Ketogenic diets are high in fat, moderate in protein and low in carbohydrates, with weak to preliminary evidence of anticancer effects, relief of side effects, and benefits on your body terrainthe internal conditions of your body, including nutritional status, fitness, blood sugar balance, hormone balance, inflammation and more.
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Modes of action: metabolism
Inducing ketosis: countering the Warburg effect
Some cancer cells within tumors, as well as tumor-associated cells (such as fibroblasts and macrophages) undergo metabolic changes in response to hypoxia (low oxygen and oxidative stress) of the tumor microenvironment.1Martinez-Outschoorn U, Sotgia F, Lisanti MP. Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Seminars in Oncology. 2014 Apr;41(2):195-216.
A key alteration of these cells is converting to a complete dependence on glucose for energy generation. These catabolic cells do not have intact mitochondria, and so normal energy production via citric acid cycling and oxidative phosphorylation is not available.
Cells with intact mitochondria can use various metabolic substrates including glucose, fatty acids, glutamine and even ketones to fuel energy production. Catabolic cancer cells and tumor associated stromal cells, on the other hand, lose the ability to make ATP in the mitochondria and instead rely solely upon metabolizing glucose via glycolysis in the cytoplasm to generate ATP.2Schroeder U, Himpe B et al. Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutrition and Cancer. 2013;65(6):843-9. This is called the Warburg effect and is a known attribute of the tumor microenvironment.
Typical Western diets high in refined carbohydrates provide this glucose substrate as well as promote the insulin pathway, releasing growth factors that are associated with promoting cancer development and progression.3Erickson N, Boscheri A, Linke B, Huebner J. Systematic review: isocaloric ketogenic dietary regimes for cancer patients. Medical Oncology. 2017 May;34(5):72. A ketogenic diet, which severely limits the supply of glucose in favor of ketones, is thought to selectively starve these tumor cells. Evidence suggests that some cancer cells appear less able to metabolize ketones compared with healthy cells.4Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends in Biochemical Sciences. 2016;41(3):211-218; Zhao L, Mao Y, Zhao Y, Cao Y, Chen X. Role of multifaceted regulators in cancer glucose metabolism and their clinical significance. Oncotarget. 2016;7(21):31572-31585; Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F, Lisanti MP. Ketone body utilization drives tumor growth and metastasis. Cell Cycle. 2012 Nov 1; 11(21): 3964–3971; Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. Journal of General Physiology. 1927;8(6):519-530.
Of note, while both caloric restriction and a ketogenic diet lower blood glucose and insulin levels, only calorie restriction also lowers fatty acids, and fatty acids may be an important part of anticancer action with some tumors. A mouse study found that only caloric restriction inhibited the growth of select pancreatic tumor allografts in mice. A ketogenic diet alone did not. Further, a higher-fat caloric-restriction diet conferred resistance to the effects of caloric restriction. Altering the fat composition of a ketogenic diet to increase levels of saturated fatty acids in tumors decreased tumor stearoyl-CoA desaturase (SCD) activity to slow tumor growth.5Lien EC, Westermark AM et al. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature. 2021 Nov;599(7884):302-307.
The impact of ketosis on cancer cells does not rely solely on the Warburg effect. The effects of ketosis may induce oxidative stress specific to cancer cells, which may potentiate the effect of chemotherapy and radiation.6Zick SM, Snyder D, Abrams DI. Pros and cons of dietary strategies popular among cancer patients. Oncology (Williston Park). 2018 Nov 15;32(11):542-7.
Reverse Warburg effect: cancer cells adapt
Researchers have proposed the reverse Warburg effect. As tumor-associated cells such as fibroblasts and immune cells struggle under the highly oxidative tumor environment, these cells lose the ability to retain oxidative phosphorylation and, instead, revert to glycolysis for energy production and start to undergo autophagy, a process of self-digestion. The glycolysis and autophagy generate many energy-rich substrates such as fatty acids, lactate, and ketones which these tumor-associated cells release. These substrates are then taken up by growing (anabolic) cancer cells as fuel.
