Ketogenic diets are now one of the, most popular diets in the mainstream consciousness. Despite this popularity, practitioners and laypeople alike often misunderstand the ketogenic diet, and there are many myths and fallacies surrounding its application and use.

It is more and more frequently claimed that keto-diets can be used as a treatment option for cancer. This is due to the observation that most cancer cells are predominantly glycolytic. In other words, cancer cells have a preference for using sugar for fuel and are quite resistant to burning fat (and ketones). This effect is known as the ‘Warburg Effect’ as it was originally described by the scientist Otto Warburg.¹

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Mutations and further growth in tumours are related to this disturbed energy metabolism and might be, in part due to the reliance on higher carbohydrate diets and overall, calorie-restricted or ketogenic diets can be effective to reduce these metabolic maladies.¹

What does the evidence say?

Reviews of the scientific literature for both animal and human studies suggest that the ketogenic diet may be practically ‘toxic’ to cancer cells and effectively starves them of fuel for continued growth and progression.^{2, 3} However, these results are highly preliminary and there are heated discussions about the accuracy of these findings, their application to wider human use, and whether ketogenic diets may promote a ‘rebound’ effect, causing greater aggressiveness of certain types of tumours, especially with longer-term use.

ketogenic diets may promote a ‘rebound’ effect, causing greater aggressiveness of certain types of tumours

What is ketosis?

Ketosis refers to the metabolic state that typically occurs during fasting or carbohydrate restriction. In this state ‘ketone bodies’ are created from fats and some amino acids. Restricting carbohydrate results in reduced insulin levels, which in turn reduces lipogenesis (the creation of fats) and the accumulation and retention of fat stores.

In the initial stages of carbohydrate restriction, the body continues to use considerable amounts of carbohydrates, which are provided by hepatic glucose output (release of glucose from the liver). When these glycogen reserves become depleted, an alternative fuel source is needed, primarily to fuel the brain and central nervous system which typically rely on glucose.^[1]

The ketone bodies provide an alternative fuel, derived from fatty acids and some amino acids, and are able to be used by most cells in the body, including neurons (cells of the nervous system).

These ketone bodies are Acetoacetate, ß-hydroxybutyric acid (BOHB) and Acetone. Ketogenesis (the creation of ketones) occurs mostly in the liver, producing acetoacetate, in turn, converted to BOHB, which functions as the main fuel ketone.^[2]

It is important to note that during ketosis blood glucose levels stay within normal limits (although usually at the lower end of normal) due to the creation of glucose (known as gluconeogenesis) from amino acids and from glycerol (the ‘backbone’ of fats) during fatty oxidation.^[3]

Fuelling normal vs cancerous cells

Cancer cells are considered to be less flexible than other cells of the body, especially those of the brain and CNS.⁴ Indeed, it is now well accepted that the majority of tumours rely on glucose for their major source of energy and this metabolic reliance is the primary basis for ketone or ketogenic diet therapy in cancer.⁵

the majority of tumours rely on glucose for their major source of energy

In fact, a glucose-ketone index (the ratio of glucose to ketones present in the blood) has been proposed as a clinical measure for the management of a ketogenic diet in cancer treatment.⁶ 

The ‘Reverse Warburg Effect’

Cancer cells can, under certain circumstances (i.e. certain cell types in response to carbohydrate deprivation) begin to exploit non-glucose fuel sources such as acetate, glutamine, and aspartate, along with the ketone bodies. This means some cancer cells might actually thrive on non-glucose fuels, especially ketone bodies, and this effect is known as the Reverse Warburg Effect.⁷ This effect has been demonstrated in brain tumour models in rats,⁸ and liver cancer.⁹ Although, Huang et al., have noticed this effect only when liver cells are starved of serum.¹⁰ Conversely, De Feyter et al., have noted that there is no difference in ketone oxidation between normal and tumorous tissue in glioma models.¹¹

The two-compartment model

An interesting aspect of the Warburg-Reverse Warburg effect is the two-compartment metabolism model in tumours. This suggests that cancer cells can induce adjacent cells (fibroblasts) to produce ketones.^{7, 12, 13}

Ketogenesis within tumour cells (to provide fuel to the cell) has also been proposed.

