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The Ketogenic Diet as an Adjuvant Therapy for Brain Tumors and Other Cancers

  • Chapter
Book cover Critical Dietary Factors in Cancer Chemoprevention

Abstract

Altered metabolism was first identified in cancer cells by Otto Warburg, who identified a higher reliance on anaerobic glycolysis rather than cellular respiration even in the presence of sufficient oxygen levels, a phenomenon called the Warburg Effect. Deregulated metabolism is now considered a driving hallmark of cancer and an attractive therapeutic target. While a great deal of work is being done to find genetic therapeutic targets that can be used for personalized medicine, current targeted approaches are typically ineffective because tumors are heterogeneous and contain multiple genetic subpopulations. This often precludes a particular targeted molecule from being found on all cells. In contrast to many genetic alterations, dysregulation of metabolism resulting in the need for high amounts of glucose is found in virtually all cancer cells. Targeting metabolism by reducing blood glucose may be a way to inhibit tumor growth since this, to a large extent, should circumvent the inherent problems associated with tumor heterogeneity. Methods that also provide an energy source for normal tissues such as ketones should reduce side effects associated with an overall reduction in blood glucose. The high-fat, low carbohydrate, and protein ketogenic diet (KD) results in reduced blood glucose and increased blood ketones, as does caloric restriction and fasting. In preclinical mouse models of malignant brain tumors, animals fed a KD had increased survival, particularly when used in combination with radiation or chemotherapy. Metabolic modulation through the use of a KD, caloric restriction, or fasting has been found to change the expression of a number of genes and pathways thought to inhibit tumor growth. Metabolic therapy has also recently been explored in other cancer types. In this chapter, we will examine the mechanisms underlying the KD which suggests its potential as an adjuvant therapy for cancer treatment.

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References

  • Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC (2012) The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS One 7(5), e36197

    Article  Google Scholar 

  • Allen BG, Bhatia SK, Buatti JM, Brandt KE, Lindholm KE, Button AM, Szweda LI, Smith B, Spitz DR, Fath MA (2013) Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clin Cancer Res 19(14):3905–3913

    Article  CAS  Google Scholar 

  • Amigo I, Kowaltowski AJ (2014) Dietary restriction in cerebral bioenergetics and redox state. Redox Biol 2:296–304

    Article  CAS  Google Scholar 

  • Anton K, Baehring JM, Mayer T (2012) Glioblastoma multiforme: overview of current treatment and future perspectives. Hematol Oncol Clin North Am 26(4):825–853

    Article  Google Scholar 

  • Arcaro A (2013) Targeting the insulin-like growth factor-1 receptor in human cancer. Front Pharmacol 4:30

    Article  CAS  Google Scholar 

  • Azad N, Zahnow CA, Rudin CM, Baylin SB (2013) The future of epigenetic therapy in solid tumours--lessons from the past. Nat Rev Clin Oncol 10(5):256–266

    Article  CAS  Google Scholar 

  • Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734

    Article  CAS  Google Scholar 

  • Bloch O, Han SJ, Cha S, Sun MZ, Aghi MK, McDermott MW, Berger MS, Parsa AT (2012) Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article. J Neurosurg 117(6):1032–1038

    Article  Google Scholar 

  • Boele FW, Heimans JJ, Aaronson NK, Taphoorn MJ, Postma TJ, Reijneveld JC, Klein M (2013) Health-related quality of life of significant others of patients with malignant CNS versus non-CNS tumors: a comparative study. J Neurooncol 115(1):87–94

    Article  Google Scholar 

  • Brennan C (2011) Genomic profiles of glioma. Curr Neurol Neurosci Rep 11(3):291–297

    Article  Google Scholar 

  • Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E (2009) Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS One 4(11), e7752

    Article  CAS  Google Scholar 

  • Cahill GF Jr, Veech RL (2003) Ketoacids? Good medicine? Trans Am Clin Climatol Assoc 114:149–161

    Google Scholar 

  • Cantor JR, Sabatini DM (2012) Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2(10):881–898

    Article  CAS  Google Scholar 

  • Champ CE, Baserga R, Mishra MV, Jin L, Sotgia F, Lisanti MP, Pestell RG, Dicker AP, Simone NL (2013) Nutrient restriction and radiation therapy for cancer treatment: when less is more. Oncologist 18(1):97–103

