Can the Ketogenic Diet Cure Cancer? What Does the Science Say?

Beforehand on this collection, I mentioned the origins of the ketogenic weight loss program and the organic function of ketone our bodies (Part 1), whether or not dwelling in a state of ketosis is regular and pure (Part 2), whether or not ketogenic diets are efficient for weight reduction (Part 3) and insulin resistance and diabetes (Part 4). On this installment, I’m going to look at the declare – now spreading like wildfire over the Web – that ketogenic diets can treatment most cancers by ravenous most cancers cells of glucose.

Does Sugar Feed Most cancers?

Right here’s a typical instance^[1] of the claims made by ketogenic weight loss program proponents:

Extraordinary claims require extraordinary proof, as astronomer Carl Sagan famously mentioned, and that is fairly a rare declare. So, how does the proof for it stack up? As you will notice, not fairly in addition to keto-enthusiasts declare.

The Proof on Ketogenic Diets and Most cancers

A 2017 systematic assessment of the printed proof for ketogenic diets in most cancers^[2] recognized 15 research (5 case reviews, 8 potential research, and a couple of retrospective research). They wrote that “no research with a methodological[ly] rigorous design was discovered” and concluded that

“proof supporting the consequences of isocaloric ketogenic dietary regimes on tumor growth and development in addition to discount in unwanted effects of most cancers remedy is lacking.”

Worryingly, in addition they commented that researchers appeared to under-report side-effects and downplay the decreased high quality of life in most cancers sufferers following ketogenic diets.

One other assessment, printed in April 2018^[3] concluded:

“The restricted variety of research and variations in research design and traits contribute to general poor high quality proof, limiting the power to attract evidence-based conclusions.”

In truth, the authors’ in depth literature search recognized a complete of solely 14 research on the consequences of the ketogenic weight loss program in most cancers sufferers printed between 1988 and 2016, that included solely 206 people. 5 of the research have been merely case reviews, thought of the bottom stage of proof in medical analysis. Sufferers have been placed on ketogenic diets for wherever from 5 days to 12 months. 9 out of the 14 research assessed the consequences of the weight loss program on tumor metabolism and/or illness development, and of those, two discovered that sufferers on the ketogenic weight loss program had worse outcomes, two confirmed various outcomes amongst members, 4 didn’t report any distinction between therapies, and one demonstrated an alteration in most cancers cell metabolism.

And a 2017 research carried out on pancreatic and lung most cancers sufferers,^[4] which was not included in both of the systematic evaluations, had inconclusive outcomes as a result of many of the sufferers had problem complying with the weight loss program, regardless of each effort made to assist them comply and suffered from many delicate to extreme unwanted effects because of it (constipation, fatigue, bloating, nausea, dehydration, esophagitis, hyperuricemia).

The Warburg Impact – Are All Most cancers Cells Hungry for Glucose?

The notion {that a} ketogenic weight loss program is an efficient remedy for most cancers rests on the commentary that the mitochondria (‘energy vegetation’) of most cancers cells have decreased effectivity, leading to a decreased vitality yield from glucose. Referred to as the ‘Warburg impact’ after Otto Warburg, who gained the 1931 Nobel Prize for Physiology or Drugs for locating it, this metabolic inefficiency leads to most cancers cells taking over extra glucose from the bloodstream.^[5]

Bloggers and authors of well-liked books have distorted this commentary into the oft-repeated declare that “sugar feeds most cancers,” which types the idea of recommendation to eradicate all types of carbohydrate from the weight loss program, together with fruit, entire grains, and legumes (meals which have been proven to cut back the danger of growing most cancers – see for instance “Greens, Fruit, and Most cancers Prevention: A Assessment,”^[6] “Entire grain consumption and most cancers: a assessment of the literature”^[7] and “Legume consumption and threat of all-cause, cardiovascular, and most cancers mortality within the PREDIMED research.”^[8]

It’s essential to comprehend that the phenomenon we name ‘most cancers’ will not be a single illness. The defining attribute of most cancers cells is that they purchase a number of mutations in genes that make them immortal and that govern their metabolic pathways. Consequently, not all most cancers cells are avid shoppers of glucose, as ketogenic weight loss program advocates declare.

In truth, in a research of 33 human most cancers cell traces, all have been discovered to specific key ketolytic enzymes,^[9] which allow them to take up ketone our bodies and use them as gas. The extent of expression diversified considerably between completely different cell traces, that means that some most cancers cell sorts have a stronger choice than others for utilizing ketone our bodies.

