Dietary Ketosis In
The Treatment of Solid Tissue Malignancy

Dr. Dana Myatt

 “Attack by stratagem: hence, to fight and conquer in all your battles is not supreme excellence;
supreme excellence consists in breaking the enemy’s resistance without fighting.”
—Sun Tzu, “The Art of War”

Many believe that cancer cells, damaged by mutation, are more resilient than normal cells. However, malignant cells are largely incapable of the metabolic flexibility displayed by normal cells, and therein lies their weakness and the potential for a gentle but highly effective point of attack.

Nutritional and botanical factors can have profound positive effects in cancer treatment, but the single most potent anti-cancer strategy documented in the medical literature strikes at the core of cancer’s metabolism: glycolysis, especially anaerobic glycolysis, and impaired mitochondrial function.

Numerous animal and human studies have demonstrated that the glycolytic pathway of cancer cells can be confounded by dietary-induced ketosis, often with profound apoptotic effects on cancer cells but without negative consequence — and in fact with protective effects — to normal cells.(1-6) Metabolic ketosis curtails cancer growth by a variety of mechanisms including:

1. Decreasing the glucose substrate required for cancer cell metabolism. Most tumors express abnormalities in the number and function of their mitochondria. (7-12) Such abnormalities prevent the bioenergetic utilization of ketone bodies, which require functional mitochondria for their oxidation.
2. Decreasing insulin, a secondary growth factor for cancer cells. (13-14)
3. Decreasing inflammation. Inflammation acts to promote cancer by altering cell-to-cell communication and delaying local detoxification.(15-25) Metabolic ketosis has significant anti-inflammatory effects. (9, 26-29)
4. Decreasing ROS production. Reactive Oxygen Species are known to promote cancer (30-33); metabolic ketosis decreases ROS production. (34-37)
5. Reversing cachexia while simultaneously decreasing tumor weight. (38-40)
6. Decreasing angiogenesis. (29, 41-42)
7. Inducing apoptosis. (11,29,38)
8. Suppressing the p53 oncogene, the most common point mutation observed in human cancer; more than 50% of all human tumors examined to date have identifiable p53 gene point mutations or deletions. A ketogenic diet has been shown to suppress the p53 oncogene in animal models. (43)
9. Acting synergistically with chemotherapy and/or specific nutritional supplementation. (44-45)

In spite of improved availability of foods containing anti-carcinogenic phytonutrients and vitamins, most types of cancer have not declined as expected. This correlates to the overall calorie increase and overweight condition of our society, a condition which puts us in “constant feast” mode instead of the periodic fasting our ancestors previously experienced. (46) Some observers feel that our previous occasional fasts, which would induce ketosis, were beneficial for cancer control. It has also been hypothesized that alternative “cancer diets” such as juice fasting, calorie restriction or the use of Coley’s toxins are effective primarily because they induce metabolic ketosis.

This presentation will serve as a review of the behavior and biochemistry of cancer cells common to all solid tissue malignancies and present a novel but well-documented clinical nutritional strategy which targets multiple cancer cell vulnerabilities while simultaneously protecting the function of normal cells and tissue.

References:

