Advertisement

Glioblastoma pp 341-363 | Cite as

Targeting Energy Metabolism in Brain Cancer with Restricted Diets

  • Thomas N. Seyfried
  • Michael A. Kiebish
  • Purna Mukherjee
Chapter

Abstract

Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As a metabolic disorder involving the dysregulation of glycolysis and respiration (Warburg effect), malignant brain cancer can be managed through changes in metabolic environment. In contrast to malignant brain tumors that are mostly dependent on glycolysis for energy, normal neurons, and glia readily transition to ketone bodies (β-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome can transition from one energy state to another. Mutations restrict genomic flexibility. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and less metabolically flexible tumor cells. This approach to brain cancer management is supported by recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with caloric restriction and the ketogenic diet. Issues of implementation and use protocols are discussed.

Keywords

Angiogenesis Apoptosis Caloric restriction Glioma Inflammation Ketone bodies Metabolic control analysis Vascularity 

References

  1. Aisenberg AC (1961) The glycolysis and respiration of tumors. Academic Press, New York, p 224Google Scholar
  2. Ali MA, Yasui F, Matsugo S, Konishi T (2000) The lactate-dependent enhancement of hydroxyl radical generation by the Fenton reaction. Free Radic Res 32:429–438PubMedCrossRefGoogle Scholar
  3. Andersson AK, Ronnback L, Hansson E (2005) Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. J Neurochem 93:1327–1333PubMedCrossRefGoogle Scholar
  4. Arismendi-Morillo GJ, Castellano-Ramirez AV (2008) Ultrastructural mitochondrial pathology in human astrocytic tumors: potentials implications pro-therapeutics strategies. J Electron Microsc 57:33–39CrossRefGoogle Scholar
  5. Aruna RM, Basu D (1976) Glycolipid metabolism in tumours of central nervous system. Indian J Biochem Biophys 13:158–160PubMedGoogle Scholar
  6. Assimakopoulou M, Sotiropoulou Bonikou G, Maraziotis T, Papadakis N, Varakis I (1997) Microvessel density in brain tumors. Anticancer Res 17:4747–4753PubMedGoogle Scholar
  7. Birkholz D, Korpal-Szczyrska M, Kaminska H, Bien E, Polczynska K, Stachowicz-Stencel T, Szolkiewicz A (2005) Influence of surgery and radiotherapy on growth and pubertal development in children treated for brain tumour. Med Wieku Rozwoj 9:463–469PubMedGoogle Scholar
  8. Birt DF, Yaktine A, Duysen E (1999) Glucocorticoid mediation of dietary energy restriction inhibition of mouse skin carcinogenesis. J Nutr 129:571S–574SPubMedGoogle Scholar
  9. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer cell 11:37–51PubMedCrossRefGoogle Scholar
  10. Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, Robison LL, Packer RJ, Oeffinger KC (2006) Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the childhood cancer survivor study. J Clin Oncol 24:5277–5282PubMedCrossRefGoogle Scholar
  11. Buzzai M, Bauer DE, Jones RG, Deberardinis RJ, Hatzivassiliou G, Elstrom RL, Thompson CB (2005) The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene 24:4165–4173PubMedCrossRefGoogle Scholar
  12. Cahill GF Jr (1970) Starvation in man. N Engl J Med 282:668–675PubMedCrossRefGoogle Scholar
  13. Cahill GF Jr, Veech RL (2003) Ketoacids? Good medicine? Trans Am Clin Climatol Assoc 114:149–161; discussion 162–143Google Scholar
  14. Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN (2007) Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 13:2038–2045PubMedCrossRefGoogle Scholar
  15. Canuto RA, Biocca ME, Muzio G, Dianzani MU (1989) Fatty acid composition of phospholipids in mitochondria and microsomes during diethylnitrosamine carcinogenesis in rat liver. Cell Biochem Funct 7:11–19PubMedCrossRefGoogle Scholar