    Article  CAS  Google Scholar 

  • Champ CE, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, Glass J, Kim L, Shi W (2014) Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol 117(1):125–131

    Article  CAS  Google Scholar 

  • Chautard E, Loubeau G, Tchirkov A, Chassagne J, Vermot-Desroches C, Morel L, Verrelle P (2010) Akt signaling pathway: a target for radiosensitizing human malignant glioma. Neuro Oncol 12(5):434–443

    CAS  Google Scholar 

  • Choi EJ, Cho BJ, Lee DJ, Hwang YH, Chun SH, Kim HH, Kim IA (2014) Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases. BMC Cancer 14:17

    Article  Google Scholar 

  • Cross JH (2013) New research with diets and epilepsy. J Child Neurol 28(8):970–974

    Article  Google Scholar 

  • Danhier P, De Saedeleer CJ, Karroum O, De PG, Porporato PE, Jordan BF, Gallez B, Sonveaux P (2013) Optimization of tumor radiotherapy with modulators of cell metabolism: toward clinical applications. Semin Radiat Oncol 23(4):262–272

    Article  Google Scholar 

  • De Lorenzo MS, Baljinnyam E, Vatner DE, Abarzua P, Vatner SF, Rabson AB (2011) Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32(9):1381–1387

    Article  CAS  Google Scholar 

  • Dirven L, Taphoorn MJ, Reijneveld JC, Blazeby J, Jacobs M, Pusic A, La SE, Stupp R, Fayers P, Efficace F (2014) The level of patient-reported outcome reporting in randomised controlled trials of brain tumour patients: a systematic review. Eur J Cancer 50(14):2432–2448

    Article  Google Scholar 

  • El-Kenawi AE, El-Remessy AB (2013) Angiogenesis Inhibitors in Cancer Therapy: Mechanistic perspective on classification and treatment rationales. Br. J, Pharmacol

    Google Scholar 

  • 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(11):3892–3899

    Article  CAS  Google Scholar 

  • Eyler CE, Foo WC, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN (2008) Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 26(12):3027–3036

    Article  CAS  Google Scholar 

  • Fan QW, Weiss WA (2010) Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. Curr Top Microbiol Immunol 347(279-96):279–296

    CAS  Google Scholar 

  • Fearon KC, Borland W, Preston T, Tisdale MJ, Shenkin A, Calman KC (1988) Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism. Am J Clin Nutr 47(1):42–48

    CAS  Google Scholar 

  • Field KM, Jordan JT, Wen PY, Rosenthal MA, Reardon DA (2014) Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies. Cancer 10

    Google Scholar 

  • Fredericks M, Ramsey RB (1978) 3-Oxo acid coenzyme A transferase activity in brain and tumors of the nervous system. J Neurochem 31(6):1529–1531

    Article  CAS  Google Scholar 

  • Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB (2008) Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 68(1):11–19

    Article  CAS  Google Scholar 

  • Fruehauf JP, Meyskens FL Jr (2007) Reactive oxygen species: a breath of life or death? Clin Cancer Res 13(3):789–794

    Article  CAS  Google Scholar 

  • Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL, Brem H, Riggins GJ (2009) Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 8(2):386–393

    Article  CAS  Google Scholar 

  • Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    Article  CAS  Google Scholar 

  • Gil Del Alcazar CR, Hardebeck MC, Mukherjee B, Tomimatsu N, Gao X, Yan J, Xie XJ, Bachoo R, Li L, Habib AA, Burma S (2014) Inhibition of DNA Double-Strand Break Repair by the Dual PI3K/mTOR Inhibitor NVP-BEZ235 as a Strategy for Radiosensitization of Glioblastoma. Clin, Cancer Res

    Google Scholar 

  • Gill BJ, Pisapia DJ, Malone HR, Goldstein H, Lei L, Sonabend A, Yun J, Samanamud J, Sims JS, Banu M, Dovas A, Teich AF, Sheth SA, McKhann GM, Sisti MB, Bruce JN, Sims PA, Canoll P (2014) MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci U S A 111(34):12550–12555

    Article  CAS  Google Scholar 

  • Gluschnaider U, Hertz R, Ohayon S, Smeir E, Smets M, Pikarsky E, Bar-Tana J (2014) Long-chain Fatty Acid analogues suppress breast tumorigenesis and progression. Cancer Res 74(23):6991–7002

    Article  CAS  Google Scholar 

  • Group TCGAR (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  CAS  Google Scholar 

  • Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB (2012) Upsides and downsides of reactive oxygen species for cancer: The roles of reactive oxygen species in tumorigenesis, prevention and therapy. Antioxid Redox Signal 16(11):1295–1322

    Article  CAS  Google Scholar 

  • Haisa M (2013) The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer. J Int Med Res 41(2):253–264

    Article  CAS  Google Scholar 

  • Harvey AE, Lashinger LM, Otto G, Nunez NP, Hursting SD (2013) Decreased systemic IGF-1 in response to calorie restriction modulates murine tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression. Mol Carcinog 52(12):997–1006

    Article  CAS  Google Scholar 

  • Heydari AR, Unnikrishnan A, Lucente LV, Richardson A (2007) Caloric restriction and genomic stability. Nucleic Acids Res 35(22):7485–7496

    Article  CAS  Google Scholar 

  • Hummel TR, Chow LM, Fouladi M, Franz D (2013) Pharmacotherapeutic management of pediatric gliomas : current and upcoming strategies. Paediatr Drugs 15(1):29–42

    Article  Google Scholar 

  • Jiang YS, Wang FR (2013) Caloric restriction reduces edema and prolongs survival in a mouse glioma model. J Neurooncol 114(1):25–32

    Article  Google Scholar 

  • Kim DY, Rho JM (2008) The ketogenic diet and epilepsy. Curr Opin Clin Nutr Metab Care 11(2):113–120

    Article  CAS  Google Scholar 

  • Kim HS, Masko EM, Poulton SL, Kennedy KM, Pizzo SV, Dewhirst MW, Freedland SJ (2012) Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer. BJU Int 110(7):1062–1069

    Article  CAS  Google Scholar 

  • Klement RJ, Champ CE (2014) Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation. Cancer Metastasis Rev 33(1):217–29

    Article  CAS  Google Scholar 

  • Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, Fritzsche I, Hauke J, Hahnen E, Coras R, Muhlebner A, El-Osta A, Blumcke I (2013) Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol 126(5):741–756

    Article  CAS  Google Scholar 

  • Lee Y, Scheck AC, Cloughesy TF, Lai A, Dong J, Farooqi HK, Liau LM, Horvath S, Mischel PS, Nelson SF (2008) Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age. BMC Med Genomics 1:52

    Article  CAS  Google Scholar 

  • Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, Hwang D, Cohen P, Bianchi G, Longo VD (2010) Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res 70(4):1564–1572

    Article  CAS  Google Scholar 

  • Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD (2012) Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 4(124):124ra27

    Article  Google Scholar 

  • Li HF, Kim JS, Waldman T (2009) Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat Oncol 4:43

    Article  CAS  Google Scholar 

  • Li W, Guo F, Wang P, Hong S, Zhang C (2014) miR-221/222 confers radioresistance in glioblastoma cells through activating Akt independent of PTEN status. Curr Mol Med 14(1):185–195

    Article  CAS  Google Scholar 

  • Liang BC, Grootveld M (2011) The importance of mitochondria in the tumourigenic phenotype: gliomas as the paradigm (review). Int J Mol Med 27(2):159–171

    Article  Google Scholar 

  • Los M, Maddika S, Erb B, Schulze-Osthoff K (2009) Switching Akt: from survival signaling to deadly response. Bioessays 31(5):492–495

    Article  CAS  Google Scholar 

  • Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM (2007) Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145(1):256–264

    Article  CAS  Google Scholar 

  • Maalouf M, Rho JM, Mattson MP (2009) The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 59(2):293–315

    Article  CAS  Google Scholar 

  • 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(5):529–539

    Article  CAS  Google Scholar 

  • Marie SK, Shinjo SM (2011) Metabolism and brain cancer. Clinics (SaoPaulo) 66(Suppl 1):33–43

    Article  Google Scholar 

  • Marsh J, Mukherjee P, Seyfried TN (2008) Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma. Clin Cancer Res 14(23):7751–7762

    Article  CAS  Google Scholar 

  • Masui K, Cloughesy TF, Mischel PS (2012) Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies. Neuropathol Appl Neurobiol 38(3):271–291

    Article  CAS  Google Scholar 

  • Maurer GD, Brucker DP, Bahr O, Harter PN, Hattingen E, Walenta S, Mueller-Klieser W, Steinbach JP, Rieger J (2011) Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer 11(315):315

