Starvation of cancer via induced ketogenesis and severe hypoglycemia

Medical Hypotheses

Volumn 84, Issue 3, 2015, Pages 162-168

  Kapelner, Adam ^a   Vorsanger, Matthew ^b  

^a CITY UNIVERSITY OF NEW YORK   (United States)

^b NEW YORK UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE; METFORMIN; ANTIDIABETIC AGENT; GLUCOSE BLOOD LEVEL;

ANAEROBIC GLYCOLYSIS; APOPTOSIS; ARTICLE; BRAIN BLOOD FLOW; CANCER CELL; CANCER THERAPY; CELL DEATH; CELL METABOLISM; CYTOTOXICITY; ENERGY METABOLISM; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLUCOSE BRAIN LEVEL; HUMAN; HYPOGLYCEMIA; KETOGENESIS; KETOGENIC DIET; LOW CARBOHYDRATE DIET; NONHUMAN; STARVATION; ADAPTATION; BIOLOGICAL MODEL; DIET THERAPY; DRUG EFFECTS; NEOPLASMS; PHYSIOLOGY; PROCEDURES;

ADAPTATION, PHYSIOLOGICAL; BLOOD GLUCOSE; GLUCONEOGENESIS; HUMANS; HYPOGLYCEMIC AGENTS; KETOGENIC DIET; METFORMIN; MODELS, BIOLOGICAL; NEOPLASMS;

EID: 84925360151     PISSN: 03069877     EISSN: 15322777     Source Type: Journal    
DOI: 10.1016/j.mehy.2014.11.002     Document Type: Article

References (92)