  16. Chance B (2005) Was Warburg right? Or was it that simple? Cancer Biol Ther 4:125–126PubMedCrossRefGoogle Scholar
  17. Cheng SY, Huang HJ, Nagane M, Ji XD, Wang D, Shih CC, Arap W, Huang CM, Cavenee WK (1996) Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc Natl Acad Sci USA 93:8502–8507Google Scholar
  18. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233PubMedCrossRefGoogle Scholar
  19. Chung HY, Kim HJ, Kim KW, Choi JS, Yu BP (2002) Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech 59:264–272PubMedCrossRefGoogle Scholar
  20. Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP (2008) Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7:71–78PubMedCrossRefGoogle Scholar
  21. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism in the brain. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry, 6th edn. Lippincott-Raven, New York, pp 637–669Google Scholar
  22. Clarson CL, Del Maestro RF (1999) Growth failure after treatment of pediatric brain tumors. Pediatrics 103:E37PubMedCrossRefGoogle Scholar
  23. Cleary MP, Jacobson MK, Phillips FC, Getzin SC, Grande JP, Maihle NJ (2002) Weight-cycling decreases incidence and increases latency of mammary tumors to a greater extent than does chronic caloric restriction in mouse mammary tumor virus-transforming growth factor-alpha female mice. Cancer Epidemiol Biomarkers Prev 11:836–843PubMedGoogle Scholar
  24. Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Stich V, Cancello R, Langin D (2004) Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 18:1657–1669PubMedCrossRefGoogle Scholar
  25. Colowick SP (1961) The status of Warburg’s theory of glycolysis and respiration in tumors. Q Rev Biol 36:273–276CrossRefGoogle Scholar
  26. Cuezva JM, Chen G, Alonso AM, Isidoro A, Misek DE, Hanash SM, Beer DG (2004) The bioenergetic signature of lung adenocarcinomas is a molecular marker of cancer diagnosis and prognosis. Carcinogenesis 25:1157–1163PubMedCrossRefGoogle Scholar
  27. Davis FG, Malmer BS, Aldape K, Barnholtz-Sloan JS, Bondy ML, Brannstrom T, Bruner JM, Burger PC, Collins VP, Inskip PD, Kruchko C, McCarthy BJ, McLendon RE, Sadetzki S, Tihan T, Wrensch MR, Buffler PA (2008) Issues of diagnostic review in brain tumor studies: from the brain tumor epidemiology consortium. Cancer Epidemiol Biomarkers Prev 17:484–489PubMedCrossRefGoogle Scholar
  28. DeBerardinis RJ (2008) Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med 10:767–777PubMedCrossRefGoogle Scholar
  29. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350PubMedCrossRefGoogle Scholar
  30. Dong W, Selgrade MK, Gilmour IM, Lange RW, Park P, Luster MI, Kari FW (1998) Altered alveolar macrophage function in calorie-restricted rats. Am J Respir Cell Mol Biol 19:462–469PubMedGoogle Scholar
  31. Duan W, Lee J, Guo Z, Mattson MP (2001) Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury. J Mol Neurosci 16:1–12PubMedCrossRefGoogle Scholar
  32. Ehsani S, Hodaie M, Liebsch NJ, Gentili F, Kiehl TR (2008) Anaplastic glioma after high-dose proton-photon radiation treatment for low-grade skull base chondrosarcoma. J Neurooncol 88:231–236PubMedCrossRefGoogle Scholar
  33. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899PubMedCrossRefGoogle Scholar
  34. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer cell 9:425–434PubMedCrossRefGoogle Scholar
  35. Fearon KC (1988) Nutritional pharmacology in the treatment of neoplastic disease. Baillieres Clin Gastroenterol 2:941–949PubMedCrossRefGoogle Scholar
  36. Fell DA, Thomas S (1995) Physiological control of metabolic flux: the requirement for multisite modulation. Biochem J 311(part 1):35–39Google Scholar