    Article  CAS  Google Scholar 

  • Mavropoulos JC, Buschemeyer WC III, Tewari AK, Rokhfeld D, Pollak M, Zhao Y, Febbo PG, Cohen P, Hwang D, Devi G, Demark-Wahnefried W, Westman EC, Peterson BL, Pizzo SV, Freedland SJ (2009) The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res (Phila) 2(6):557–565

    Article  CAS  Google Scholar 

  • Medova M, Aebersold DM, Zimmer Y (2013) The molecular crosstalk between the MET receptor tyrosine kinase and the DNA damage response-biological and clinical aspects. Cancers(Basel) 6(1):1–27

    Google Scholar 

  • Morris AAM (2005) Cerebral ketone body metabolism. J Inherit Metab Dis 28:109–121

    Article  CAS  Google Scholar 

  • Mukherjee P, Sotnikov AV, Mangian HJ, Zhou JR, Visek WJ, Clinton SK (1999) Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J Natl Cancer Inst 91(6):512–523

    Article  CAS  Google Scholar 

  • 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(10):1615–1621

    Article  CAS  Google Scholar 

  • 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(16):5622–5629

    Article  CAS  Google Scholar 

  • Mulrooney TJ, Marsh J, Urits I, Seyfried TN, Mukherjee P (2011) Influence of caloric restriction on constitutive expression of NF-kappaB in an experimental mouse astrocytoma. PLoS One 6(3), e18085

    Article  CAS  Google Scholar 

  • Munshi A, Ramesh R (2013) Mitogen-Activated Protein Kinases and Their Role in Radiation Response. Genes Cancer 4(9-10):401–408

    Article  CAS  Google Scholar 

  • 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(6):693–697

    Article  CAS  Google Scholar 

  • 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(2):202–208

    Article  CAS  Google Scholar 

  • Negi A, Ramarao P, Kumar R (2013) Recent advancements in small molecule inhibitors of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase as anticancer agents. Mini Rev Med Chem 13(5):653–681

    Article  CAS  Google Scholar 

  • Nijsten MW, van Dam GM (2009) Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Med Hypotheses 73(1):48–51

    Article  CAS  Google Scholar 

  • Obre E, Rossignol R (2015) Emerging concepts in bioenergetics and cancer research: Metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol 59C:167–181. doi:10.1016/j.biocel.2014.12.008

    Article  CAS  Google Scholar 

  • Patel M, Vogelbaum MA, Barnett GH, Jalali R, Ahluwalia MS (2012) Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions. Expert. Opin. Investig, Drugs

    Google Scholar 

  • Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suva ML, Regev A, Bernstein BE (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344(6190):1396–1401

    Article  CAS  Google Scholar 

  • Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP (2010) Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res Treat 123(2):333–344

    Article  CAS  Google Scholar 

  • Poff 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

    Article  CAS  Google Scholar 

  • Puzio-Kuter AM (2011) The role of p53 in metabolic regulation. Genes Cancer 2(4):385–391

    Article  CAS  Google Scholar 

  • Qureshi IA, Mehler MF (2013) Developing epigenetic diagnostics and therapeutics for brain disorders. Trends Mol Med 19(12):732–741

    Article  CAS  Google Scholar 

  • Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD (2008) Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A 105(24):8215–8220

    Article  CAS  Google Scholar 

  • Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD (2010) Fasting and differential chemotherapy protection in patients. Cell Cycle 9(22):4474–4476

    Article  CAS  Google Scholar 

  • Rao RD, Mladek AC, Lamont JD, Goble JM, Erlichman C, James CD, Sarkaria JN (2005) Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia 7(10):921–929

    Article  CAS  Google Scholar 

  • Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19(1):25–31

    Article  CAS  Google Scholar 

  • Rous P (1914) The influence of diet on transplanted and spontaneous mouse tumors. J Exp Med 20(5):433–451

    Article  CAS  Google Scholar 

  • Saenko Y, Cieslar-Pobuda A, Skonieczna M, Rzeszowska-Wolny J (2013) Changes of reactive oxygen and nitrogen species and mitochondrial functioning in human K562 and HL60 cells exposed to ionizing radiation. Radiat Res 180(4):360–366

    Article  CAS  Google Scholar 

  • Safdie F, Brandhorst S, Wei M, Wang W, Lee C, Hwang S, Conti PS, Chen TC, Longo VD (2012) Fasting enhances the response of glioma to chemo- and radiotherapy. PLoS One 7(9), e44603

