Metabolic Therapies – Kosmos Publications

November 28, 2023 By Angie N Choi, EdD, Author of Whole New Me: Healing From Cancer in Body, Mind, and Spirit The metabolic approach to cancer impairs cancer cells' metabolism. There are several metabolic approaches or treatments that may be combined for even greater effectiveness in reducing tumors. In this article, metabolic activity in cancer will be explained along with several metabolic treatments like the ketogenic diet, other dietary therapies, glutamine inhibition, antiparasitic medication, fasting, and hyperbaric oxygen therapy. I combined several of these metabolic therapies successfully to heal from ovarian cancer. I was diagnosed with a large tumor, the size of a cantaloupe, on my left ovary and decided to do standard treatment, a total hysterectomy with salpingo-oopherectomy (surgical removal of fallopian tubes and ovaries) to remove the tumor. During the debulking process however, spillage occurred, so my oncologist recommended 6 rounds of chemotherapy. I opted out of chemotherapy and chose a metabolic approach to cancer instead. I was concerned about my quality of life during and after standard treatment as well as secondary cancers related to chemotherapy.1-3 The metabolic approach, based upon Dr. Thomas Seyfried’s research on cancer as a metabolic disease,4 provided the scientific basis to make evidence-based, informed decisions to pursue non-toxic therapies for cancer treatment. Metabolic activity in cancer Metabolism refers to the process of converting energy from food into cellular energy, a series of biochemical processes that results in the production of adenosine triphosphate or ATP, energy-carrying molecules.5 When food is initially eaten, it is in large macromolecules that must be broken down into simple compounds through enzymatic actions.6 Proteins are broken down into amino acids, carbohydrates into glucose, and fats into fatty acids and glycerol. Oxygen is required to produce energy from eating food, and this process is called aerobic (with oxygen) respiration. There are three main steps involved in aerobic respiration.7 Glycolysis Tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or Citric acid cycle Electron transport chain Glycolysis, the first phase, is the process where glucose is converted into pyruvate, the end product of glycolysis. Then, the next steps for pyruvate depend upon whether cells have 1) mitochondria and 2) sufficient oxygen or not. Mitochondria are organelles in cells that generate the majority of the chemical energy needed for biochemical reactions. If cells have mitochondria and sufficient oxygen is present, then the citric acid cycle is initiated followed by the electron transport chain process which can yield up to 32 ATP. This process is called oxidative phosphorylation. However, if cells do not have mitochondria (like bacteria) or enough oxygen is not present, then, pyruvate converts to lactate molecules which is referred to as anaerobic (without oxygen) glycolysis. Tumor cells have a special feature in relation to glycolysis where they take the path of anaerobic glycolysis even though they have mitochondria and sufficient oxygen is present. This means the pyruvate created during glycolysis converts to lactate – instead of following the pathway of aerobic respiration ― and only yields 2 ATP per glucose molecule. This is a highly inefficient route that cancer cells take. Why would cancer cells that require enormous amounts of energy for their rapid growth take this paradoxically inefficient pathway given that they have mitochondria and enough oxygen is present? It is because they have damaged mitochondria and cannot properly use oxygen to produce energy (to “breathe” or respirate), thereby requiring a primitive, fermentation (anaerobic) process instead.8 In the 1920s, Dr. Otto Warburg, a German physiologist, physician, and Nobel laureate (1931), observed that cancer cells, unlike healthy cells, fermented glucose (an anaerobic process) at abnormally high rates even when sufficient oxygen was present.9 This observation of cancer cells’ abnormal behavior was eponymously called the Warburg effect. Electron microscopy, unavailable during Warburg’s time, has since revealed that almost all cancer cells have damaged mitochondria.10 Metabolic Therapies for Cancer There are several metabolic therapies for cancer that are promising as listed below. Ketogenic Diet Calorie Reduction Diet Extremely Low Carbohydrate Diet Glutamine Inhibition (Antiparasitic medications) Fasting (water fasting, short-term fasting, intermittent fasting) Hyperbaric Oxygen Therapy Ketogenic diet A ketogenic diet is a high fat, moderate protein, and low carbohydrate diet that produces ketone bodies instead of glucose as fuel for the body. When we stop eating carbohydrates whether through a carbohydrate-restrictive