Experiments show that some tumor cells are able to use lactate and ketones for energy.7Schroeder U, Himpe B et al. Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutrition and Cancer. 2013;65(6):843-9; Martinez-Outschoorn UE, Lisanti MP, Sotgia F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Seminars in Cancer Biology. 2014 Apr;25:47-60; Martinez-Outschoorn UE, Lin Z et al. Ketone body utilization drives tumor growth and metastasis. Cell Cycle. 2012 Nov 1;11(21):3964-71; Maurer GD, Brucker DP et al. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer. 2011 Jul 26;11:315; Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. British Journal of Cancer 2003;89:1375–82. In this way, tumor-associated cells essentially feed growing cancer cells, the reverse Warburg effect.8Bonuccelli G, Tsirigos A et al. Ketones and lactate can actually “fuel” tumor growth, angiogenesis and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 2010;9:3506–14; Martinez-Outschoorn UE, Prisco M et al. Ketones and lactate increase cancer cell “stemness”, driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via metabolo-genomics. Cell Cycle 2011;10:1271–86. “In vitro data showed that cancer cells not only adapt to the situation but develop mutations and characteristics of stem cells. One hypothesis is that the [ketogenic] diet puts the tumor under stress and thus selects for resistance and malignancy. In an experiment on mice, the tumors in the diet-treated group initially grew less but later tumor growth accelerated and exceeded that of the control group.”9Huebner J, Marienfeld S et al. Counseling patients on cancer diets: a review of the literature and recommendations for clinical practice. Anticancer Research 2014;34:39–48.
Researchers propose that the Warburg and reverse Warburg effects are not totally competitive, but rather reflect the ability of cancer cells to use different metabolic substrates depending upon what is available and what mutations are present.10Yaojie Fu, Shanshan Liu et al. The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy. Oncotarget. 2017 Aug 22; 8(34): 57813–57825; Branco AF, Ferreira A et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. European Journal of Clinical Investigation. 2016 Mar;46(3):285-98.
The glycolytic pattern is not the only way cancer metabolizes glucose, and therapeutics including the ketogenic diet targeting glycolysis in cancer patients have not always had positive responses.11Yaojie Fu, Shanshan Liu et al. The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy. Oncotarget. 2017 Aug 22; 8(34): 57813–57825.
Lower risk of cachexia
Ketogenic diets may have a protein-sparing effect that preserves lean body mass, reducing the risk or severity of cancer cachexia.12Zick SM, Snyder D, Abrams DI. Pros and cons of dietary strategies popular among cancer patients. Oncology (Williston Park). 2018 Nov 15;32(11):542-7.
Notable preclinical evidence; clinical evidence is summarized in How can a ketogenic diet help me? What the research shows ›
Improving treatment outcomes: preclinical evidence
- Prolonged survival among mice with metastatic cancer treated with a KD combined with hyperbaric oxygen compared to using either therapy alone13Poff AM, Ari C, Seyfried TN, D’Agostino DP. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One. 2013 Jun 5;8(6):e65522.
- Better survival times among mice mostly with brain cancers but also prostate, stomach, or colorectal cancers fed an unrestricted KD compared to a high carbohydrate standard diet in a meta-analysis of preclinical trials14Klement RJ, Champ CE, Otto C, Kämmerer U. Anti-tumor effects of ketogenic diets in mice: a meta-analysis. PLoS One. 2016 May 9;11(5):e0155050.
- Improved survival15Stafford P, Abdelwahab MG, Kim DY, Preul MC, Rho JM, Scheck AC. The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutrition & Metabolism (Lond). 2010 Sep 10;7:74. or slower tumor growth16Scheck AC, Abdelwahab MG et al. Abstract 638: Mechanistic studies of the ketogenic diet as an adjuvant therapy for malignant gliomas. Cancer Research. 2010 Apr; 70 ( 8 Suppl ):638. in mice with glioma fed a KD
- Enhanced antitumor effects of radiation among mice with malignant glioma fed a KD compared to a standard diet17Abdelwahab MG, Fenton KE et al. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS One. 2012;7(5):e36197; Scheck AC, Abdelwahab MG et al. Abstract 638: Mechanistic studies of the ketogenic diet as an adjuvant therapy for malignant gliomas. Cancer Research. 2010 Apr; 70 ( 8 Suppl ):638.