    Article  CAS  Google Scholar 

  • Saleh AD, Simone BA, Palazzo J, Savage JE, Sano Y, Dan T, Jin L, Champ CE, Zhao S, Lim M, Sotgia F, Camphausen K, Pestell RG, Mitchell JB, Lisanti MP, Simone NL (2013) Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle 12(12):1955–1963

    Article  CAS  Google Scholar 

  • Sanli T, Steinberg GR, Singh G, Tsakiridis T (2014) AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther 15(2):156–169

    Article  CAS  Google Scholar 

  • Santivasi WL, Xia F (2014) 2014. Ionizing radiation-induced DNA damage, response, and repair. Antioxid Redox Signal 21(2):251–9

    Article  CAS  Google Scholar 

  • Scheck AC, Abdelwahab MG, Stafford P, Kim DY, Iwai S, Preul MC, Rho JM (2011) Mechanistic studies of the ketogenic diet as an adjuvant therapy for malignant gliomas. Cancer Res 70(8 Suppl):638, Ref Type: Abstract

    Google Scholar 

  • Scheck AC, Abdelwahab MG, Fenton K, Stafford P (2012) The ketogenic diet for the treatment of glioma: Insights from genetic profiling. Epilepsy Res 100:327–337

    Article  CAS  Google Scholar 

  • Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123(9):3664–3671

    Article  CAS  Google Scholar 

  • Seyfried TN (2012) Cancer as a metabolic disease: on the origin, management and prevention of cancer. John Wiley and Sons Inc, Hoboken, NJ

    Book  Google Scholar 

  • Seyfried TN, Mukherjee P (2005) Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab 2:30–38

    Article  CAS  Google Scholar 

  • 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(7):1375–1382

    Article  CAS  Google Scholar 

  • Seyfried TN, Kiebish MA, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P (2011) Metabolic management of brain cancer. Biochim Biophys Acta 1807(6):577–594

    Article  CAS  Google Scholar 

  • Seyfried TN, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P (2012) Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res 100(3):310–326

    Article  CAS  Google Scholar 

  • Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN (2010) Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro 2(3), e00038

    Article  CAS  Google Scholar 

  • Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le MN, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339(6116):211–214

    Article  CAS  Google Scholar 

  • Shukla SK, Gebregiworgis T, Purohit V, Chaika NV, Gunda V, Radhakrishnan P, Mehla K, Pipinos II, Powers R, Yu F, Singh PK (2014) Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab 2:18

    Article  Google Scholar 

  • Singh P, Alex JM, Bast F (2014) Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol 31(1):805

    Article  CAS  Google Scholar 

  • Skinner R, Trujillo A, Ma X, Beierle EA (2009) Ketone bodies inhibit the viability of human neuroblastoma cells. J Pediatr Surg 44(1):212–216

    Article  Google Scholar 

  • Stafford P, Abdelwahab MG, Kim DY, Preul MC, Rho JM, Scheck AC (2010) The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab (Lond) 7:74

    Article  CAS  Google Scholar 

  • Stafstrom CE, Rho JM (2012) The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol 3:59

    Article  CAS  Google Scholar 

  • 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(16):5643–5650

    Article  CAS  Google Scholar 

  • Tisdale MJ, Brennan RA (1983) Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues. Br J Cancer 47(2):293–297

    Article  CAS  Google Scholar 

  • Tisdale MJ, Brennan RA, Fearon KC (1987) Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J Cancer 56(1):39–43

    Article  CAS  Google Scholar 

  • Urits I, Mukherjee P, Meidenbauer J, Seyfried TN (2012) Dietary restriction promotes vessel maturation in a mouse astrocytoma. J Oncol 2012:264039

    Article  Google Scholar 

  • Vadlakonda L, Dash A, Pasupuleti M, Anil KK, Reddanna P (2013) The Paradox of Akt-mTOR Interactions. Front Oncol 3:165

    Google Scholar 

  • van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJ, Jaeckle K, Junck L, Armstrong T, Choucair A, Waldman AD, Gorlia T, Chamberlain M, Baumert BG, Vogelbaum MA, MacDonald DR, Reardon DA, Wen PY, Chang SM, Jacobs AH (2011) Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 12(6):583–593