1. Abdelwahab M.G., Fenton K.E., Preul M.C., Rho J.M., Lynch A., Stafford P., et al. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PloS One 2012, 7(5):e36197.
2. Aggarwal S. Targeted cancer therapies. Nat Rev Drug Discovery 2010, 9(6):427-428.
3. Allen B.G., Bhatia S.K., Buatti J.M., Brandt K.E., Lindholm K.E., Button A.M., et al. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clin Cancer Res: Off J Am Assoc Cancer Res 2013, 19(14):3905-3913.
4. Aykin-Burns N., Ahmad I.M., Zhu Y., Oberley L.W., Spitz D.R. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 2009, 418(1):29-37.
5. Ben-Ami H., Nagachandran P., Mendelson A., Edoute Y. Drug-induced hypoglycemic coma in 102 diabetic patients. Arch Internal Med 1999, 159(3):281-284.
6. Ben Sahra I., Le Marchand-Brustel Y., Tanti J.-F., Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug?. Mol Cancer Ther 2010, 9(5):1092-1099.
7. Borg M.A., Sherwin R.S., Borg W.P., Tamborlane W.V., Shulman G.I. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J Clin Invest 1997, 99(2):361-365.
8. Buzzai M., Bauer D.E., Jones R.G., Deberardinis R.J., Hatzivassiliou G., Elstrom R.L., et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene 2005, 24(26):4165-4173.
9. Cahill G., Veech R.L. Ketoacids? Good medicine?. Trans Am Clin Climatol Assoc 2003, 114:149-163.
10. Cahill G.F. Starvation in man. New Engl J Med 1970, 282:668-675.
11. Cahill G.F. Starvation. Trans Am Clin Climatol Assoc 1983, 94:1-21.
12. Carracedo A., Cantley L.C., Pandolfi P.P. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 2013, 13(4):227-232.
13. Chakrabarty M.L. Blood-sugar levels in slow starvation. The Lancet 1948, 251(6503):596-597.
14. Chang H.T., Olson L.K., Schwartz K.A. Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutr Metab 2013, 10(1):47.
15. Conway M.J., Goodner C.J., Werrbach J.H., Gale C.C. Studies of substrate regulation in fasting. J Clin Invest 1969, 48:1349-1362.
16. De Lorenzo M.S., Baljinnyam E., Vatner D.E., Abarzúa P., Vatner S.F., Rabson A.B. Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 2011, 32(9):1381-1387.
17. Deberardinis R.J., Sayed N., Ditsworth D., Thompson C.B. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 2008, 18(1):54-61.
18. Demetrakopoulos G.E., Linn B., Amos H. Rapid loss of ATP by tumor cells deprived of glucose: contrast to normal cells. Biochem Biophys Res Commun 1978, 82(3):787-794.
19. Drenick E.J., Alvarez L.C., Tamasi G.C., Brickman A.S. Resistance to symptomatic insulin reactions after fasting. J Clin Invest 1972, 51(10):2757-2762.
20. Elliott R., Barnett B. Ultrastructural observation of mitochondria in human breast carcinoma cells. Microsc Microanal 2011, 17(suppl 2):194-195.
21. Fine E., Segal-Isaacson C., Feinman R., Sparano J. Carbohydrate restriction in patients with advanced cancer: a protocol to assess safety and feasibility with an accompanying hypothesis. Community Oncol 2008, 5(1):22-26.
22. Fine E.J., Segal-Isaacson C.J., Feinman R.D., Herszkopf S., Romano M.C., 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):1028-1035.
23. Fine R.J., Miller A., Quadros E.V., Sequeira J.M., Feinman R.D. Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell Int 2009, 9(14):1-11.
24. Frier B.M., Schernthaner G., Heller S.R. Hypoglycemia and cardiovascular risks. Diabetes Care 2011, 34(suppl 2):S132-S137.
25. Ganapathy-Kanniappan S., Vali M., Kunjithapatham R., Buijs M., Syed L.H., Rao P.P., et al. 3-Bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr Pharm Biotechnol 2010, 11(5):510-517.
26. Graham N.A., Tahmasian M., Kohli B., Komisopoulou E., Zhu M., Vivanco I., et al. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol 2012, 8(589):1-16.
27. Gullino P., Grantham F., Courtney A., Losonczy I. Relationship between oxygen and glucose consumption by transplanted tumors in vivo. Cancer Res 1967, 27:1041-1052.
28. Holm E., Hagmüller E., Staedt U., Schlickeiser G., Gunther H.J., Leweling H., et al. Substrate balances across colonic carcinomas in humans. Cancer Res 1995, 55:1373-1378.
29. Husain Z., Seth P., Sukhatme V.P. Tumor-derived lactate and myeloid-derived suppressor cells: linking metabolism to cancer immunology. Oncoimmunology 2013, 2(11):e26383.
30. Iqbal M.A., Siddiqui F.A., Gupta V., Chattopadhyay S., Gopinath P., Kumar B., et al. Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer 2013, 12(1):72.
31. Jalving M., Gietema J.A., Lefrandt J.D., de Jong S., Reyners A.K.L., Gans R.O.B., et al. Metformin: taking away the candy for cancer?. Eur J Cancer 2010, 46(13):2369-2380.