However, in contrast to this theory of cancer-cells ‘co-opting’ nearby cells to produce ketone fuels for their use, other studies suggest that ketone production in cancer cells and nearby cells reduces the growth of tumours.¹⁴

Cancer cells can, under certain circumstances, begin to exploit non-glucose fuels

Figure 1. The Autophagic Tumour Stroma Model of Cancer¹³

Effects of the ketogenic diet and ketones in vitro and in vivo in animal models

The effects of ketogenic diets in animal models are mixed. Systematic reviews and meta-analyses show a positive role for the ketogenic diet for arresting cancer growth and improving survival times in animal models (especially for brain tumours).¹⁵

• Mice fed a ketogenic diet had significantly reduced tumour growth, and prolonged survival relative to mice fed a ‘western-style’ diet.¹⁶
• Mice supplemented with exogenous ketone supplements showed decreased proliferation and viability of cancer cells grown even in the presence of high glucose.
• This dietary ketone supplementation also prolonged survival in mice with systemic metastatic cancer by over 50% ( p < 0.05)
• …and Ketone administration showed anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction.¹⁷
• A review of 12 studies indicated significant improvements in survival as a result of a keto-diet. (MR = 0.85  and HR = 0.55)¹⁸

The ketogenic diet in humans

Total carbohydrate intake and blood glucose levels are associated with tumour growth and development, and keto-diets are tolerated well and, at least in the short-term, do not provide for significant adverse effects.¹⁹

In a review of the literature by Chung and colleagues, focussed on human studies, the main outcomes identified from the available literature (consisting of 10 studies) were improvement of body weight, improved body-composition (fat to lean mass), improved serum blood profiles, and reduction in markers for tumour progression (i.e. TKTL1), with no significant changes in quality of life. They concluded that “The ketogenic diet may be efficacious in certain cancer subtypes whose outcomes appear to correlate with metabolic status, but the results are not yet supportive and inconsistent. Therefore, it warrants further studies”.²⁰

The ketogenic diet may be efficacious in certain cancer subtypes whose outcomes appear to correlate with metabolic status

The positive effects of a keto diet for cancer in humans are likely to result from not only the reduction in glucose as a primary fuel for cancer but also due to protection against oxidative stress and inflammation, signalling cell death of cancer cells, inhibition of growth factors that encourage cancer growth (i.e. IGF-1), and the potentiation of both radiation and chemotherapy.⁵

Table 1. Clinical experience with calorie restriction or a ketogenic diet in cancer patients

Ketogenic diets with hyperbaric oxygen therapy

Mice treated with ketogenic diet plus hyperbaric oxygen therapy exhibited decreased tumour growth, reduced metastatic spread to the lungs, kidneys, spleen, adipose, and liver, decreased liver tumour vascularisation, and lived twice as long as controls.²¹

Factors to consider in the use of the ketogenic diet in cancer treatment

Ketolytic vs glycolytic enzymes in cancer cell types

It is becoming clear that at least some cancer cells, can ‘rewire’ their metabolic machinery to use ketone bodies and other alternate fuel substrates.

Ketolytic or glycolytic enzymes aid the breakdown and usage of either ketones or glucose respectively and the presence of these in cells can tell us a lot about which fuels they prefer. For example, liver cells are usually unable to use ketone bodies. However, in hepatocellular carcinomas, the ketolytic enzyme 3-oxoacid CoA-transferase 1 (OXCT1) can be activated in a carbohydrate-restricted state. This can protect the cancer cells from autophagy (self-destruction of abnormal tissue like cancer cells) and enhance tumour growth.¹⁰ Conversely, fibroblasts (nearby cells) expressing the glycolytic enzymes pyruvate kinases (PKM1 or PKM2) increased the growth of human breast cancer cells.²²

some cancer cells, can ‘rewire’ their metabolic machinery to use ketone bodies and other alternate fuel substrates

Ketone or glucose dominant cell types

The evidence is certainly not clear on whether any particular cancer type of cell type is mostly ketone or glucose using and we need to always remember that cancer is not one disease, it is many types, and that even the same cancer type in a person may contain many different sub-types of cells.