    Article  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 1029–1033

    Google Scholar 

  • Vanitallie TB, Nufert TH (2003) Ketones: metabolism's ugly duckling. Nutr Rev 61(10):327–341

    Article  Google Scholar 

  • Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr (2001) Ketone bodies, potential therapeutic uses. IUBMB Life 51(4):241–247

    Article  CAS  Google Scholar 

  • Venneti S, Thompson CB (2013) Metabolic modulation of epigenetics in gliomas. Brain Pathol 23(2):217–221

    Article  CAS  Google Scholar 

  • Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  Google Scholar 

  • Wang Y, Yuan JL, Zhang YT, Ma JJ, Xu P, Shi CH, Zhang W, Li YM, Fu Q, Zhu GF, Xue W, Lei YH, Gao JY, Wang JY, Shao C, Yi CG, Wang H (2013) Inhibition of both EGFR and IGF1R sensitized prostate cancer cells to radiation by synergistic suppression of DNA homologous recombination repair. PLoS One 8(8), e68784

    Article  CAS  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530

    Article  CAS  Google Scholar 

  • Ward PS, Thompson CB (2012) Metabolic reprogramming: A cancer hallmark even Warburg did not anticipate. Cancer Cell 21:297–308

    Article  CAS  Google Scholar 

  • Weinberg F, Chandel NS (2009) Reactive oxygen species-dependent signaling regulates cancer. Cell Mol Life Sci 66(23):3663–3673

    Article  CAS  Google Scholar 

  • Weller M, Stupp R, Hegi M, Wick W (2012) Individualized targeted therapy for glioblastoma: fact or fiction? Cancer J 18(1):40–44

    Article  CAS  Google Scholar 

  • Weroha SJ, Haluska P (2012) The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am 41(2):335–50, vi

    Article  CAS  Google Scholar 

  • Wolf A, Agnihotri S, Guha A (2010) Targeting metabolic remodeling in glioblastoma multiforme. Oncotarget 1(7):552–562

    Article  Google Scholar 

  • Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC (2015) The ketogenic diet alters the hypoxic response and affects expression of proteins associated with angiogenesis, invasive potential and vascular permeability in a mouse glioma model. PLoS One 10(6):e0130357

    Google Scholar 

  • Woolf EC, Stafford P, Abdelwahab MG, Fenton KE, Preul MC, Scheck AC (2013) The ketogenic diet potentiates radiation therapy in a mouse model of glioma: effects on inflammatory pathways and reactive oxygen species. Cancer Res 73:4441

    Article  Google Scholar 

  • Yang C, Sudderth J, Dang T, Bachoo RG, McDonald JG, DeBerardinis RJ (2009) Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res 69(20):7986–7993

    Article  CAS  Google Scholar 

  • Yun J, Johnson JL, Hanigan CL, Locasale JW (2012) Interactions between epigenetics and metabolism in cancers. Front Oncol 2:163

    Article  Google Scholar 

  • Zhang H, Gu C, Yu J, Wang Z, Yuan X, Yang L, Wang J, Jia Y, Liu J, Liu F (2014) Radiosensitization of glioma cells by TP53-induced glycolysis and apoptosis regulator knockdown is dependent on thioredoxin-1 nuclear translocation. Free Radic Biol Med 69C:239–248

    Article  CAS  Google Scholar 

  • 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 (Lond) 4:5

    Article  CAS  Google Scholar 

  • Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, Seyfried TN (2010) Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: case report. Nutr Metab 7:33–53

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Neuro-Oncology Research, Barrow Neurological Institute, 350 W Thomas Rd., Phoenix, AZ, 85013, USA

    Kenneth S. Brooks, Eric C. Woolf & Adrienne C. Scheck

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  1. Kenneth S. Brooks
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  2. Eric C. Woolf
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  3. Adrienne C. Scheck
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Correspondence to Adrienne C. Scheck .

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  1. Prince Fahd Research Chair, Department of Medical Laboratory Technology, FAMS, University of Tabuk, Tabuk, Saudi Arabia

    Mohammad Fahad Ullah

  2. Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA

    Aamir Ahmad

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Brooks, K.S., Woolf, E.C., Scheck, A.C. (2016). The Ketogenic Diet as an Adjuvant Therapy for Brain Tumors and Other Cancers. In: Ullah, M., Ahmad, A. (eds) Critical Dietary Factors in Cancer Chemoprevention. Springer, Cham. https://doi.org/10.1007/978-3-319-21461-0_5

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