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Richard Nixon signed the National Cancer Act in 1971 in efforts to strengthen the war against cancer. Despite significant advances in technology, research and resources; cancer deaths per 100,000 have fallen a dismal 5%. The cancer community continues to debate on the origins of cancer; is it genomic instability or impaired energy metabolism? Without a clear sense of what is driving neoplasia, the direction for future research and treatment strategies remain divergent and elusive.

There has been an emergence of research challenging the dogma that cancer is dictated by oncogenes, nuclear genetics and somatic mutations, and is instead steered by dysregulated respiration and energetics. The human genome project identified that no specific gene mutation or chromosomal abnormality is common to any one cancer. In fact, it is predicted there are 700 million gene mutations, making a common treatment plan nearly impossible to tackle the many unique defects in cancer cells. The metabolic theory proposes that mitochondrial damage and associated stress signaling precedes the upregulation of oncogenes and malignant tumor manifestation. This theory is based on the work of Otto Warburg that identified many cancer cells lose their ability for mitochondrial respiration with a reliance on fermentable aerobic glycolysis. In normal cells, aerobic glycolysis produces pyruvate that is converted and moved into the Kreb cycle when oxygen is present. Most tumor cells, however, have damaged respiration components, unable to advance pyruvate for further oxidation in the Kreb cycle, despite the presence of oxygen. Pyruvate is instead converted to lactate acid in tumor cells, similar to anaerobic respiration in normal cells. Only those tumor cells capable of attaining energy through this fermentation process are able to become a viable cancer cell. The inability for tumor cells to use oxidative phosphorylation reduces the amount of ATP produced. Many tumor cells use an alternative fuel source, glutamate to compensate for energy deficiencies. Since anaerobic-derived fermentation is necessary for tumor cells to thrive, it seems logical to reduce fermentable fuels (glutamate and glucose) and increase non-fermentable fuels (ketone bodies).

The ketogenic diet consist of a high proportion of healthy fats, variable protein, and low carbs. This inversion of the Food Pyramid Guide allows our body to produce an alternative fuel source called Ketone bodies from our richest source of stored energy, adipose tissue.

Our healthy cells are brilliantly adaptable! Human cells depend on the ability to be metabolically flexible in their use of various fuel sources when the environment introduces a change in availability. Humans have evolutionary conserved the adaptation to use ketone bodies as an alternative fuel source in all domains of life including; eukarya, bacteria and archaea. This is a product of millions of years of environmental forcing and variability selection, such as hypoxia, food scarcity and famine.

Metabolically active tissues, particularly the brain, heart and skeletal muscle rely on ketone body oxidation during a myriad of physiological states including, fasting, starvation, neonatal period, post-exercise, pregnancy, and adherence to low-carbohydrate diets. During this altered state, the body takes advantage of its stored depot of energy and mobilizes fatty acids in adipose tissue. When fatty acids are mobilized, they are sent to the liver for conversion to ketone bodies. Ketone bodies are delivered to extrahepatic tissues (brain, heart and muscle), catabolized in the mitochondria to acetyl-CoA, making it available to the Kreb cycle for terminal oxidation as an carbohydrate-alternative energy source.


1. STARVING CANCER-Attack on Glycoloysis

In 1927, Otto Warburg was the first to identify that cancer cells use glucose as their preferred fuel source, even under hypoxic conditions (Warburg Effect). An increase in tumor cell growth and energy production has been shown to be reliant on increased glucose uptake and metabolism.

Although tumor cells thrive on glucose, they are unable or have a reduced ability to be "flexible" in their use of ketone bodies as a fuel source. Most tumors have abnormal and damaged mitochondria including defects in Kreb cycle components, alterations in electron transport, and deficiency in oxidative phosphorylation, that would make it difficult or impossible to metabolize ketone bodies. The ketogenic diet as a therapy takes advantage of the Warburg Effect, by inhibiting glycolysis and depriving tumor cells of their preferred fuel source and ATP energy production.