  37. Fisher PG, Buffler PA (2005) Malignant gliomas in 2005: where to GO from here? JAMA 293:615–617PubMedCrossRefGoogle Scholar
  38. Floridi A, Paggi MG, Fanciulli M (1989) Modulation of glycolysis in neuroepithelial tumors. J Neurosurg Sci 33:55–64PubMedGoogle Scholar
  39. Folkman J (1992) The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71PubMedGoogle Scholar
  40. Fredericks M, Ramsey RB (1978) 3-Oxo acid coenzyme A transferase activity in brain and tumors of the nervous system. J Neurochem 31:1529–1531PubMedCrossRefGoogle Scholar
  41. Freeman JM, Freeman JB, Kelly MT (2000) The ketogenic diet: a treatment for epilepsy, 3rd edn. Demos, New York, p 236Google Scholar
  42. Freeman JM, Kossoff EH, Hartman AL (2007a) The ketogenic diet: one decade later. Pediatrics 119:535–543PubMedCrossRefGoogle Scholar
  43. Freeman JM, Kossoff EH, Freeman JB, Kelly MT (2007b) The ketogenic diet: a treatment for children and others with epilepsy, 4th edn. Demos, New York, p 309Google Scholar
  44. Galarraga J, Loreck DJ, Graham JF, DeLaPaz RL, Smith BH, Hallgren D, Cummins CJ (1986) Glucose metabolism in human gliomas: correspondence of in situ and in vitro metabolic rates and altered energy metabolism. Metab Brain Dis 1:279–291PubMedCrossRefGoogle Scholar
  45. Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312:1158–1159PubMedCrossRefGoogle Scholar
  46. Gottlieb E, Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev 5:857–866Google Scholar
  47. Greene AE, Todorova MT, McGowan R, Seyfried TN (2001) Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia 42:1371–1378PubMedCrossRefGoogle Scholar
  48. Greene AE, Todorova MT, Seyfried TN (2003) Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies. J Neurochem 86:529–537PubMedCrossRefGoogle Scholar
  49. Greenspan RJ (2001) The flexible genome. Nat Rev Genet 2:383–387PubMedCrossRefGoogle Scholar
  50. Gullino PM, Ziche M, Alessandri G (1990) Gangliosides, copper ions and angiogenic capacity of adult tissues. Cancer Metastasis Rev 9:239–251PubMedCrossRefGoogle Scholar
  51. Gupta T, Sarin R (2002) Poor-prognosis high-grade gliomas: evolving an evidence-based standard of care. Lancet Oncol 3:557–564PubMedCrossRefGoogle Scholar
  52. Guzman M, Blazquez C (2004) Ketone body synthesis in the brain: possible neuroprotective effects. Prostaglandins, leukotrienes, and essential fatty acids 70:287–292PubMedCrossRefGoogle Scholar
  53. Haces ML, Hernandez-Fonseca K, Medina-Campos ON, Montiel T, Pedraza-Chaverri J, Massieu L (2008) Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp Neurol 211:85–96PubMedCrossRefGoogle Scholar
  54. Hartman AL, Vining EP (2007) Clinical aspects of the ketogenic diet. Epilepsia 48:31–42PubMedCrossRefGoogle Scholar
  55. Hsu SC, Volpert OV, Steck PA, Mikkelsen T, Polverini PJ, Rao S, Chou P, Bouck NP (1996) Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer Res 56:5684–5691PubMedGoogle Scholar
  56. Ikezaki K, Black KL, Conklin SG, Becker DP (1992) Histochemical evaluation of energy metabolism in rat glioma. Neurol Res 14:289–293PubMedGoogle Scholar
  57. Imamura K, Takeshima T, Kashiwaya Y, Nakaso K, Nakashima K (2006) d-beta-hydroxybutyrate protects dopaminergic SH-SY5Y cells in a rotenone model of Parkinson’s disease. J Neurosci Res 84:1376–1384PubMedCrossRefGoogle Scholar
  58. Izycka-Swieszewska E, Rzepko R, Borowska-Lehman J, Stempniewicz M, Sidorowicz M (2003) Angiogenesis in glioblastoma–analysis of intensity and relations to chosen clinical data. Folia Neuropathol 41:15–21PubMedGoogle Scholar
  59. Jendraschak E, Sage EH (1996) Regulation of angiogenesis by SPARC and angiostatin: implications for tumor cell biology. Semin Cancer Biol 7:139–146PubMedCrossRefGoogle Scholar