1.) Al-Zaid NS, Dashti HM, Mathew TC, Juggi JS. Low carbohydrate ketogenic diet enhances cardiac tolerance to global ischaemia. Acta Cardiol. 2007 Aug;62(4):381-9.
2.) Kodde IF, van der Stok J, Smolenski RT, de Jong JW. Metabolic and genetic regulation of cardiac energy substrate preference. Comp Biochem Physiol A Mol Integr Physiol. 2007 Jan;146(1):26-39. Epub 2006 Oct 3.
3.) Smith SL, Heal DJ, Martin KF.KTX 0101: a potential metabolic approach to cytoprotection in major surgery and neurological disorders. CNS Drug Rev. 2005 Summer;11(2):113-40
4.) Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149-61; discussion 162-3.
5.) Suzuki M, Suzuki M, Sato K, Dohi S, Sato T, Matsuura A, Hiraide A. Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol. 2001 Oct;87(2):143-50
6.) Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL.D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5440-4.
7.) Meixensberger J, Herting B, Roggendorf W, Reichmann H: Metabolic patterns in malignant gliomas. J Neurooncol 1995, 24:153-161
8.) Pedersen PL: Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 1978, 22:190-274.
9.) 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. Br J Cancer. 2003 Oct 6;89(7):1375-82.
10.) Fearon KC.: Nutritional pharmacology in the treatment of neoplastic disease. Baillieres Clin Gastroenterol. 1988 Oct;2(4):941-9.
11.) Skinner R, Trujillo A, Ma X, Beierle EA. Ketone bodies inhibit the viability of human neuroblastoma cells. J Pediatr Surg. 2009 Jan;44(1):212-6; discussion 216.
12.) Muti P, Quattrin T, Grant BJ, Krogh V, Micheli A, Schünemann HJ, Ram M, Freudenheim JL, Sieri S, Trevisan M, Berrino F. Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev, 2002 Nov;11(11):1361-8.
13.) Venkateswaran V, Haddad AQ, Fleshner NE, Fan R, Sugar LM, Nam R, Klotz LH, Pollak M. Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts.J Natl Cancer Inst. 2007 Dec 5;99(23):1793-800. Epub 2007 Nov 27.
14.) Borugian MJ, Sheps SB, Kim-Sing C, Van Patten C, Potter JD, Dunn B, Gallagher RP, Hislop TG. Insulin, macronutrient intake, and physical activity: are potential indicators of insulin resistance associated with mortality from breast cancer? Cancer Epidemiol Biomarkers Prev. 2004 Jul;13(7):1163-72.
15.) Khan G.: Epstein-Barr virus, cytokines, and inflammation: A cocktail for the pathogenesis of Hodgkin’s lymphoma? Exp Hematol. 2006 Apr;34(4):399-406.
16.) Dalgleish AG, O’Byrne K. Inflammation and cancer: the role of the immune response and angiogenesis. Cancer Treat Res. 2006;130:1-38.
17.) Schottelius AJ, Dinter H.: Cytokines, NF-kappaB, microenvironment, intestinal inflammation and cancer. Cancer Treat Res. 2006;130:67-87.
18.) Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S.: Plasma C-reactive protein and risk of colorectal cancer in a nested case-control study: Japan public health center-based prospective study. Cancer Epidemiol Biomarkers Prev. 2006 Apr;15(4):690-5.
19.) Dobrovolskaia MA, Kozlov SV.: Inflammation and cancer: when NF-kappaB amalgamates the perilous partnership.Curr Cancer Drug Targets. 2005 Aug;5(5):325-44.
20.) Naldini A, Carraro F.: Role of inflammatory mediators in angiogenesis. Curr Drug Targets Inflamm Allergy. 2005 Feb;4(1):3-8.
21.) Ohshima H, Tazawa H, Sylla BS, Sawa T.: Prevention of human cancer by modulation of chronic inflammatory processes. Mutat Res. 2005 Dec 11;591(1-2):110-22. Epub 2005 Aug 3.
22.) Coussens LM, Werb Z.: Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7.
23.) Stewart JW, Koehler K, Jackson W, Hawley J, Wang W, Au A, Myers R, Birt DF: Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition.Carcinogenesis 2005, 26:1077-1084
24.) Zhu Z, Jiang W, Thompson HJ: Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas. Carcinogenesis 2003, 24:1225-1231.
25.) Patel NV, Finch CE: The glucocorticoid paradox of caloric restriction in slowing brain aging.Neurobiol Aging 2002, 23:707-717.
26.) Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet.Behav Pharmacol. 2006 Sep;17(5-6):431-9.
27.) Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2009 Mar;59(2):293-315. Epub 2008 Sep 25.
28.) Garai J, Lóránd T, Molnár V. Ketone bodies affect the enzymatic activity of macrophage migration inhibitory factor. Life Sci. 2005 Aug 5;77(12):1375-80.
29.) Seyfried TN, Kiebish M, Mukherjee P, Marsh J. Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets. Epilepsia. 2008 Nov;49 Suppl 8:114-6.
30.) Shi DY, Xie FZ, Zhai C, Stern JS, Liu Y, Liu SL. The role of cellular oxidative stress in regulating glycolysis energy metabolism in hepatoma cells. Mol Cancer. 2009 Jun 5;8(1):32. [Epub ahead of print]
31.) Halliwell B. Oxidative stress and cancer: have we moved forward? Biochem J. 2007 Jan 1;401(1):1-11.
32.) Brown N., Bicknell R. Hypoxia and oxidative stress in breast cancer: Oxidative stress – its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res 2001, 3:323-327.
33.) Wiseman H, Halliwell B: Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 1996, 313:17-29.
34.) Veech RL: The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004, 70:309-319.
35.) Veech RL: Metabolic control analysis of ketone and insulin action: Implications for phenotyping of disease and design of therapy. Lecture: The Dynamic and Energetic Basis of Health and Aging Monday, Nov 11 – Wednesday, Nov 13, 2002, The Cloister’s, NIH, Bethesda MD.
36.) Masuda R, Monahan JW, Kashiwaya Y: D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res 2005, 80:501-509.
37.) Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007 Jan;48(1):43-58.
38.) Beck SA, Tisdale MJ. Effect of insulin on weight loss and tumour growth in a cachexia model. Br J Cancer. 1989 May;59(5):677-81.
39.) Tisdale MJ, Brennan RA, Fearon KC. Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J Cancer. 1987 Jul;56(1):39-43
40.) Beck SA, Tisdale MJ. Nitrogen excretion in cancer cachexia and its modification by a high fat diet in mice. Cancer Res. 1989 Jul 15;49(14):3800-4.
41.) Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer.Nutr Metab (Lond). 2007 Feb 21;4:5.
42.) Seyfried TN, Mukherjee P. Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (Lond). 2005 Oct 21;2:30.
43.) Berrigan D, Perkins SN, Haines DC, Hursting SD.: Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis. 2002 May;23(5):817-22.
44.) Marsh J, Mukherjee P, Seyfried TN. Drug/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-D-glucose and the restricted ketogenic diet. Nutr Metab (Lond). 2008 Nov 25;5:33.
45.) Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, Voelker HU, Thiede A, Coy JF. 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 Apr 30;8:122.
46.) Wargovich MJ, Cunningham JE.:Diet, individual responsiveness and cancer prevention. J Nutr. 2003 Jul;133(7 Suppl):2400S-2403S.