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  • Inhibition of glucose uptake and metabolism has shown to suppress known oncogenic pathways and result in phenotypic reversion of malignant cells
  • A direct correlation exists between glucose availability and tumor growth rate, size, and proliferation
  • Hyperglycemia in disease states, such as obesity and diabetes, have been shown to provide a microenvironment that results in higher risk of some cancers
  • There have been successful encounters of the use of metformin, a drug to lower blood sugar levels, to decrease the risk and mortality of several lines of cancer

2. CLOSING CANCER HIGHWAYS-Attack on Insulin Signaling

Insulin signaling has been found to be upstream of most major pathways and cancer signaling proteins (mTOR, PI3K, AMPK, AKT, RAF/RAS). An increase in insulin, glucose and/or IGF1 all bind PI3K and initiate cancer signaling proteins and pathways. Exercise, ketones, and fasting all help to sensitize insulin receptors and pull glucose into healthy cells, making it unavailable to tumor cells. In normal subjects, a Ketogenic diet has shown to increase insulin sensitivity, with evidence of a 50% decrease in circulating insulin. There is no foreseeable reason that the diet would not have the same effects in cancer patients. In addition, the diet could assist drugs such as Metformin to drive down glucose availability and increase insulin sensitivity as a cancer therapy.

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  • There has been incredible energy around the use of Metformin in anti-cancer treatments. This drug is the most widely prescribed drug for type 2 diabetes mellitus that decreases glucose absorption from the small intestine, increases glucose uptake in cells, inhibits gluconeogenesis, and decreases plasma free fatty acid concentration.
  • Metformin has been associated with decreasing risk of developing cancer and reducing cancer related mortality
  • Metformin has been shown to increase radiation sensitivity and immunotherapy drugs and significantly impact cancer proliferation and apoptosis
  • The benefits of Metformin related to anti-cancer have been attributed to mTOR inhibition. This is mediated by reducing the downstream effects of IGF-I
  • Concerns have been raised on the clinical utility of Metformin due to its side effect profile including GI stress and pain-associated reduced compliance. If only there was a more natural way to take advantage of the Warburg Effect and inhibit insulin signaling upstream of cancer pathways. WAIT! This is the SAME mechanism suggested for the ketogenic diet and without side effects of drugs!

3. SIGNAL DEATH-Attack on Immortality

The ability for tumor cells to evade cell death while maintaining a high level of reactive oxygen species is a hallmark of cancer cells. Environmental conditions associated with cancers, as well as chemotherapy and radiation all cause the tumor cell environment to have abnormally high levels of reactive species. As tumor cells use glucose through glycolysis, antioxidants are produced, such as ribose 5 phosphate. This production of antioxidants allows the cell to keep their heightened reactive species at bay and escape cell death. By reducing glucose availability and therefore glycolysis, the ability of the tumor cells to produce antioxidants would be reduced. In theory, this could raise reactive oxygen species within the tumor cells which would signal apoptosis.

4. BLOOD STANDSTILL-Attack on Angiogenesis

Sustained angiogenesis is another hallmark of tumor cells and has been shown to be rate limiting in growth and proliferation. Tumor cells’ sustained lactate production increases acidity, which signals immune activation for increased blood flow and network.

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  • In 1914, Dr. Rous was the first to point out that a restricted diet may inhibit tumor growth by delaying tumor angiogenesis.
  • A ketogenic diet with restriction showed reduction in angiogenesis in brain, prostate and breast cancer.
  • The degree of vascularity highly correlates with the malignancy and invasiveness of tumor cells with better prognosis for tumors with a reduced vascular network.


DNA methylation, and in particular silencing of tumor-suppressor genes by promoter hypermethylation, has been the most widely studied epigenetic modification in human tumors. A typical characteristic of human cancer is the deregulation of DNA methylation and posttranslational histone modifications. A widely studied mechanism, histone deacetylation (HDAC) involves a class of enzymes that remove acetyl groups from lysine residues residing on histones and non-histone proteins. This has fatal consequence of gene transcription-deregulation, potentially playing an active role in tumor onset and progression. This makes HDACs attractive candidate targets for anticancer drugs and therapies.

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Histone deacetylase inhibitors (HDIs) are actively being tested for their ability to reverse the abnormal gene expression patterns inherent to the cancer epigenome and for their ability to enhance other antitumor therapies through inhibition of histone deacetylases.

Exciting new data shows that β-hydroxybutyrate (βHB), the major ketone elevated in the blood as a result of the ketogenic diet, inhibits HDACs (1, 3, and 4). βHB have shown to induce dose-dependent histone hyperacetylation in treated cultured cells. Fasting also induces prominent histone hyperacetylation, which supports the notion that a restricted ketogenic diet is an exciting supportive therapy that may support altering the epigenetic landscape for cancer treatments.

Field Pioneers...

A few pioneers in the anti-cancer field fighting the good fight to promote and test the Metabolic Theory of Cancer can be found here and are worth visiting...

Created By
Amy Gyorkos

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