costly, and generally less focused in their therapeutic action than dietary energy restriction. It should be noted that the medium-chain fatty acids that are present during the consumption of a ketogenic diet directly inhibit glutamate receptors. (284) Shukla et al observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. (285) According to Dr. Seyfried: “Most human metastatic cancers have multiple characteristics of macrophages. We found that neoplastic cells with macrophage characteristics are heavily dependent on glutamine for growth. We have not yet found any tumor cell that can survive for very long under prolonged restriction of glucose and glutamine. Furthermore, we have not yet found any fatty acid or ketone body that can replace either glucose or glutamine as a growth metabolite. It, therefore, becomes essential to simultaneously restrict both glucose and glutamine while placing the person in nutritional ketosis for successful cancer management.” 

Although dietary energy restriction and anti-glycolytic cancer drugs will have therapeutic efficacy against many tumors that depend largely on glycolysis and glucose for growth, these therapeutic approaches could be less effective against those tumor cells that depend more heavily on glutamine than on glucose for energy. Glutamine is a major energy metabolite for many tumor cells and especially for cells of hematopoietic or myeloid lineage. Green tea polyphenol (EGCG) targets glutamine metabolism by inhibiting glutamate dehydrogenase activity under low glucose conditions (see section below). (221, 286-290) In addition, mebendazole, curcumin and resveratrol inhibit glutaminolysis. (13, 291) Glioblastoma, breast cancer, pancreatic cancer, lung cancer, prostate cancer, and lymphoma may depend on glutamine as a source of energy. (13)

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