Breast cancer (mammary cancer)
- Slower mammary tumor growth and increased tumor latency in mice fed a KD,18Gluschnaider U, Hertz R et al. Long-chain fatty acid analogues suppress breast tumorigenesis and progression. Cancer Research. 2014 Dec 1;74(23):6991-7002. and this effect was increased when mice were also treated with metformin19Zhuang Y, Chan DK, Haugrud AB, Miskimins WK. Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo. PLoS One. 2014 Sep 25;9(9):e108444.
- Reduced tumor weight among animals transplanted with MAC16 colon adenocarcinoma fed a KD20Beck SA, Tisdale MJ. Nitrogen excretion in cancer cachexia and its modification by a high fat diet in mice. Cancer Research. 1989 Jul 15;49:3800–4.
- Delayed tumor growth in a mouse stomach cancer xenograft model fed a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides compared to an unrestricted standard diet21Otto C, Kaemmerer U et al. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 2008;8:122.
- Slower tumor growth among lung cancer xenograft mice treated with KD and radiation compared to radiation alone (assuming a standard diet), or when KD was used with carboplatin and radiation compared to controls22Allen BG, Bhatia SK et al. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clinical Cancer Research. 2013 Jul 15;19(14):3905-13.
- Higher tumor NADH and less tumor growth, tripling the survival benefits of chemotherapy alone, in mice fed a ketogenic diet added to chemotherapy; chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system23Yang L, TeSlaa T et al. Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth. Med. 2022;3(2):119-136.e8.
Insufficient (preclinical) evidence of slower tumor growth and improved survival, and little difference in effect with 0% compared to 20% carbohydrate in the diet
- Reduced prostate tumor growth and prolonged survival among mice with an unrestricted no-carbohydrate ketogenic diet compared to Western diet24Freedland SJ, Mavropoulos J et al. Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate. 2008 Jan 1;68:11–9.
- Prolonged survival among prostate cancer xenograft mice with a no-carbohydrate ketogenic diet compared to either a low-fat/high-carbohydrate diet or a high-fat/moderate-carbohydrate diet, in amounts to maintain similar body weights across groups25Mavropoulos JC, Buschemeyer WC et al. The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prevention Research (Philadelphia, Pennsylvania). 2009 Jun;2:557–65.
- No slowing of adenocarcinoma development among prostate cancer xenograft mice with an unrestricted no-carbohydrate ketogenic diet compared to an unrestricted Western diet26Allott EH, Macias E et al. Impact of carbohydrate restriction in the context of obesity on prostate tumor growth in the Hi-Myc transgenic mouse model. Prostate Cancer and Prostatic Diseases. 2017 Jun;20(2):165-171. Note: the mice in this study on the ketogenic diet had higher body weights at 6 months, and the authors conclude that “although carbohydrate restriction within the context of obesity may reduce obesity-associated systemic inflammation, it is not sufficient to counteract obesity-associated tumor growth.” Calorie restriction with KD may be important.
- Slower prostate cancer tumor growth among castrated mice with a 20% carbohydrate diet (calorie-controlled relative to the Western diet) compared to an unrestricted Western diet, and similar to 0% and 10% carbohydrate diets27Caso J, Masko EM et al. The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model. Prostate. 2013 Apr;73(5):449-54.
- Similar survival among mice with prostate cancer with a low-carbohydrate diet (10–20% carbohydrate kcal) compared to a calorie-maintained no-carbohydrate ketogenic diet (0% carbohydrate kcal)28Masko EM, Thomas JA et al. Low-carbohydrate diets and prostate cancer: How low is “low enough”? Cancer Prevention Research (Philadelphia, Pennsylvania). 2010 Sep;3(9):1124-31.
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