The influence of ketogenic therapy on the 5 R’s of radiobiology

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:e36197.
   PubMed Web of Science ®Google Scholar
• Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, Venkataraman S, Mackey MA, Flanagan SW, Oberley LW, et al. 2005. Mitochondrial O2*- and H2O2 mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem. 280:4254–4263.
   PubMed Web of Science ®Google Scholar
• Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. 2014. Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol. 2:963–970.
   PubMed Web of Science ®Google Scholar
• Allen BG, Bhatia SK, Buatti JM, Brandt KE, Lindholm KE, Button AM, Szweda LI, Smith BJ, Spitz DR, Fath MA, et al. 2013. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clin Cancer Res. 19:3905–3913.
   PubMed Web of Science ®Google Scholar
• Apontes P, Leontieva OV, Demidenko ZN, Li F, Blagosklonny MV. 2011. Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture. Oncotarget 2:222–233.
   PubMed Web of Science ®Google Scholar
• Aykin-Burns N, Ahmad IM, Zhu Y, Oberley LW, Spitz DR. 2009. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J. 418:29–37.
   PubMed Web of Science ®Google Scholar
• Azzam EI, Jay-Gerin JP, Pain D. 2012. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 327:48–60.
   PubMed Web of Science ®Google Scholar
• Bae HR, Kim DH, Park MH, Lee B, Kim MJ, Lee EK, Chung KW, Kim SM, Im DS, Chung HY, et al. 2016. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 7:66444–66454.
   PubMed Web of Science ®Google Scholar
• Bennett MH, Feldmeier J, Smee R, Milross C. 2012. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev. 4:CD005007.
   PubMed Web of Science ®Google Scholar
• Berardi MJ, Fantin VR. 2011. Survival of the fittest: metabolic adaptations in cancer. Curr Opin Genet Dev. 21:59–66.
   PubMed Web of Science ®Google Scholar
• Bhatt AN, Chauhan A, Khanna S, Rai Y, Singh S, Soni R, Kalra N, Dwarakanath BS. 2015. Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells. BMC Cancer. 15:1–12.
   PubMed Web of Science ®Google Scholar
• Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, Emionite L, Lavarello C, Amaro A, Petretto A, et al. 2015. Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget. 6:11806–11819.
   PubMed Web of Science ®Google Scholar
• Cannino G, Di Liegro CM, Rinaldi AM. 2007. Nuclear-mitochondrial interaction. Mitochondrion. 7:359–366.
   PubMed Web of Science ®Google Scholar
• Cantó C, Auwerx J. 2012. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev. 64:166–187.
   PubMed Web of Science ®Google Scholar
• Chang HT, Olson LK, Schwartz KA. 2013. Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutr Metab (Lond). 10:47
   PubMed Web of Science ®Google Scholar
• Cullingford TE. 2004. The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders. Prostaglandins Leukot Essent Fat Acids. 70:253–264.
   PubMed Web of Science ®Google Scholar
• D’Aronzo M, Vinciguerra M, Mazza T, Panebianco C, Saracino C, Pereira SP, Graziano P, Pazienza V. 2015. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. Oncotarget. 6:18545–51857.
   PubMed Web of Science ®Google Scholar
• Dong JT. 2013. Anticancer activities of PPARγ in breast cancer are context-dependent. Am J Pathol. 182:1972–1975.
   PubMed Web of Science ®Google Scholar
• Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ. 2012. The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell. 48:612–626.
   PubMed Web of Science ®Google Scholar
• Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, Cheng C-W, Brandhorst S, Cohen P, Wei M, et al. 2016. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 16:360.
   PubMed Web of Science ®Google Scholar
• El Naqa I. 2014. The role of quantitative PET in predicting cancer treatment outcomes. Clin Transl Imaging. 2:305–320.
   Google Scholar
• Eijkelenboom A, Burgering BMT. 2013. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 14:83–97.
   PubMed Web of Science ®Google Scholar
• Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD. 2009. Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell Int. 9:14.
   PubMed Web of Science ®Google Scholar
• Foray N. 2016. Victor despeignes, the forgotten pioneer of radiation oncology. Int J Radiat Oncol Biol Phys. 96:717–721.
   PubMedGoogle Scholar
• Fredericks M, Ramsey RB. 1978. 3-Oxo acid coenzyme A transferase activity in brain and tumors of the nervous system. J Neurochem. 31:1529–1531.
   PubMed Web of Science ®Google Scholar
• Gabriel AM, Alan CR, Thomas NS. 2017. Ultrastructural characterization of the Mitochondria-associated membranes abnormalities in human astrocytomas: functional and therapeutics implications. Ultrastruct Pathol. 41:234–244.
   PubMed Web of Science ®Google Scholar
• Gaude E, Frezza C. 2014. Defects in mitochondrial metabolism and cancer. Cancer Metab. 2:10.
   PubMedGoogle Scholar
• Gillies RJ, Robey I, Gatenby RA. 2008. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 49:24S–42S.