32. Jelluma N., Yang X., Stokoe D., Evan G.I., Dansen T.B., Haas-Kogan D.A. Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes. Mol Cancer Res 2006, 4(5):319-330.
33. Jiang Y., Wang F. Caloric restriction reduces edema and prolongs survival in a mouse glioma model. J Neurooncol 2013, 114(1):25-32.
34. Jose C., Bellance N., Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma?. Biochim Biophys Acta 2011, 1807(6):552-561.
35. Kim S.H., Kim J.H., Hahn E.W. Selective potentiation of hyperthermic killing of hypoxic cells by 5-thio-d-glucose. Cancer Res 1978, 38:2935-2938.
36. Klement R.J., Champ C.E. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation. Cancer Metastasis Rev 2014, 217-229.
37. Koppenol W.H., Bounds P.L., Dang C.V. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011, 11(5):325-337.
38. Kossoff E.H., Turner Z., Bergey G.K. Home-guided use of the ketogenic diet in a patient for more than 20years. Pediatr Neurol 2007, 36(6):424-425.
39. Lee C., Raffaghello L., Brandhorst D., Safdie F.M., Bianchi G., Martin-Montalvo A., et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 2012, 4(124):124ra27.
40. Li Y., Liu L., Tollefsbol T.O. Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 2010, 24(5):1442-1453.
41. Magee B.A., Potezny N., Rofe A.M., Conyers R.A. The inhibition of malignant cell growth by ketone bodies. Aust J Exp Biol Med Sci 1979, 57(5):529-539.
42. Majumdar A.P.N., Banerjee S., Nautiyal J., Patel B.B., Patel V., Du J., et al. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutrition and cancer 2009, 61(4):544-553.
43. Martinez-Outschoorn U.E., Prisco M., Ertel A., Tsirigos A., Lin Z., Pavlides S., 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(8):1271-1286.
44. Masko E.M., Thomas J.A., Antonelli J.A., Lloyd J.C., Phillips T.E., Poulton S.H., et al. Low-carbohydrate diets and prostate cancer: how low is low enough?. Cancer Prev Res 2010, 3(9):1124-1131.
45. Mavropoulos J.C., Buschemeyer W.C., Tewari A.K., Rokhfeld D., Pollak M., Zhao Y., et al. The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res 2009, 2(6):557-565.
46. Mavropoulos J.C., Isaacs W.B., Pizzo S.V., Freedland S.J. Is there a role for a low-carbohydrate ketogenic diet in the management of prostate cancer?. Urology 2006, 68(1):15-18.
47. McCall A.L., Fixman L.B., Fleming N., Tornheim K., Chick W., Ruderman N.B. Chronic hypoglycemia increases brain glucose transport. Am J Physiol 1986, 251:E442-E447.
48. McDonald L. The ketogenic diet: a complete guide for the dieter and practitioner 1998, Morris Publishing, Austin, TX.
49. Moreno-Sánchez R., Rodríguez-Enríquez S., Marín-Hernández A., Saavedra E. Energy metabolism in tumor cells. The FEBS J 2007, 274(6):1393-1418.
50. Morris A.A.M. Cerebral ketone body metabolism. J Inherit Metab Dis 2005, 28(2):109-121.
51. Mukherjee P., Abate L.E., Seyfried T.N. Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res 2004, 10:5622-5629.
52. Mukherjee P., El-Abbadi M.M., Kasperzyk J.L., Ranes M.K., Seyfried T.N. Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model. Br J Cancer 2002, 86:1615-1621.
53. National Research Council (US) Food & Nutrition Board. Recommended dietary allowances. National Academy Press; 1989.
54. Neal E.G., Chaffe H., Schwartz R.H., Lawson M.S., Edwards N., Fitzsimmons G., et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008, 7(6):500-506.
55. New York Times. Sugar and cancer. Dec 24; 1887.
56. Niakan B. Spontaneous remission of cancer: steady and aggressive malignant growth faced with hypoxia or hypoglycemia. Med Hypotheses 2010, 75(6):505-506.
57. Oleksyszyn J. The complete control of glucose level utilizing the composition of ketogenic diet with the gluconeogenesis inhibitor, the anti-diabetic drug metformin, as a potential anti-cancer therapy. Med Hypotheses 2011, 77(2):171-173.
58. Oleksyszyn J., Wietrzyk J., Psurski M. Cancer could it be cured? A spontaneous regression of cancer, cancer energy metabolism, hyperglycemia-hypoglycemia, metformin, warburg and crabtree effects and a new perspective in cancer treatment. J Cancer Sci & Therapy 2014, 06(03):56-61.
59. Otto C., Kaemmerer U., Illert B., Muehling B., Pfetzer N., Wittig R., 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.
60. Owen O.E., Morgan A.P., Kemp H.G., Sullivan J.M., Herrera M.G., Cahill G.F. Brain metabolism during fasting. J Clin Invest 1967, 46(10):1589-1595.
61. Pedersen P.L. Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 1977, 22:190-274.