  60. Jukich PJ, McCarthy BJ, Surawicz TS, Freels S, Davis FG (2001) Trends in incidence of primary brain tumors in the United States, 1985–1994. Neuro Oncol 3:141–151PubMedGoogle Scholar
  61. Kaatsch P, Rickert CH, Kuhl J, Schuz J, Michaelis J (2001) Population-based epidemiologic data on brain tumors in German children. Cancer 92:3155–3164PubMedCrossRefGoogle Scholar
  62. Kaiser J (1999) No meeting of minds on childhood cancer. Science 286:1832–1834PubMedCrossRefGoogle Scholar
  63. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL (2000) d-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci USA 97:5440–5444PubMedCrossRefGoogle Scholar
  64. Kiebish MA, Seyfried TN (2005) Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors. BMC cancer 5:102PubMedCrossRefGoogle Scholar
  65. Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN (2008a) Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: Lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res 49:2545–2556PubMedCrossRefGoogle Scholar
  66. Kiebish MA, Han X, Cheng H, Seyfried TN (2008a) Mitochondrial lipidome and electron transport chain alterations in non-metastatic and metastatic murine brain tumors. J Neurochem 104:37–38Google Scholar
  67. Kiebish MA, Han X, Cheng H, Seyfried NT (2009) In vitro growth environment produces lipidomic and electron transport chain abnormalities in mitochondria from non-tumorigenic astrocytes and brain tumors. ASN Neuro 1(3):art:e00011.doi:10.1042/AN20090011Google Scholar
  68. Kim DO, Davis LM, Sullivan PG, Maalouf M, Simeone TA, Brederode JV, Rho JM (2007) Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 10:1316–1326CrossRefGoogle Scholar
  69. Kirsch WM, Schulz Q, Van Buskirk J, Nakane P (1972) Anaerobic energy metabolism in brain tumors. Prog Exp Tumor Res (Fortschritte der experimentellen Tumorforschung) 17:163–191Google Scholar
  70. Kirsch M, Schackert G, Black PM (2000) Anti-angiogenic treatment strategies for malignant brain tumors. J Neurooncol 50:149–163PubMedCrossRefGoogle Scholar
  71. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 324:269–275PubMedCrossRefGoogle Scholar
  72. Kossoff EH, Rowley H, Sinha SR, Vining EP (2008a) A prospective study of the modified Atkins diet for intractable epilepsy in adults. Epilepsia 49:316–319PubMedCrossRefGoogle Scholar
  73. Kossoff EH, Laux LC, Blackford R, Morrison PF, Pyzik PL, Hamdy RM, Turner Z, Nordli DR Jr (2008b) When do seizures usually improve with the ketogenic diet? Epilepsia 49:329–333PubMedCrossRefGoogle Scholar
  74. Kritchevsky D (1999) Fundamentals of nutrition: applications to cancer research. In: Heber D, Blackburn GL, Go VLW (eds) Nutritional oncology. Academic, Boston, MA, pp 5–10Google Scholar
  75. Landau BR, Laszlo J, Stengle J, Burk D (1958) Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-d-glucose. J Natl Cancer Inst 21:485–494PubMedGoogle Scholar
  76. Leon SP, Folkerth RD, Black PM (1996) Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77:362–372PubMedCrossRefGoogle Scholar
  77. Lichtor T, Dohrmann GJ (1986) Respiratory patterns in human brain tumors. Neurosurgery 19:896–899PubMedCrossRefGoogle Scholar
  78. Lowry JK, Snyder JJ, Lowry PW (1998) Brain tumors in the elderly: recent trends in a Minnesota cohort study. Arch Neurol 55:922–928PubMedCrossRefGoogle Scholar
  79. Magee BA, Potezny N, Rofe AM, Conyers RA (1979) The inhibition of malignant cell growth by ketone bodies. Aust J Exp Biol Med Sci 57:529–539PubMedCrossRefGoogle Scholar
  80. Mahoney LB, Denny CA, Seyfried TN (2006) Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans. Lipids Health Dis 5:13PubMedCrossRefGoogle Scholar
  81. Mangiardi JR, Yodice P (1990) Metabolism of the malignant astrocytoma. Neurosurgery 26:1–19PubMedCrossRefGoogle Scholar