   PubMed Web of Science ®Google Scholar
• Graham NA, Tahmasian M, Kohli B, Komisopoulou E, Zhu M, Vivanco I. 2012. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol. 8:589.
   PubMed Web of Science ®Google Scholar
• de Groot S, Vreeswijk MP, Welters MJ, Gravesteijn G, Boei JJ, Jochems A, Houtsma D, Putter H, van der Hoeven JJ, Nortier JW, et al. 2015. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer. 15:652.
   PubMed Web of Science ®Google Scholar
• Groselj B, Sharma NL, Hamdy FC, Kerr M, Kiltie a. E. 2013. Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signalling and repair. Br J Cancer. 108:748–754.
   PubMed Web of Science ®Google Scholar
• Grubbé EH. 1933. Priority in the therapeutic use of X-rays. Radiology. 21:156–162.
   Google Scholar
• Guckenberger M, Klement RJ, Allgäuer M, Appold S, Dieckmann K, Ernst I, Ganswindt U, Holy R, Nestle U, Nevinny-Stickel M, et al. 2013. Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer. Radiother Oncol. 109:13–20.
   PubMed Web of Science ®Google Scholar
• Hall A, Meyle KD, Lange MK, Klima M, Sanderhoff M, Dahl C, Abildgaard C, Thorup K, Moghimi SM, Jensen PB, et al. 2013. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the V600EBRAF oncogene. Oncotarget. 4:584–599.
   PubMed Web of Science ®Google Scholar
• Holm E, Hagmüller E, Staedt U, Schlickeiser G, Günther HJ, Leweling H, Tokus M, Kollmar HB. 1995. Substrate balances across colonic carcinomas in humans. Cancer Res. 55:1373–1378.
   PubMed Web of Science ®Google Scholar
• Holm E, Kämmerer U. 2011. Lipids and carbohydrates in nutritional concepts for tumor patients. Aktuel Ernahrungsmed. 36:286–298.
   Google Scholar
• Huisman SA, Bijman-Lagcher W, Ijzermans JNM, Smits R, de Bruin RWF. 2015. Fasting protects against the side effects of irinotecan but preserves its anti-tumor effect in Apc15lox mutant mice. Cell Cycle. 14:2333–2339.
   PubMed Web of Science ®Google Scholar
• Huisman SA, de Bruijn P, Ghobadi Moghaddam-Helmantel IM, IJzermans JNM, Wiemer EAC, Mathijssen RHJ, de Bruin RWF. 2016. Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice. Br J Pharmacol. 173:804–814.
   PubMed Web of Science ®Google Scholar
• Husain Z, Huang Y, Seth P, Sukhatme VP. 2014. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 191:1486–1495.
   Web of Science ®Google Scholar
• İyikesici MS, Slocum AK, Slocum A, Berkarda FB, Kalamian M, Seyfried TN. 2017. Efficacy of metabolically supported chemotherapy combined with ketogenic diet, hyperthermia, and hyperbaric oxygen therapy for stage IV triple-negative breast cancer. Cureus. 9:e1445.
   PubMed Web of Science ®Google Scholar
• Jelluma N, Yang X, Stokoe D, Evan GI, Dansen TB, Haas-Kogan DA. 2006. Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes. Mol Cancer Res. 4:319–330.
   PubMed Web of Science ®Google Scholar
• Jeong J, Juhn K, Lee H, Kim S, Min B, Lee K, Cho M, Park G, Lee K. 2007. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med. 39:8–13.
   PubMed Web of Science ®Google Scholar
• Jha B, Pohlit W. 1992. Effect of 2-deoxy-d-glucose on DNA double strand break repair, cell survival and energy metabolism in euoxic Ehrlich ascites tumour cells. Int J Radiat Biol. 62:409–415.
   PubMed Web of Science ®Google Scholar
• Jiang YS, Wang FR. 2013. Caloric restriction reduces edema and prolongs survival in a mouse glioma model. J Neurooncol. 114:25–32.
   PubMed Web of Science ®Google Scholar
• Kadochi Y, Mori S, Fujiwara-Tani R, Luo Y, Nishiguchi Y, Kishi S, Fujii K, Ohmori H, Kuniyasu H. 2017. Remodeling of energy metabolism by a ketone body and medium-chain fatty acid suppressed the proliferation of CT26 mouse colon cancer cells. Oncol Lett. 14:673–680.
   PubMed Web of Science ®Google Scholar
• Kallinowski F, Vaupel P, Runkel S, Berg G. 1988. Glucose uptake, lactate release, ketone body turnover, metabolic micromilieu, and pH distributions in human breast cancer xenografts in nude rats. Cancer Res. 48:7264–7272.
   PubMed Web of Science ®Google Scholar
• Kam WWY, Banati RB. 2013. Effects of ionizing radiation on mitochondria. Free Radic Biol Med. 65:607–619.
   PubMed Web of Science ®Google Scholar
• Kam WWY, McNamara AL, Lake V, Banos C, Davies JB, Kuncic Z, Banati RB. 2013. Predicted ionisation in mitochondria and observed acute changes in the mitochondrial transcriptome after gamma irradiation: A Monte Carlo simulation and quantitative PCR study. Mitochondrion. 13:736–742.