diet or fasting, our bodies burn their glucose stores in the liver in the form of glycogen and metabolically switch over to using ketones for fuel.11 This change in diet effectively starves cancer cells of glucose, their primary fuel source. Humans have evolved to be able to survive on ketones when food is scarce as our early ancestors experienced when they could not obtain food. The body and the brain are able to utilize ketones for energy. Cancer cells however are unable to fuel their rapid growth without glucose, though they can adapt to use glutamine. This metabolic inflexibility in cancer cells allows us to exploit this weakness by adopting a ketogenic diet.12 Healthy cells are able to use ketones to create energy for the body to use, but cancer cells cannot use ketones and effectively starve, which makes them vulnerable to cellular death or apoptosis. In my case, a therapeutic ketogenic diet was the main therapy in the metabolic approach to cancer. My macronutrient ratio for fats, protein, and carbohydrates was 7:2:1 for each meal. For example, if I had a meal of 500 calories, 350 calories (70%) were fat, 100 (20%) were protein, and 50 (10%) were carbohydrates. The major portion of each meal was unsaturated fats such as avocados, olives, butter, macadamia nut butter, and olive, avocado and coconut oils. For protein, I ate foods with higher fat content such as eggs, salmon, mackerel, sardines, and lamb. I could only have a few grams of carbohydrates each meal in the form of cucumbers, salad greens, and cruciferous vegetables. All of these food sources were organic, pasture-raised, and wild-caught to minimize exposure to grains in feed, GMOs, pesticides, antibiotics, and hormones. Additionally, even though I was on a ketogenic diet, I still needed to limit my overall calorie intake. A therapeutic ketogenic diet is effective for managing cancer, but when combined with calorie restriction, the anti-cancer effects increase. I wrote another article on my experience with the ketogenic diet starving cancer cells of glucose for those who want more information. Dietary metabolic therapies The foundations of metabolic therapies are primarily dietary and involve either restricted caloric intake or low glucose consumption. Early studies noted the positive effects of caloric reduction on tumors in mice.13,14 Other researchers found that the positive effects on tumor cells were due to caloric content independent of dietary content.15 The caloric count of the food was more significant than the nutritional content or specified diet for fighting tumor growth.16 In comparisons between caloric restriction and a ketogenic diet for brain cancer, results indicated a synergistic effect between the two metabolic treatments. For example, when mice were fed a ketogenic diet but could eat as much as they liked, tumors did not shrink; however, if they ate a reduced-calorie ketogenic diet that lowered body weight, tumors reduced significantly.17,18 Glutamine inhibition Besides glucose, glutamine, an amino acid derived from protein, also feeds some types of cancer cells. Glutamine is the most abundant amino acid circulating in the body so there is no specific diet that can completely eliminate glutamine,19 but studies have indicated that glutamine antagonists are effective for various types of cancer.20 The glutamine suppressor 6-diazo-5-oxo-L-norleucine (DON) in combination with a ketogenic diet was found to be effective in killing tumor cells and reversing disease symptoms in brain tumors in mice.21 Despite its effectiveness as a glutamine antagonist, DON produces toxicity and side effects which has prevented it from reaching clinical trials.22 It is also difficult to obtain, expensive, and must be delivered intravenously. Antiparasitic medication Antiparasitic medications, commonly used to treat worms, have similar therapeutic efficacy as DON and can be repurposed (used off-prescription) to treat cancer.23-25 Antiparasitic drugs like mebendezole are inexpensive and have a record of low toxicity in humans.26 Other studies have indicated that prolonged use of some antiparasitic medications like albendazole cause liver toxicity.27 The efficacy of antiparasitic medications is greater when combined with ketogenic dietary therapy as cancer cells undergo increased metabolic pressure.28 The combination of a ketogenic diet with glutamine inhibition creates a press-pulse effect that has greater efficacy than either alone.29 The ketogenic diet acts as a long-term pressure (press) and antiparasitic medication acts as an intermittent and concentrated stressor (pulse) to devastate tumor cells. In my case, I used a therapeutic ketogenic diet along with the canine antiparasitic febendezole. Prior to working with an integrative doctor, I was unable to get mebendazole as it requires a prescription from