Apparently, the researchers discovered “no correlation between glycometabolism and ketone physique metabolism,” that means that most cancers cells with excessive glycometabolism (use of glucose as a gas) didn’t essentially have a decrease stage of key ketolytic enzymes. Some most cancers cells, it appears, are in a position to make use of glucose and ketone our bodies interchangeably, relying on what is obtainable to them.

Some most cancers cells present a powerful choice for utilizing ketone our bodies, they usually trigger the physique to make extra ketones with the intention to gas their development. An oncogenic (cancer-causing) mutation within the BRAF V600E gene^[10] prompts MEK1, which stimulates the expansion of most cancers. Which sorts of most cancers does this mutation happen in?

• Over 50% of melanomas
• 10% of colorectal cancers
• 100% of furry cell leukemias
• 5% of a number of myelomas

For individuals whose cancers specific this BRAF V600E mutation, adopting a ketogenic weight loss program would pour gas on the hearth; in mice who have been implanted with human melanomas expressing the BRAF V600E mutation, a excessive fats weight loss program “elevated development charges, lots and sizes of tumors”.^[11]

The Reverse Warburg Impact

Researchers have additionally recognized a ‘reverse Warburg impact‘^[12] through which fibroblasts (connective tissue cells that produce the extracellular matrix, or stroma, through which all cells, together with most cancers cells, reside) ‘feed’ ketone our bodies to adjoining most cancers cells, stimulating tumor development and metastasis. The human MDA-MB-231 breast most cancers cell line has been discovered to overexpress key enzymes concerned in ketone metabolism.

Right here is how the researchers described the two-way relationship between most cancers cells and surrounding fibroblasts that will increase the quantity of ketones accessible to gas tumor development:

Ketogenic fibroblasts promote the expansion of adjoining breast most cancers cells by driving elevated mitochondrial biogenesis. Thus, the tumor stroma could function a reservoir for ketone physique manufacturing, whereas most cancers cells upregulate the enzymes required for ketone physique re-utilization, driving oxidative mitochondrial metabolism (OXPHOS) in epithelial most cancers cells.

One other staff of researchers concluded that “ketone our bodies behave as onco-metabolites, and we straight present that the [ketolytic] enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes.”^[13]

Furthermore, an enzyme concerned within the technology of ketone our bodies was discovered to be upregulated in excessive grade prostate most cancers,^[14] and the focus of the ketone physique β-hydroxybutyrate was increased in these cells. This means that aggressive prostate most cancers cells use ketone our bodies to “achieve a survival benefit permitting them to grow to be more and more aggressive and achieve androgen-independent properties.”

This can be a crucial level, as a result of typical prostate most cancers remedy contains androgen blockade, however androgen deprivation decreases the power of prostate most cancers cells to take up glucose from the bloodstream and use it as a gas. This “lower within the exercise of the glycolytic pathway locations prostate most cancers cells underneath stress to generate vitality in a fast method with the intention to perform crucial mobile capabilities. One avenue by which such an impact could be achieved is to extend vitality manufacturing by the breakdown of fatty acids by way of the β-oxidation pathway” – that’s, by utilizing ketone our bodies.

Ketone our bodies have been additionally discovered to extend the expansion price of HeLa cells,^[15] a cervical most cancers cell line that’s extensively utilized in most cancers analysis.

Do Ketone Our bodies Have Particular Anti-Most cancers Results?

The cancer-controlling results of ketogenic diets are sometimes attributed to the ketone our bodies themselves. For instance, improved mitochondrial perform has been discovered to inhibit most cancers cell development and reverse the resistance of most cancers cells to chemotherapy medicine.^[16] Ketogenic weight loss program advocates credit score the ketone physique β-hydroxybutyrate (BHB) with being answerable for bettering mitochondrial respiration.^[17]

There isn’t any proof {that a} ketogenic weight loss program protects in opposition to the event of most cancers, and proof for its advantages in most cancers therapy is sparse and inconsistent.

Nonetheless, analysis by Dr. Valter Longo and his co-workers on fasting and fasting-mimicking diets signifies that ketosis will not be required to enhance mitochondrial perform and induce ‘differential stress sensitization’ (additionally referred to as differential stress resistance) – a situation through which most cancers cells are weakened and made inclined to chemotherapy, whereas regular, wholesome cells are strengthened and made immune to it.^[18] As an alternative, decreased ranges of insulin-like development issue 1 (IGF-1) and mechanistic goal of rapamycin (mTOR) induce differential stress sensitization. Each IGF-1 and mTOR are decreased by fasting, and applicable protein diets.