Possibly more ketolytic

HeLa (Ovarian cancer cells from the infamous Henrietta Lacks cell line) have a high expression of ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1). ²³

In mice with HeLa xenografts, keto-diet increased tumour growth and mouse survival decreased, whereas the keto-diet inhibited the growth of PANC-1 xenograft tumours. BOHB added to each cell culture resulted in a significantly increased proliferation of HeLa cells, while downregulation of ketolytic enzymes rendered HeLa cells sensitive to the keto-diet in vitro and vivo.²³

Possibly more glycolytic

Human pancreatic adenocarcinoma cells (PANC-1) have a low expression of the ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase 1 (OXCT1) respectively.

In mice, a ketogenic diet inhibited the growth of PANC-1 xenograft tumours. BOHB added to each cell culture did not result in a significant increase in PANCI-1 cells.²³

In Glioblastoma multiforme (GBM), an aggressive brain cancer, enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). 

in 34 human cholangiocellular carcinomas (CCCs) and adjacent normal tissue by using tissue microarrays, mitochondrial mass, as indicated by VDAC1 expression, was significantly increased in CCCs compared to corresponding normal tissue (p < 0.0001). VDAC1 levels were inversely correlated with UICC (Union Internationale Contre le Cancer) cancer stage classification (p = 0.0065). Furthermore, significantly lower VDAC1 was present in patients with lymph node involvement (p = 0.02). Consistent with this, patients whose carcinomas expressed VDAC1 at low to moderate levels had significantly reduced survival compared to high expressors (p < 0.05). Therefore, low mitochondrial mass is associated with more aggressive CCC. These metabolic features are indicative of a Warburg phenotype in CCCs. This metabolic signature has potential therapeutic implications because tumours with low mitochondrial function may be targeted by metabolic therapies such as a high-fat, low-carbohydrate ketogenic diet.²⁴

Mixed results in brain cancers

Conversely, while Chang and colleagues in an earlier paper had found low expression of ketolytic enzymes (OXCT1 and BDH1) in 14 of 17 GBM samples, this was not found in 4 of 5 anaplastic gliomas (i.e. anaplastic astrocytoma). At least one of the glycolytic enzymes was positive in 13 of 17 GBMs and all 5 anaplastic gliomas.²⁵ This suggests that ketogenic diets are more appropriate for GBM than anaplastic glioma and that attention should be paid to overall fuel availability rather than just to glucose vs ketone availability.

Glutamine usage by cancer cells

Glutamine, the most abundant amino acid in muscle tissue, can also be used as fuel by many cancer cells. It has been suggested that protein and glutamine be limited in the diet to reduce glutamine availability, but due to cachexia, this could, in fact, increase glutamine availability to glutamine-using cancer cells.

In a recent study, the glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with an energy-restricted ketogenic diet to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. This strategy helped to kill tumour cells while reversing disease symptoms, and improved  mouse survival.²⁶

Genetic proclivity?

When BRCA1 (a tumour suppressor gene) is knocked out in human fibroblasts, they exhibit an over 5-fold increase in ketone body production.²⁷ Similarly, a loss of Cav-1 (another tumour suppression gene candidate) is associated with an early increase in tumour recurrence. People lacking this gene expression also suffer mitochondrial dysfunction associated with the reverse Warburg effect.²⁸

Is the cancer stable or not?

Fine and colleagues have demonstrated that those stable vs progressive exhibit 3-fold higher BOHB levels and experience better overall results from KDs.¹⁹

What does this all mean?

Keto-diets increase the production and use of ketone bodies (especially BOHB) and reduce the body’s reliance on glucose.

The overall weight of evidence from in vitro and in vivo studies, in both animals and humans suggests that keto-diets reduce tumour growth and proliferation and increase survival times.

However, the human evidence, especially for which cancer types and cells might respond ‘best’ to a keto diet, is lacking, and the potential for an aggressive ‘rebound’ growth that can occur in some cancer cells (mostly shown in vitro), when exposed to higher amounts of ketone bodies, is a concern.

Overall, it does appear that clinical outcomes are improved by lower carbohydrate (not necessarily keto) wholefood-based diets, sufficient in fatty acids and protein,⁵ in contrast to previous best-care models that prioritised carbohydrate and were of poorer quality overall.