  82. Mantis JG, Centeno NA, Todorova MT, McGowan R, Seyfried TN (2004) Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies. Nutr Metab 1:11CrossRefGoogle Scholar
  83. Marsh J, Mukherjee P, Seyfried TN (2008a) Drug/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-d-glucose and the restricted ketogenic diet. Nutr Metab 5:33CrossRefGoogle Scholar
  84. Marsh J, Mukherjee P, Seyfried TN (2008a) Akt-dependent proapoptotic effects of caloric restriction on late-stage management of a PTEN/TSC2-deficient mouse astrocytoma. Proc Am Assoc Cancer Res 99:1250Google Scholar
  85. Masuda R, Monahan JW, Kashiwaya Y (2005) d-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res 80:501–509PubMedCrossRefGoogle Scholar
  86. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 Regulates mitochondrial respiration. Science 312:1650–1653PubMedCrossRefGoogle Scholar
  87. McGirt MJ, Chaichana KL, Gathinji M, Attenello F, Than K, Ruiz AJ, Olivi A, Quinones-Hinojosa A (2008) Persistent outpatient hyperglycemia is independently associated with decreased survival after primary resection of malignant brain astrocytomas. Neurosurgery 63:286–291; discussion 291Google Scholar
  88. McLendon RE, Halperin EC (2003) Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer 98:1745–1748PubMedCrossRefGoogle Scholar
  89. Meixensberger J, Herting B, Roggendorf W, Reichmann H (1995) Metabolic patterns in malignant gliomas. J Neurooncol 24:153–161PubMedCrossRefGoogle Scholar
  90. Mies G, Paschen W, Ebhardt G, Hossmann KA (1990) Relationship between blood flow, glucose metabolism, protein synthesis, glucose and ATP content in experimentally-induced glioma (RG1 2.2) of rat brain. J Neurooncol 9:17–28PubMedCrossRefGoogle Scholar
  91. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274:1393–1418PubMedCrossRefGoogle Scholar
  92. Morris AA (2005) Cerebral ketone body metabolism. J Inherit Metab Dis 28:109–121PubMedCrossRefGoogle Scholar
  93. Morris EB, Gajjar A, Okuma JO, Yasui Y, Wallace D, Kun LE, Merchant TE, Fouladi M, Broniscer A, Robison LL, Hudson MM (2007) Survival and late mortality in long-term survivors of pediatric CNS tumors. J Clin Oncol 25:1532–1538PubMedCrossRefGoogle Scholar
  94. Mott RT, Turner KC, Bigner DD, McLendon RE (2008) Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Lab Invest J Neurosurg 108:330–335Google Scholar
  95. Mukherjee 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 91:512–523PubMedCrossRefGoogle Scholar
  96. Mukherjee P, Zhau J-R, Sotnikov AV, Clinton SK (1999a) Dietary and nutritional modulation of tumor angiogenesis. In: Teicher BA (ed) Antiangiogenic agents in cancer therapy. Humana, Totowa, NJ, pp 237–261Google Scholar
  97. Mukherjee P, El-Abbadi MM, Kasperzyk JL, Ranes MK, Seyfried TN (2002) Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model. Br J Cancer 86:1615–1621PubMedCrossRefGoogle Scholar
  98. Mukherjee P, Abate LE, Seyfried TN (2004) Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res 10:5622–5629PubMedCrossRefGoogle Scholar
  99. Nagamatsu S, Nakamichi Y, Inoue N, Inoue M, Nishino H, Sawa H (1996) Rat C6 glioma cell growth is related to glucose transport and metabolism. Biochem J 319 (part 2):477–482Google Scholar
  100. Nebeling LC, Lerner E (1995) Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer. J Am Diet Assoc 95:693–697PubMedCrossRefGoogle Scholar
  101. Nebeling LC, Miraldi F, Shurin SB, Lerner E (1995) Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr 14:202–208PubMedGoogle Scholar
  102. Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, Kuwano M (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5:1107–1113PubMedGoogle Scholar
