Can the Ketogenic Diet Improve Cancer Therapy?

Interest in the ketogenic diet (KD) is booming. For example, a “ketogenic diet” topic search on Google Trends shows searches have increased ninefold during the past two years. This is remarkable, considering the KD has been around since the 1920s, when it was first introduced as an epilepsy treatment. So why are people suddenly so keto-curious? And why are establishment watchdogs attacking the KD, like US News and World Report, which in January, 2018, ranked the KD dead last on its “Best Diets” list?[1]

The answers to these questions probably involve the KD’s recent success in treating a variety of chronic conditions. In January, 2018, for example, The Journal of the American Medical Association (JAMA) published a glowing review of the KD, noting, “[the ketogenic diet] could be game changing for the field of chronic disease.”[2] Although the JAMA article didn’t mention cancer – it focused on type-2 diabetes and weight loss – during the past several years, research regarding the KD and cancer has accelerated, and its success may now pose a threat to the $107 billion cancer drug industry.[3]

Figure 1. A Google Trends “ketogenic diet” topic search shows a huge surge during the past two years.

In this article, we’ll examine the KD-cancer research, but understanding this research requires first addressing a much more fundamental topic. The aforementioned cancer drug industry rests tediously upon a dogmatic stance – that cancer is a genetic disease. This dogma is echoed by every major cancer institution, including the National Cancer Institute, which asserts, “Cancer is a genetic disease—that is, cancer is caused by certain changes to genes that control the way our cells function, especially how they grow and divide.”[4]

In opposition to this dogma, there exists a provocative theory, which says cancer is a metabolic disease. The dogma says cancer is caused by changes within cell nuclei, which result in the activation of oncogenes and the mutation and subsequent inactivation of tumor suppressor genes.[5] The metabolic theory says cancer is caused by mitochondrial damage inflicted primarily by reactive oxygen species (ROS). Beyond some threshold of ROS damage, the mitochondria signal the nuclei, delivering the message that survival now depends on shifting from normal energy metabolism (respiration) to a form of energy metabolism known as the Warburg effect (described below).

Dr. Thomas Seyfried, a contemporary pioneer of the metabolic theory of cancer, says the genetic theory “reigns as the most widely accepted view of the origin of cancer and is the justification for developing personalized genetic therapies…the theory is presented as if it were dogma in most current college textbooks of genetics, biochemistry, and cell biology.”[6] But if cancer is a genetic disease arising from nuclear mutations, then transferring a tumorous nucleus into a normal cell’s cytoplasm should promote tumorigenesis. Likewise, transferring a normal nucleus into a tumorous cytoplasm should not promote tumorigenesis. Unfortunately for the genetic theory, the studies show otherwise.

For a landmark paper published in 2014 in Carcinogenesis, Seyfried and fellow researchers Roberto Flores, Angela Poff and Dominic D’Agostino, reviewed the many studies regarding nuclear transfer.[7] Collectively, these studies cast doubt on the genetic theory, while bolstering the metabolic theory. As depicted in the following image, the researchers explained, “The results suggest that tumors do not arise from nuclear genomic defects alone and that normal mitochondria can suppress tumorigenesis.”[8]

Figure 2. Transferring a tumorous nucleus into a normal cell does not promote new cancer, whereas transferring a normal nucleus into a tumorous cell does, thus suggesting that mitochondria play a dominant role in tumorigenesis.[9]

 

The Warburg Effect

Seyfried et al. have proposed that reactive oxygen species (ROS) from a wide variety of sources cause mitochondrial damage, which leads to respiratory dysfunction. These ROS sources include the following, and more:

  •         Smoking
  •         Environmental toxins
  •         Chronic stress
  •         Inflammation
  •         Viruses
  •         Aging

Eventually, accumulated ROS damage prevents cells from maintaining energy homeostasis via respiration (normal energy metabolism). As shown in the figure below, this causes a mitochondrial stress response or retrograde signaling, which in turn causes the following:

  •         Oncogene activation
  •         Tumor suppressor gene inactivation
  •         Genomic instability
  •         Shift from respiration to fermentation (the Warburg Effect)

Figure 3. Adopted from (2014) Seyfried et al.[10]

Otto Warburg was a Nobel Prize-winning German biochemist, who, during the 1920’s, discovered that cancer cells exhibit altered energy metabolism. Rather than generating ATP via respiration, cancer cells voraciously consume glucose and generate ATP via fermentation. Respiration, which happens in the presence of oxygen, is far more efficient than fermentation, but cancer cells nevertheless exhibit fermentation, whether oxygen is present or not.