a doctor. Most conventional physicians will not prescribe medications off label, but integrative doctors who understand the metabolic approach will be more supportive. It is also important to be under the care of medical doctor or naturopathic doctor who understands metabolic therapy for cancer when doing this approach. Initially, instead of mebendazole, I used febendezole which is typically used to deworm dogs. A prescription was not required to get it, but as with any drug, its toxicity, side effects, and long-term repercussions must be carefully considered. I found a material safety data sheet (MSDS) compiled by the company that produced the canine medication that indicated its chemical composition and toxicological information. I decided to take the risk and was on the medication for two months. The combination was effective and brought my cancer antigen levels way down to the lowest end of normal levels. Fasting Fasting is another metabolic therapy for cancer, but it can be difficult for people to do prolonged fasts especially if they are already in a weakened state. Calorie-restrictive diets are most effective soon after diagnosis when individuals have greater energy. Intermittent fasting (IF) is an alternative for those unable to undergo strict water fasts and shows promise for inhibiting tumor growth, though the relationship between long-term IF and harm from low calorie intake is not well studied.30 For patients undergoing chemotherapy, short-term fasting reduced treatment side effects, protected healthy cells from the toxicity of treatment, and demonstrated greater efficacy on cancer cells.31,32 In my case, after recovering from surgery, I combined intermittent fasting with the therapeutic ketogenic diet. I ate during a 6-hour window from 9:00 am to 3:00 pm (breakfast and lunch) and fasted until the next day. Approximately once a month, I also did a 1-3 day water fast. This combination put further metabolic pressure on cancer cells. Hyperbaric oxygen therapy Hyperbaric oxygen therapy (HBO) is another metabolic therapy that raises the amount of oxygen in tissues expressed in atmospheres (atmospheric pressure at sea level).33 Cancer cells thrive in hypoxic (low oxygen) environments by adapting their cellular metabolism. HBO saturates cells with oxygen to put metabolic stress on tumor cells. HBO exhibited anti-cancer effects (decrease in blood glucose, decrease in tumor growth rate and increase in mean survival time) in mice when combined with a ketogenic diet but not as a stand-alone treatment.34 Although there were concerns about HBO’s safety and a potential proliferative effect for tumors in early research, recent research indicated that HBO had a low risk of complications, did not increase growth in tumors, and reduced cancer growth for breast cancer, but not for cervical and bladder cancers.35 In conclusion, the commonality in these metabolic therapies for cancer management is that the combination of metabolic therapies is more effective than any alone. In fact, some therapies alone may not have much of an effect on tumor cells. I used a combination approach with a therapeutic ketogenic diet (with calorie reduction) and antiparasitic medication in a press pulse fashion. A therapeutic ketogenic diet, calorie reduction diet, or intermittent fasting could act as a long-term stressor (a press) on tumor cells and glutamine inhibition could act as an intermittent but concentrated stressor (a pulse) to devastate already weakened cancer cells.36 When I stopped taking the antiparasitic drugs, I continued the ketogenic diet and combined it with daily intermittent fasting, periodic short-term water fasting, and calorie reduction and the results were effective. My cancer antigens levels went down to extremely low levels and a CT-scan nine months later showed no evidence of disease. Metabolic therapy for cancer worked well for me, and others should be informed of these treatment options. Each person’s cancer can present differently, but what is common to all types of cancer is that they have damaged mitochondria. That is why a metabolic approach can be effective across many types of cancer. As always though with cancer, individuals may present with diverse physical, mental, and environmental terrain, and many may have undergone standard treatments like surgery, chemotherapy, or radiation, so the impact of dietary therapies must be considered individually. Moreover, some dietary therapies may be better for some individuals given their conditions. Working with certified nutritionists or naturopathic doctors (NDs) who specialize in the metabolic approach is highly recommended while also keeping your conventional oncologists or doctors informed. Here's another article on cancer nutritionists or oncology dietitians if you'd like to read more. They can be helpful allies on the road to recovering from cancer. References 1Aidan JC, Priddee NR, McAleer JJ. Chemotherapy causes cancer! A case report of therapy related acute myeloid leukemia in early stage breast cancer. Ulst Med J. 2013;82(2):97-99. 