  103. Oudard S, Arvelo F, Miccoli L, Apiou F, Dutrillaux AM, Poisson M, Dutrillaux B, Poupon MF (1996) High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss. Br J Cancer 74:839–845PubMedGoogle Scholar
  104. Oudard S, Boitier E, Miccoli L, Rousset S, Dutrillaux B, Poupon MF (1997) Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure. Anticancer Res 17:1903–1911PubMedGoogle Scholar
  105. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF Jr (1967) Brain metabolism during fasting. J Clin Invest 46:1589–1595PubMedCrossRefGoogle Scholar
  106. Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007:pe14Google Scholar
  107. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedCrossRefGoogle Scholar
  108. Patel NV, Finch CE (2002) The glucocorticoid paradox of caloric restriction in slowing brain aging. Neurobiol Aging 23:707–717PubMedCrossRefGoogle Scholar
  109. Patel MS, Russell JJ, Gershman H (1981) Ketone-body metabolism in glioma and neuroblastoma cells. Proc Natl Acad Sci USA 78:7214–7218PubMedCrossRefGoogle Scholar
  110. Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25:4633–4646PubMedCrossRefGoogle Scholar
  111. Pennathur S, Ido Y, Heller JI, Byun J, Danda R, Pergola P, Williamson JR, Heinecke JW (2005) Reactive carbonyls and polyunsaturated fatty acids produce a hydroxyl radical-like species: a potential pathway for oxidative damage of retinal proteins in diabetes. J Biol Chem 280:22706–22714Google Scholar
  112. Pfeifer HH, Thiele EA (2005) Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 65:1810–1812PubMedCrossRefGoogle Scholar
  113. Portais JC, Voisin P, Merle M, Canioni P (1996) Glucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR. Biochimie 78:155–164PubMedCrossRefGoogle Scholar
  114. Potts R (1996) Humanity’s descent: the consequences of ecological instability. William Morrow, New York, p 325Google Scholar
  115. Potts R (2002) Complexity of adaptibility in human evolution. In: Goodman M, Moffat AS (eds) Probing human origins. American Academy of Arts & Sciences, Cambridge, MA, pp 33–57Google Scholar
  116. Rasnick D, Duesberg PH (1999) How aneuploidy affects metabolic control and causes cancer. Biochem J 340 (part 3):621–630Google Scholar
  117. Rebrin I, Kamzalov S, Sohal RS (2003) Effects of age and caloric restriction on glutathione redox state in mice. Free Radic Biol Med 35:626–635PubMedCrossRefGoogle Scholar
  118. Rhodes CG, Wise RJ, Gibbs JM, Frackowiak RS, Hatazawa J, Palmer AJ, Thomas DG, Jones T (1983) In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas. Ann Neurol 14:614–626PubMedCrossRefGoogle Scholar
  119. Ristow M (2006) Oxidative metabolism in cancer growth. Curr Opin Clin Nutr Metab Care 9:339–345PubMedCrossRefGoogle Scholar
  120. Roeder LM, Poduslo SE, Tildon JT (1982) Utilization of ketone bodies and glucose by established neural cell lines. J Neurosci Res 8:671–682PubMedCrossRefGoogle Scholar
  121. Roslin M, Henriksson R, Bergstrom P, Ungerstedt U, Bergenheim AT (2003) Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J Neurooncol 61:151–160PubMedCrossRefGoogle Scholar
  122. Rous P (1914) The influence of diet on transplanted and spontaneous mouse tumors. J Exp Med 20:433–451PubMedCrossRefGoogle Scholar
  123. Ruggeri BA, Klurfeld DM, Kritchevsky D (1987) Biochemical alterations in 7, 12-dimethylbenz[a]anthracene-induced mammary tumors from rats subjected to caloric restriction. Biochim Biophys Acta 929:239–246PubMedCrossRefGoogle Scholar
  124. Salas A, Yao YG, Macaulay V, Vega A, Carracedo A, Bandelt HJ (2005) A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Med 2:e296PubMedCrossRefGoogle Scholar
  125. Schlame M, Rua D, Greenberg ML (2000) The biosynthesis and functional role of cardiolipin. Prog Lipid Res 39:257–288PubMedCrossRefGoogle Scholar