The following figure, adapted from Thompson et al. (2009), shows that when oxygen is readily available (respiration), glucose reduces to pyruvate, the vast majority of that pyruvate enters the mitochondrion, gets converted into acetyl-CoA, enters the Krebs cycle, and finally yields about 36 moles of ATP per mole of glucose.[11] A lack of oxygen, however, prevents pyruvate from entering the mitochondrion. In this case (fermentation), pyruvate reduces to lactate. When you are doing long-distance running, for example, the burn you feel in your muscles is the build-up of lactic acid. This form of metabolism only yields about 2 moles of ATP per mole of glucose.

Figure 4. Healthy cells generate an abundance of energy via respiration when oxygen is present, or a small amount via fermentation when oxygen is lacking. Cancer cells generate energy mostly via fermentation (the Warburg Effect), whether oxygen is present or not.[12]

Cancer cells exhibit aerobic glycolysis, which can be thought of as a combination of respiration and fermentation, but heavily slanted towards the latter. Whether oxygen is present or not, cancer cells reduce glucose to pyruvate; next, they reduce most of that pyruvate, via fermentation, to lactate. Since cancer cells only yield about 4 moles of ATP per mole of glucose, they have voracious appetites for glucose, and in most cases, their survival demands a steady supply.

 

Cancer’s Other Loves

Cancer loves glucose. But cancer cells are sophisticated and some don’t rely only on glucose for their energy needs. Glutamine is the most abundant free amino acids in the human body and one of the most readily available amino acids in food.[13] Some, but not all, cancer cells utilize glutamine for their energy needs. Although glutamine can be synthesized from glucose, some cancer cells exhibit “glutamine addiction,” meaning they require exogenous glutamine for survival.[14]

Figure 5. In cancer cells, the Warburg Effect ensures that pyruvate is mostly converted into lactate, rather than entering the mitochondrion and proceeding through the Krebs cycle (TCA cycle). As a secondary fuel source, and to maintain a functioning Krebs cycle, some cancer cells rely on elevated glutamine metabolism.[15]

CSo cancer likes an environment with lots of glucose and lots of glutamine. But it also likes insulin and IGF-1 because these molecules fuel the mTOR pathway – a signaling pathway, which is present in all cells. The mTOR pathway regulates cell proliferation, meaning whether a cell will divide (proliferate) or die (apoptosis). In cancer cells, this pathway is overactive, thereby contributing to cancer’s rapid, uncontrolled proliferation.[16] The following diagram, adapted from Branco et al., shows how insulin and IGF-1 fuel the mTOR pathway, while also foreshadowing the potential of the KD to circumvent this problem.[17]

Figure 6. In cancer cells, the presence of elevated insulin and elevated IGF-1, over-activates mTOR via PI3K/Akt signaling, thereby enabling rapid proliferation.[18]

 

Summary of Cancer Cell Abnormalities

The metabolic theory of cancer maintains that ROS damage to the mitochondria results in impaired energy metabolism. This causes a mitochondrial stress response or retrograde signaling, which in turn triggers changes within the nuclei, including the activation of oncogenes and the mutation and subsequent inactivation of tumor suppressor genes. At the same time, energy metabolism shifts from normal respiration to fermentation, whether oxygen is available or not, a phenomenon known as the Warburg Effect.

Because of the above-mentioned changes, cancer cells have voracious appetites for glucose. Many cancer cells also rely on glutamine as a primary or secondary fuel source. Moreover, cancer cells thrive in an environment of elevated insulin and IGF-1, which fuels the mTOR pathway, thereby enabling rapid proliferation.

A final, another very important difference between cancer cells and normal cells is that cancer cells cannot metabolize ketones.