Fasting, Plant-Based mostly Diets, and Most cancers

Fasting has been discovered to lower side-effects and enhance the tumor cell-killing results of each typical cytotoxic chemotherapy^[19] and tyrosine kinase inhibitors.^[20] Cycles of fasting adopted by refeeding stimulate rejuvenation of stem cells, together with these in bone marrow, permitting blood counts to ‘bounce again’ quicker after cytotoxic chemotherapy.^[21]

There isn’t any proof {that a} ketogenic weight loss program protects in opposition to the event of most cancers, and proof for its advantages in most cancers therapy is sparse and inconsistent. In stark distinction, an entire meals, plant-based dietary sample not solely reduces the danger of growing most cancers (each due to the cancer-fighting plant meals it contains, and due to the cancer-promoting animal meals that it excludes^[22]), but in addition exhibits promise in treating not less than sure sorts of most cancers.

For instance, a randomised managed trial of a low fats, excessive advanced carbohydrate plant-based weight loss program (the direct reverse of a ketogenic weight loss program) was proven to considerably lower PSA (prostate-specific antigen) and dramatically cut back the danger of development in males with early stage prostate most cancers, and favorably have an effect on a variety of genes concerned in most cancers.^[23]

Water-only fasting adopted by an entire meals, plant-based weight loss program with no added sugar, salt or oil – once more, excessive in advanced carbohydrates, low in fats and comparatively low in protein was proven to shrink lymphoma and preserve remission.^[24]

Ultimate ideas: analysis persistently signifies that diets wealthy in minimally-processed plant meals^[25] promote wholesome longevity. In an e mail alternate about ketogenic diets (shared along with his permission), Dr. Valter Longo’s colleague and co-author, Dr. Sebastian Brandhorst, made 2 crucial factors:

1. The comparatively excessive protein content material of most ketogenic diets does usually not align with diets which are most useful almost about human well being and lifespan.
2. Fasting and FMDs [fasting mimicking diets] induce mobile atrophy that’s adopted by a stem-cell primarily based regeneration/rejuvenation upon regular caloric consumption; to one of the best of my data this has not been demonstrated for ketogenic diets. We consider that this may solely be achieved by periodic hunger [fasting]/refeeding intervals.

In different phrases, the ketogenic weight loss program will not be conducive to human longevity, and doesn’t provide the advantages that fasting (and plant-based diets) present for most cancers sufferers, when it comes to decreasing the side-effects of medical therapy and enhancing its effectiveness.

The extraordinary declare that ketogenic diets treatment most cancers is not supported by extraordinary proof, however by a patchwork of conjectures and hypotheses concerning the metabolism of most cancers cells.

Study extra concerning the ketogenic weight loss program from the earlier articles on this collection:

Half 1 – What Is the Ketogenic Diet?
Half 2 – Is the Ketogenic Diet Natural for Humans?
Half 3 – Does the Ketogenic Diet Really Work for Weight Loss?
Half 4 – Can the Ketogenic Diet Reverse Type 2 Diabetes?