  126. Seo JH, Lee YM, Lee JS, Kang HC, Kim HD (2007) Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios–comparison of 3:1 with 4:1 diet. Epilepsia 48:801–805PubMedCrossRefGoogle Scholar
  127. Seyfried TN (2001) Perspectives on brain tumor formation involving macrophages, glia, and neural stem cells. Perspect Biol Med 44:263–282PubMedCrossRefGoogle Scholar
  128. Seyfried TN, Mukherjee P (2005a) Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab 2:30CrossRefGoogle Scholar
  129. Seyfried TN, Mukherjee P (2005a) Anti-angiogenic and pro-apoptotic effects of dietary restriction in experimental brain cancer: role of glucose and ketone bodies. In: Meadows GG (ed) Integration/interaction of oncologic growth, vol 15, 2nd edn. Kluwer Academic, New York, pp 259–270Google Scholar
  130. Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P (2003) Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 89:1375–1382PubMedCrossRefGoogle Scholar
  131. Shelton HM (1974) Fasting for renewal of life. Am Nat Hygene Society, Tampa, FL, p 314Google Scholar
  132. Smallbone K, Gatenby RA, Gillies RJ, Maini PK, Gavaghan DJ (2007) Metabolic changes during carcinogenesis: potential impact on invasiveness. J Theor Biol 244:703–713PubMedCrossRefGoogle Scholar
  133. Sokoloff B, Eddy WH, Saelhof CC, Beach J (1955) Glucose antagonists in experimental cancer. AMA Arch Pathol 59:729–732PubMedGoogle Scholar
  134. Sonnenschein C, Soto AM (1999) The society of cells: cancer and the control of cell proliferation. Springer, New York, p 154Google Scholar
  135. Sonnenschein C, Soto AM (2000) Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog 29:205–211PubMedCrossRefGoogle Scholar
  136. Spindler SR (2005) Rapid and reversible induction of the longevity anticancer and genomic effects of caloric restriction. Mech Ageing Dev 126:960–966PubMedCrossRefGoogle Scholar
  137. Spitz DR, Sim JE, Ridnour LA, Galoforo SS, Lee YJ (2000) Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? Ann N Y Acad Sci 899:349–362PubMedCrossRefGoogle Scholar
  138. Stafstrom CE, Rho JM (2004) Epilepsy and the ketogenic diet. Humana, Totowa, NJ, p 352Google Scholar
  139. Stewart JW, Koehler K, Jackson W, Hawley J, Wang W, Au A, Myers R, Birt DF (2005) Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition. Carcinogenesis 26:1077–1084PubMedCrossRefGoogle Scholar
  140. Strohman R (2002) Maneuvering in the complex path from genotype to phenotype. Science 296:701–703PubMedCrossRefGoogle Scholar
  141. Strohman R (2003) Thermodynamics–old laws in medicine and complex disease. Nat Biotechnol 21:477–479PubMedCrossRefGoogle Scholar
  142. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C (1994) Macrophages and angiogenesis. J Leukoc Biol 55:410–422PubMedGoogle Scholar
  143. Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shirai S, Nose T (1996) Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:2185–2190PubMedGoogle Scholar
  144. Tannenbaum A (1942) The genesis and growth of tumors. II. Effects of caloric restriction per se. Cancer Res 2:460–467Google Scholar
  145. Tannenbaum A (1959) Nutrition and cancer. In: Homburger F (ed) Physiopathology of cancer. Paul B. Hober, New York, pp 517–562Google Scholar
  146. Thomas S, Fell DA (1998) A control analysis exploration of the role of ATP utilisation in glycolytic-flux control and glycolytic-metabolite-concentration regulation. Eur J Biochem/FEBS 258:956–967CrossRefGoogle Scholar
  147. Thompson HJ, McGinley JN, Spoelstra NS, Jiang W, Zhu Z, Wolfe P (2004) Effect of dietary energy restriction on vascular density during mammary carcinogenesis. Cancer Res 64:5643–5650PubMedCrossRefGoogle Scholar