 

Why the Ketogenic Diet Should Improve Cancer Therapy

By reducing carbohydrates to an absolute minimum (usually less than 5 percent% of total calories), glucose and glycogen become depleted. At this point, the body starts burning fat as its primary fuel source. We can generate ATP from fat directly via beta-oxidation, or free fatty acids can enter the liver and get converted into ketones. For a recap on the mechanisms behind ketosis, see our previous article.

Note that a KD formulated for cancer typically reduces protein to around 5 percent% of calories, in addition to reducing carbohydrates. Accordingly, a KD for cancer has fat accounting for upwards of 90 percent% of total calories. In theory, this diet should be ideal for cancer therapy because it does the opposite of everything cancer wants. For example, because it drastically reduces carbs, glucose becomes less available, which means blood glucose levels will typically decrease. In turn, insulin also decreases. Because the cancer-formulated KD also decreases protein, glutamine becomes less available. Also, when protein consumption goes down, IGF-1 goes down. Moreover, tumor cells are unable to metabolize ketones, and for many tumor cells, ketones can be toxic.[19]

So how does the KD fare when put to the test? The following images are from a 2007 preclinical mouse trial published by Seyfried et al. in Nutrition and Metabolism.[20] There were three groups, each of which was given malignant brain cancer. The 1st group ate a standard diet, ad libitum, meaning the mice could eat as much as they desired. The 2nd group ate a KD, ad libitum. Finally, the 3rd group ate a calorie-restricted KD. The 3rd group fared much better than the other two, demonstrating lower glucose levels, higher ketone levels (β-OHB), and smaller tumors.

Figure 7. Comparison of blood glucose and blood ketone (β-OHB) levels of mice with malignant glioma eating an unrestricted standard diet (SD-UR), unrestricted KD (KC-UR), or a calorie-restricted KD (KC-R)[21]

Figure 8. Tumor weights of mice with malignant glioma eating an unrestricted standard diet (SD-UR), unrestricted KD (KC-UR), or a calorie-restricted KD (KC-R)[22]

The next study, again from Seyfried et al., was published in 2012 in PLoS One. For this study, mice were given malignant brain cancer and then divided into one of four groups: (1) standard diet, ad libitum, (2) KD, ad libitum, (3) standard diet (ad libitum) plus radiation, (4) KD (ad libitum) plus radiation. Group 2 fared marginally better than group 1, with respect to survival time.[23] Group 4, however, outlived the study, which cut off at 250 days, thus median survival went from 28 days on the KD to over 250 days by combining the KD with radiation.

Figure 9. Survival time of mice with malignant glioma eating an unrestricted standard diet or KD with or without radiation therapy[24]

Finally, in 2013, Seyfried, Poff, and D’Agostino published a remarkable study showing the combined effects of hyperbaric oxygen therapy (HBO2T) and the KD on mice with metastatic cancer.[25] The image below shows bioluminescent photography representing tumor activity. Again, each group was eating al libitum, so one would expect the results to be even better with calorie restriction. Nevertheless, impressive synergies were achieved by combining the KD with HBO2T. The authors remarked, “Indeed, in our present study, HBO2T alone did not improve the outcome of VM mice with metastatic cancer, but combining HBO2T with KD elicited a dramatic therapeutic effect.”

Figure 10. Bioluminescent imagery showing tumor activity of mice with metastatic cancer on either an ad libitum standard diet, ad libitum standard diet plus HBO2T, ad libitum KD, or ad libitum KD plus HBO2T.[26]

 

Conclusions

The studies above are representative of the larger body of research on the KD and cancer therapy. One can draw the overall conclusion that the KD is insufficient as a standalone cancer therapy, but that it works well synergistically when combined with other therapies. Those other therapies could include any of the following, and more:

  •         Standard of care (radiation, chemotherapy)
  •         Calorie restriction
  •         Exogenous ketone supplementation
  •         Immunotherapy
  •         Berberine/metformin
  •         Hyperbaric oxygen therapy

Most studies conducted thus far have been preclinical animal trials, but the success of those trials, along with the gradual weakening of the “cancer is a genetic disease” dogma, has prompted increased interest in the KD. Currently, according to clinicaltrials.gov, there are 23 clinical trials (human studies) in progress pertaining to the KD and cancer.