62. Phelps M.E. PET: molecular imaging and its biological applications 2004, Springer.
63. Phinney S.D., Bistrian B.R., Wolfe R.R., Blackburn G.L. The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. Metabolism 1983, 32(8):757-768.
64. Poff A.M., Ari C., Seyfried T.N., D'Agostino D.P. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PloS One 2013, 8(6):e65522.
65. Priebe A., Tan L., Wahl H., Kueck A., He G., Kwok R., et al. Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells. Gynecol Oncol 2011, 122(2):389-395.
66. Robinson A.M., Williamson D.H. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980, 60(1):143-187.
67. Sawai M., Yashiro M., Nishiguchi Y., Ohira M., Hirakawa K. Growth-inhibitory effects of the ketone body, monoacetoacetin, on human gastric cancer cells with succinyl-CoA: 3-oxoacid CoA-transferase (SCOT) deficiency. Anticancer Res 2004, 24(4):2213-2217.
68. Schmidt M., Pfetzer N., Schwab M., Strauss I., Kämmerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr Metab 2011, 8(1):54.
69. Seyfried T. Cancer as a metabolic disease: on the origin, management, and prevention of cancer 2012, John Wiley & Sons.
70. Seyfried T.N., Flores R.E., Poff A.M., D'Agostino D.P. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 2014, 35(3):515-527.
71. Seyfried T.N., Kiebish M., Mukherjee P., Marsh J. Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets. Epilepsia 2008, 49(suppl 8):114-116.
72. Seyfried T.N., Sanderson T.M., El-Abbadi M.M., McGowan R., Mukherjee P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 2003, 89(7):1375-1382.
73. Seyfried T.N., Shelton L.M. Cancer as a metabolic disease. Nutr Metab 2010, 7(7):1--22.
74. Shelton L.M., Huysentruyt L.C., Mukherjee P., Seyfried T.N. Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro 2010, 2(3):e00038.
75. Simone B.A., Champ C.E., Rosenberg A.L., Berger A.C., Monti D.A., Dicker A.P., et al. Selectively starving cancer cells through dietary manipulation: methods and clinical implications. Future Oncol 2013, 9(7):959-976.
76. Singh N.P., Lai H.C. Artemisinin induces apoptosis in human cancer cells. Anticancer Res 2004, 24(4):2277-2280.
77. Sivananthan AP. Effects of a ketogenic diet on tumor progression in breast cancer (Ph.D. thesis). Icahn School of Medicine at Mount Sinai; 2013.
78. Skinner R., Trujillo A., Ma X., Beierle E.A. Ketone bodies inhibit the viability of human neuroblastoma cells. J Pediatr Surg 2009, 44(1):212-216. [discussion 216].
79. Sokoloff L. Metabolism of ketone bodies by the brain. Ann Rev Med 1973, 24:271-280.
80. Spitz D.R., Sim J.E., Ridnour L.A.A., Galoforo S.S., Lee Y.J. Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism?. Ann New York Acad Sci 2000, 899:349-362.
81. Stafford P., Abdelwahab M.G., Kim D.Y., Preul M.C., Rho J.M., Scheck A.C. The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab 2010, 7:74.
82. Stewart W.K., Fleming L.W. Features of a successful therapeutic fast of 382 days' duration. Postgrad Med J 1973, 49(569):203-209.
83. Tan-Shalaby J., Seyfried T. Ketogenic diet in advanced cancer: a pilot feasibility and safety trial in the veterans affairs cancer patient population. J Clin Trials 2013, 3(04):4-7.
84. Tin M.M.Y., Cho C.-H., Chan K., James A.E., Ko J.K.S. Astragalus saponins induce growth inhibition and apoptosis in human colon cancer cells and tumor xenograft. Carcinogenesis 2007, 28(6):1347-1355.
85. van Poelje P.D., Potter S.C., Erion M.D. Diabetes - perspectives in drug therapy. Handb Exp Pharmacol 2011, 203:279-301.
86. Vogelstein B., Papadopoulos N., Velculescu V.E., Zhou S., Diaz L.A., Kinzler K.W. Cancer genome landscapes. Science 2013, 339(6127):1546-1558.
87. Warburg O., Posener K., Negelein E. Ueber den stoffwechsel der tumoren. Biochem Z 1924, 152(1):319-344.
88. Waxman S.G., Kocsis J.D., Stys P.K. The axon: structure, function, and pathophysiology 1995, Oxford University Press.
89. Woolf E.C., Scheck A.C. The ketogenic diet for the treatment of malignant glioma. J Lipid Res 2014, 1-19.
90. Yuneva M. Finding an "Achilles' heel" of cancer: The role of glucose and glutamine metabolism in the survival of transformed cells. Cell Cycle 2008, 7(14):2083-2089.
91. Zhou W., Mukherjee P., Kiebish M.A., Markis W.T., Mantis J.G., Seyfried T.N. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab 2007, 4:5.
92. Zuccoli G., Marcello N., Pisanello A., Servadei F., Vaccaro S., Mukherjee P., et al. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: case report. Nutr Metab 2010, 7(33):1-7.