  148. Tisdale MJ (1984) Role of acetoacetyl-CoA synthetase in acetoacetate utilization by tumor cells. Cancer Biochem Biophys 7:101–107PubMedGoogle Scholar
  149. Tisdale MJ (1997) Biology of cachexia. J Natl Cancer Inst 89:1763–1773PubMedCrossRefGoogle Scholar
  150. Tisdale MJ, Brennan RA (1983) Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues. Br J Cancer 47:293–297PubMedGoogle Scholar
  151. Todorov PT, Wyke SM, Tisdale MJ (2007) Identification and characterization of a membrane receptor for proteolysis-inducing factor on skeletal muscle. Cancer Res 67:11419–11427PubMedCrossRefGoogle Scholar
  152. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, Amon A (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317:916–924PubMedCrossRefGoogle Scholar
  153. VanItallie TB, Nufert TH (2003) Ketones: metabolism’s ugly duckling. Nutr Rev 61:327–341PubMedCrossRefGoogle Scholar
  154. Veech RL (2002) Metabolic control analysis of ketone and insulin action: Implications for phenotyping of disease and design of therapy. http://www.biodynamichealthaging.org/
  155. Veech RL (2004) 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 70:309–319PubMedCrossRefGoogle Scholar
  156. Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr (2001) Ketone bodies, potential therapeutic uses. IUBMB Life 51:241–247PubMedCrossRefGoogle Scholar
  157. Vogt AM, Nef H, Schaper J, Poolman M, Fell DA, Kubler W, Elsasser A (2002) Metabolic control analysis of anaerobic glycolysis in human hibernating myocardium replaces traditional concepts of flux control. FEBS Lett 517:245–250PubMedCrossRefGoogle Scholar
  158. Vredenburgh JJ, Desjardins A, Herndon JE II, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259Google Scholar
  159. Wallace DC (2005) Mitochondria and cancer: Warburg addressed. Cold Spring Harbor Symp Quant Biol 70:363–374PubMedCrossRefGoogle Scholar
  160. Warburg O (1931) The metabolism of tumours. Richard R Smith, New York, p 327Google Scholar
  161. Warburg O (1956) On the origin of cancer cells. Science 123:309–314PubMedCrossRefGoogle Scholar
  162. Weindruch R, Walford RL (1988) The retardation of aging and disease by dietary restriction. Thomas, Springfield, IL, p 436Google Scholar
  163. Weindruch R, Walford RL, Fligiel S, Guthrie D (1986) The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 116:641–654PubMedGoogle Scholar
  164. Wesseling P, Ruiter DJ, Burger PC (1997) Angiogenesis in brain tumors; pathobiological and clinical aspects. J Neurooncol 32:253–265PubMedCrossRefGoogle Scholar
  165. Wittig R, Coy JF (2007) The role of glucose metabolism and glucose-associated signaling in cancer. Perspect Med Chem 1:64–82Google Scholar
  166. Wu M, Neilson A, Swift AL, Moran R, Tamagnine J, Parslow D, Armistead S, Lemire K, Orrell J, Teich J, Chomicz S, Ferrick DA (2007) Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am J Physiol 292:C125–C136CrossRefGoogle Scholar
  167. Yamada KA, Rensing N, Thio LL (2005) Ketogenic diet reduces hypoglycemia-induced neuronal death in young rats. Neurosci Lett 385:210–214PubMedCrossRefGoogle Scholar
  168. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN (2007) The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab 4:5CrossRefGoogle Scholar
  169. Zhu Z, Jiang W, Thompson HJ (2003) Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas. Carcinogenesis 24:1225–1231PubMedCrossRefGoogle Scholar
  170. Zimmerman HM (1955) The nature of gliomas as revealed by animal experimentation. Am J Pathol 31:1–29PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York 2010

Authors and Affiliations

  • Thomas N. Seyfried
    • 1
  • Michael A. Kiebish
  • Purna Mukherjee
  1. 1.Biology DepartmentBoston CollegeBostonUSA

Personalised recommendations