If you follow cancer research for the next several years, you’re likely to hear much more about the metabolic theory of cancer and much more about the KD as an effective treatment adjuvant. Perhaps some day the future “standard of care” will even include the KD. After all, as JAMA reported earlier this year, the KD has the potential to be “game changing for the field of chronic disease.”[27]

 

References

[1] LaMotte S. (Jan 4, 2018). ‘Best diets’ ranking puts keto last, DASH first. CNN. Retrieved from https://edition.cnn.com/2018/01/04/health/keto-worst-diet-2018/index.html

[2] Abbasi J. (Jan 2018). Interest in the Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes. JAMA, 319(3). Retrieved from https://jamanetwork.com/journals/jama/article-abstract/2669724

[3] Tirrell M. (Jun 2, 2016). The world spent this much on cancer drugs last year. CNBC. Retrieved from https://www.cnbc.com/2016/06/02/the-worlds-2015-cancer-drug-bill-107-billion-dollars.html

[4] National Cancer Institute. (Oct 2017). The Genetics of Cancer. Retrieved from https://www.cancer.gov/about-cancer/causes-prevention/genetics

[5] Lee EYHP, et al. (Oct 2010). Oncogenes and Tumor Suppressor Genes. Cold Spring Harb Perspect Biol., 2(10). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944361/

[6] Seyfried T. (Jul 2015). Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol., 3(43). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493566/

[7] Seyfried T, et al. (Mar 2014). Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis, 35(3). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/

[8] Seyfried T, et al. (Mar 2014). Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis, 35(3). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/

[9] Seyfried T, et al. (Mar 2014). Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis, 35(3). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/

[10] Seyfried T, et al. (Mar 2014). Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis, 35(3). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/

[11] Vander Heiden MG, et al. (May 2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19460998

[12] Vander Heiden MG, et al. (May 2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19460998

[13] Roth E. (2013). “The cell- and immune-modulating properties of glutamine” from Diet, Immunity and Inflammation. Woodhead Publishing Series. Retrieved from https://www.sciencedirect.com/science/article/pii/B9780857090379500205

[14] Wise DR, et al. (Aug 2010). Glutamine Addiction: A New Therapeutic Target in Cancer. Trends Biochem Sci., 35(8). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917518/

[15] Erickson JW, et al. (Dec 2010). Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget, 1(8). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21234284

[16] Pópulo H, et al. (2012). The mTOR Signalling Pathway in Human Cancer. Int J Mol Sci., 13(2). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291999/

[17] Branco AF, et al. (Mar 2016). Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest., 46(3). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26782788

[18] Branco AF, et al. (Mar 2016). Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest., 46(3). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26782788

[19] Seyfried T, et al. (Jun 2011). Metabolic management of brain cancer. Biochimica et Biophysica Acta (BBA) – Bioenergetics, 1807(6). Retrieved from https://www.sciencedirect.com/science/article/pii/S0005272810006857

[20] Zhou W, et al. (Feb 2007). The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond)., 4(5). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17313687

[21] Zhou W, et al. (Feb 2007). The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond)., 4(5). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17313687

[22] Zhou W, et al. (Feb 2007). The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond)., 4(5). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17313687

[23] Abdelwahab MG, et al. (May 2012). The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. PLoS One, 7(5) Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22563484

[24] Abdelwahab MG, et al. (May 2012). The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. PLoS One, 7(5) Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22563484

[25] Poff AM, et al. (Jun 2013). The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One, 8(6). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23755243

[26] Poff AM, et al. (Jun 2013). The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One, 8(6). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23755243

[27] Abbasi J. (Jan 2018). Interest in the Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes. JAMA, 319(3). Retrieved from https://jamanetwork.com/journals/jama/article-abstract/2669724

 

About Christopher James Clark, B.B.A.

Christopher James Clark, B.B.A.Christopher James Clark, B.B.A. is an award-winning writer, consultant, and chef with specialized knowledge in nutritional science and healing cuisine. He has a Business Administration degree from the University of Michigan and formerly worked as a revenue management analyst for a Fortune 100 company. For the past decade-plus, he has been designing menus, recipes, and food concepts for restaurants and spas, coaching private clients, teaching cooking workshops worldwide, and managing the kitchen for a renowned Greek yoga resort. Clark is the author of the critically acclaimed, award-winning book, Nutritional Grail.

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