Overall, it does appear that clinical outcomes are improved by lower carbohydrate (not necessarily keto) wholefood-based diets, sufficient in fatty acids and protein

Ketogenic supplements such as medium-chain triglycerides, which encourage ketonaemia and ketogenesis and exogenous ketones, which provide ketonaemia without ketogenesis, also provide novel and interesting treatment approaches that warrant further investigation.¹⁷

Final ‘take-home’ points

• Overloading with any fuel could be detrimental to treating cancer
• Don’t ‘chase ketones’
• Practitioners should be aware of the emerging evidence for ketone vs glucose use by different cancer types
• I do not believe protein should be restricted as a greater potential for damage exists from muscle-wasting, and this also frees up large amounts of glutamine (is there a possible role for leucine?)

It’s important to remember that the research on ketogenic diets, ketones, and keto-supplements (and any diet!) for cancer is in its infancy.

It is crucial for anyone seeking treatment for cancer, and interested in using keto, to consult with a qualified, registered practitioner, well-versed in cancer and ketogenic diets.

It is crucial for anyone seeking treatment for cancer, and interested in using keto, to consult with a qualified, registered practitioner, well-versed in cancer and ketogenic diets

References

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2.     Bozzetti F, Zupec-Kania B. Toward a cancer-specific diet. Clinical Nutrition. 2015(0).

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4.     Seyfried BT, Kiebish M, Marsh J, Mukherjee P. Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. Journal of cancer research and therapeutics. 2009;5 Suppl 1:S7-15.

5.     Bozzetti F, Zupec-Kania B. Toward a cancer-specific diet. Clinical Nutrition. 2016;35(5):1188-95.

6.     Meidenbauer JJ, Mukherjee P, Seyfried TN. The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer. Nutr Metab (Lond). 2015;12:12.

7.     Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, et al. Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 2010;9(17):3506-14.

8.     De Feyter HM, Behar KL, Rao JU, Madden-Hennessey K, Ip KL, Hyder F, et al. A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth. Neuro-oncology. 2016;18(8):1079-87.

9.     Zhang WW, Churchill S, Lindahl R, Churchill P. Regulation of D-beta-hydroxybutyrate dehydrogenase in rat hepatoma cell lines. Cancer research. 1989;49(9):2433-7.

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14.   Grabacka MM, Wilk A, Antonczyk A, Banks P, Walczyk-Tytko E, Dean M, et al. Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells. Frontiers in endocrinology. 2016;7:5.

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16.   Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, et al. Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. The Prostate. 2008;68(1):11-9.

17.   Poff AM, Ari C, Arnold P, Seyfried TN, D’Agostino DP. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International Journal Of Cancer. 2014;135(7):1711-20.

18.   Klement RJ, Champ CE, Otto C, Kammerer U. Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis. PloS one. 2016;11(5):e0155050.

19.   Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28(10):1028-35.

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21.   Poff A, Ward N, Seyfried T, Agostino D. Abstract 1159: Ketosis and hyperbaric oxygen elicit potent anti-cancer effects in vitro and in vivo. Cancer research. 2015;75(15 Supplement):1159.

22.   Chiavarina B, Whitaker-Menezes D, Martinez-Outschoorn UE, Witkiewicz AK, Birbe R, Howell A, et al. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer biology & therapy. 2011;12(12):1101-13.

23.   Zhang J, Jia PP, Liu QL, Cong MH, Gao Y, Shi HP, et al. Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo. J Lipid Res. 2018;59(4):625-34.

24.   Feichtinger RG, Neureiter D, Kemmerling R, Mayr JA, Kiesslich T, Kofler B. Low VDAC1 Expression Is Associated with an Aggressive Phenotype and Reduced Overall Patient Survival in Cholangiocellular Carcinoma. Cells. 2019;8(6):539.

25.   Chang HT, Olson LK, Schwartz KA. Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutrition & Metabolism. 2013;10(1):47.

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[1] For an in-depth explanation of why fat is inefficiently used by neurons see The Carbohydrate Appropriate Diet

[2] Technically BOHB is not a ketone body as the ketone moiety has been reduced to a hydroxyl group

[3] In silico models further suggest a plausible conversion of fatty acids to glucose more likely to occur in periods of carbohydrate restriction.