2Vega-Stromberg T. Chemotherapy-induced secondary malignancies. J Infus Nurs. 2003;26(6):353. 3Boffetta P, Kaldor JM. Secondary malignancies following cancer chemotherapy. Acta Oncologica. 1994;33(6): 591-598. 4Seyfried TN. Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer. John Wiley & Sons; 2012. 5Dashty, M. (2013). A quick look at biochemistry: carbohydrate metabolism. Clinical biochemistry, 46(15), 1339-1352. 6Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. How Cells Obtain Energy from Food. 7Bonora M, Patergnani S, Rimessi A, De Marchi E, et al. ATP synthesis and storage. Purinergic Signal. 2012 Sep;8(3):343-57. 8Seyfried TN. Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer. John Wiley & Sons; 2012. 9Koppenol, WH, Bounds, PL, & Dang, CV (2011). Otto Warburg’s contributions to current concepts of cancer metabolism. Nature Reviews Cancer, 11(5), 325-337. 10Glancy B. Visualizing Mitochondrial Form and Function within the Cell. Trends Mol Med. 2020 Jan;26(1):58-70. 11Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014 Feb 04;19(2):181-92. 12Seyfried TN. Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer. John Wiley & Sons; 2012. 13Rous P (1914) The influence of diet on transplanted and spontaneous mouse tumors. J Exp Med 20: 433–451 14Tannenbaum A, Silverstone H. The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice. Cancer Res. 1949;9(12):724–7. 15Tannenbaum A. The initiation and growth of tumors. Introduction I. Effects of underfeeding. Am J Cancer. 1940;38:335-350. 16Mukherjee P, Sotnikov AV, Mangian HJ, Zhou JR, Visek WJ, Clinton SK (1999a) Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J Natl Cancer Inst 91: 512–523 17Seyfried, TN, Sanderson, T., El-Abbadi, MM, McGowan, R, & Mukherjee, P. (2003). Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. British journal of cancer, 89(7), 1375-1382. 18Zhou, W., Mukherjee, P., Kiebish, M.A. et al. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 4, 5 (2007). 19Scriver, C. R., & Rosenberg, L. E. (1973). Amino acid metabolism and its disorders. Major Problems in Clinical Pediatrics, 10, 1–478. 20Li T, Copeland C, Le A. Glutamine Metabolism in Cancer. 2021 May 21. In: Le A, editor. The Heterogeneity of Cancer Metabolism [Internet]. 2nd edition. Cham (CH): Springer; 2021. 21Mukherjee, P., Augur, Z. M., Li, M., Hill, C., Greenwood, B., Domin, M. A., … & Seyfried, T. N. (2019). Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Communications Biology, 2(1), 200 22Li T, Copeland C, Le A. Glutamine Metabolism in Cancer. 2021 May 21. In: Le A, editor. The Heterogeneity of Cancer Metabolism [Internet]. 2nd edition. Cham (CH): Springer; 2021. 23Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience. 2014 Jul 10;8:443. 24Elayapillai, S, Ramraj, S, Benbrook, DM, et al. (2021). Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer. Gynecologic oncology, 160(1), 302-311. 25Bai, RY, Staedtke, V, Rudin, CM, Bunz, F, & Riggins, GJ. (2015). Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis. Neuro-oncology, 17(4), 545-554. 26Keystone JS, Murdoch JS(1979). Drugs Five Years Later: Mebendazole. Annals of Internal Medicine, 91(4), 582-586. 27Chai, JY, Jung, BK, & Hong, SJ(2021). Albendazole and mebendazole as anti-parasitic and anti-cancer agents: an update. The Korean Journal of Parasitology, 59(3), 189. 28Seyfried, TN, Mukherjee, P, Iyikesici, MS, Slocum, A, et al. (2020). Consideration of ketogenic metabolic therapy as a complementary or alternative approach for managing breast cancer. Frontiers in Nutrition, 21. 29Seyfried, TN, Yu, G, Maroon, JC, & D’Agostino, DP. (2017). Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutrition & metabolism, 14, 1-17. 30Zhao X, Yang J, Huang R, Guo M, Zhou Y, Xu L. The role and its mechanism of intermittent fasting in tumors: friend or foe? Cancer Biol Med. 2021 Feb 15;18(1):63-73. 31Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009; 1:988-1007 . 32de Groot, S., Pijl, H., van der Hoeven, J. J., & Kroep, J. R. (2019). Effects of short-term fasting on cancer treatment. Journal of Experimental & Clinical Cancer Research, 38(1), 1-14. 33Tibbles, PM, & Edelsberg, JS. (1996). Hyperbaric-oxygen therapy. New England Journal of Medicine, 334(25), 1642-1648. 34Poff, AM, Ari, C, Seyfried, TN, & D’Agostino, DP. (2013). The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PloS one, 8(6), e65522. 35Moen I, Stuhr LE. Hyperbaric oxygen therapy and cancer–a review. Target Oncol. 2012 Dec;7(4):233-42. 36Seyfried, TN, Yu, G, Maroon, JC, & D’Agostino, DP. (2017). Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutrition & metabolism, 14, 1-17.