References

1. https://thetruthaboutcancer.com/ketogenic-diet-weakens-cancer-cells/ – accessed 30 November 2018
2. Erickson, N., Boscheri, A., Linke, B. & Huebner, J., (2017), Systematic assessment: isocaloric ketogenic dietary regimes for most cancers sufferers. Med Oncol.;34(5):72. https://www.ncbi.nlm.nih.gov/pubmed/28353094
3. Oliveira, C.L.P., Mattingly, S., Schirrmacher, R., Sawyer, M.B., Nice, E.J. & Prado, C.M. (2018), A Dietary Perspective of Ketogenic Weight loss program in Most cancers: A Narrative Assessment. J Acad Nutr Weight loss program.;118(4):668-688. https://www.ncbi.nlm.nih.gov/pubmed/28366810
4. Zahra, A., Fath, M.A., Opat, E., et al. (2017), Consuming a Ketogenic Weight loss program whereas Receiving Radiation and Chemotherapy for Domestically Superior Lung Most cancers and Pancreatic Most cancers: The College of Iowa Expertise of Two Part 1 Medical Trials. Radiat Res.;187(6):743-754. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510645/
5. Schwartz, L., Seyfried, T., Alfarouk, Ok.O., Da Veiga Moreira, J. & Fais, S., (2017), Out of Warburg impact: An efficient most cancers therapy concentrating on the tumor particular metabolism and dysregulated pH. Semin Most cancers Biol.;43:134-138. https://www.ncbi.nlm.nih.gov/pubmed/28122260
6. Steinmetz, Ok.A. & Potter, J.D. (1996), Greens, Fruit, and Most cancers Prevention: A Assessment. J Am Weight loss program Assoc.; 96:1027-1039.
7. Jacobs, D.R. Jr, Slavin, J. & Marquart, L. (1995), Entire grain consumption and most cancers: a assessment of the literature. Nutr Most cancers.;24(3):221-9.
8. Papandreou, C., Becerra-Tomás, N., Bulló, M., Martínez-González, M.Á. et al (2018), Legume consumption and threat of all-cause, cardiovascular, and most cancers mortality within the PREDIMED research. Clin Nutr.;pii: S0261-5614(17)31439-5. https://www.ncbi.nlm.nih.gov/pubmed/29352655
9. Zhang, J., Jia, P.P., Liu, Q.L., et al (2018), Low ketolytic enzyme ranges in tumors predict ketogenic weight loss program responses in most cancers cell traces in vitro and in vivo. J Lipid Res.;59(4):625-634. https://www.ncbi.nlm.nih.gov/pubmed/29414764
10. Xia, S., Lin, R., Jin, L., et al (2017). Prevention of Dietary-Fats-Fueled Ketogenesis Attenuates BRAF V600E Tumor Development. Cell Metab.;25(2):358-373. https://www.ncbi.nlm.nih.gov/pubmed/28089569
11. Ibid.
12. Bonuccelli, G., Tsirigos, A., Whitaker-Menezes, D. et al (2010), Ketones and lactate “gas” tumor development and metastasis: Proof that epithelial most cancers cells use oxidative mitochondrial metabolism. Cell Cycle;9(17):3506-14. https://www.ncbi.nlm.nih.gov/pubmed/20818174
13. Martinez-Outschoorn, U.E., Lin, Z., Whitaker-Menezes, D., Howell, A., Sotgia, F. & Lisanti, M.P., (2012), Ketone physique utilization drives tumor development and metastasis. Cell Cycle.;11(21):3964-71. https://www.ncbi.nlm.nih.gov/pubmed/23082722
14. Saraon, P., Cretu, D., Musrap, N., et al. (2013), Quantitative proteomics reveals that enzymes of the ketogenic pathway are related to prostate most cancers development. Mol Cell Proteomics.;12(6):1589-601. https://www.ncbi.nlm.nih.gov/pubmed/23443136
15. Zhang, J., Jia, P.P., Liu, Q.L., et al (2018), ibid.
16. Schwartz, L., Seyfried, T., Alfarouk, Ok.O., Da Veiga Moreira, J. & Fais, S., (2017), ibid.
17. Miller, V.J., Villamena, F.A. & Volek, J.S, (2018), Dietary Ketosis and Mitohormesis: Potential Implications for Mitochondrial Operate and Human Well being. J Nutr Metab. 2018:5157645. https://www.ncbi.nlm.nih.gov/pubmed/29607218
18. Di Biase, S. & Longo, V.D. (2015), Fasting-induced differential stress sensitization in most cancers therapy. Mol Cell Oncol.;3(3):e1117701. https://www.ncbi.nlm.nih.gov/pubmed/27314084
19. Safdie, F.M., Dorff, T., Quinn, D., et al. (2009), Fasting and most cancers therapy in people: A case collection report. Growing old (Albany NY).;1(12):988-1007. https://www.ncbi.nlm.nih.gov/pubmed/20157582/
20. Caffa, I., D’Agostino, V., Damonte, P., et al (2015). Fasting potentiates the anticancer exercise of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget;6(14):11820-32. https://www.ncbi.nlm.nih.gov/pubmed/25909220
21. Cheng, C.W., Adams, G.B., Perin, L., et al. (2014), Extended fasting reduces IGF-1/PKA to advertise hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell.;14(6):810-23. https://www.ncbi.nlm.nih.gov/pubmed/24905167
22. Campbell, T.C. (2017), Most cancers Prevention and Remedy by Wholistic Diet. J Nat Sci.; 3(10): e448. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646698/
23. Frattaroli, J., Weidner, G., Dnistrian, A.M. et al (2008), Medical occasions in prostate most cancers way of life trial: outcomes from two years of follow-up. Urology. 72(6):1319-23. https://www.ncbi.nlm.nih.gov/pubmed/18602144
24. Goldhamer. A.C., Klaper, M,, Foorohar, A. & Myers, T.R., (2015), Water-only fasting and an completely plant meals weight loss program within the administration of stage IIIa, low-grade follicular lymphoma. BMJ Case Rep.;2015:bcr2015211582. https://www.ncbi.nlm.nih.gov/pubmed/26655228
25. Fontana, L., Partridge, L. & Longo, V.D. (2010), Extending wholesome life span–from yeast to people. Science.;328(5976):321-6. https://www.ncbi.nlm.nih.gov/pubmed/20395504