   PubMed Web of Science ®Google Scholar
• Klein S, Wolfe RR. 1992. Carbohydrate restriction regulates the adaptive response to fasting. Am J Physiol. 262:E631–E636.
   PubMedGoogle Scholar
• Klement RJ. 2013. Calorie or carbohydrate restriction? The ketogenic diet as another option for supportive cancer treatment. Oncologist. 18:1056.
   PubMed Web of Science ®Google Scholar
• Klement RJ. 2014. Mimicking caloric restriction: what about macronutrient manipulation? A response to Meynet and Ricci. Trends Mol Med. 20:471–472.
   PubMed Web of Science ®Google Scholar
• Klement RJ. 2017. Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation. Med Oncol. 34:132.
   PubMed Web of Science ®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. 33:217–229.
   PubMed Web of Science ®Google Scholar
• Klement RJ, Champ CE, Otto C, Kämmerer U. 2016. Anti-tumor effects of ketogenic diets in mice: a meta-analysis. PLoS One. 11:e0155050
   PubMed Web of Science ®Google Scholar
• Klement RJ, Fink MK. 2016. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer. Oncogenesis. 5:e193.
   PubMed Web of Science ®Google Scholar
• Kong G, Huang Z, Ji W, Wang X, Liu J, Wu X, Huang Z, Li R, Zhu Q. 2017. The ketone metabolite β-hydroxybutyrate attenuates oxidative stress in spinal cord injury by suppression of class I histone deacetylases. J Neurotrauma. 34:2645–2655.
   PubMed Web of Science ®Google Scholar
• Kopeina GS, Senichkin VV, Zhivotovsky B. 2017. Caloric restriction – a promising anti-cancer approach: from molecular mechanisms to clinical trials. Biochim Biophys Acta. 1867:29–41.
   PubMed Web of Science ®Google Scholar
• Kruszewski M, Szumiel I. 2005. Sirtuins (histone deacetylases III) in the cellular response to DNA damage-facts and hypotheses. DNA Repair (Amst). 4:1306–1313.
   PubMed Web of Science ®Google Scholar
• Kurtak KA. 2014. Dietary and nutritional manipulation of the nuclear transcription factors peroxisome proliferator-activated receptor and sterol regulatory element-binding proteins as a tool for reversing the primary diseases of premature death and delaying aging. Rejuvenation Res. 17:140–144.
   PubMed Web of Science ®Google Scholar
• Larsen NB, Rasmussen M, Rasmussen LJ. 2005. Nuclear and mitochondrial DNA repair: similar pathways?. Mitochondrion. 5:89–108.
   PubMed Web of Science ®Google Scholar
• Lashinger LM, O’Flanagan CH, Dunlap SM, Rasmussen AJ, Sweeney S, Guo JY, Lodi A, Tiziani S, White E, Hursting SD. 2016. Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors. Cancer Metab. 4:18.
   PubMed Web of Science ®Google Scholar
• Leach JK, Tuyle GV, Lin P, Schmidt-ullrich R, Mikkelsen RB. 2001. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res. 61:3894–3901.
   PubMed Web of Science ®Google Scholar
• Lee C, Longo VD. 2011. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 30:3305–3316.
   PubMed Web of Science ®Google Scholar
• Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, et al. 2012. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 4:124ra27.
   PubMed Web of Science ®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. 70:1564–1572.
   PubMed Web of Science ®Google Scholar
• Liang J, Slingerland JM. 2003. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2:339–345.
   PubMed Web of Science ®Google Scholar
• Lindblom E, Antonovic L, Dasu A, Lax I, Wersäll P, Toma-Dasu I. 2014. Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability. Radiat Oncol. 9:149.
   PubMed Web of Science ®Google Scholar
• Liu J, Hou M, Yuan T, Yi G, Zhang S, Shao X, Chen J, Jia X, He Z. 2012. Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair. Oncol Rep. 28:1406–1412.
   PubMed Web of Science ®Google Scholar
• Lomax ME, Folkes LK, O’Neill P. 2013. Biological consequences of radiation-induced DNA damage: Relevance to radiotherapy. Clin Oncol (R Coll Radiol). 25:578–585.
   PubMed Web of Science ®Google Scholar
• López-Ríos F, Sánchez-Aragó M, García-Garía E, Ortega ÁD, Berrendero JR, Pozo-Rodríguez F, López-Encuentra Á, Ballestín C, Cuezva JM. 2007. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res. 67:9013–9017.
   PubMed Web of Science ®Google Scholar
• Lv M, Zhu X, Wang H, Wang F, Guan W. 2014. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. PLoS One. 9:e115147.
   PubMed Web of Science ®Google Scholar
• Mahoney LB, Denny CA, Seyfried TN. 2006. Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans. Lipids Health Dis. 5:13.
   PubMed Web of Science ®Google Scholar
• Mailloux RJ, Harper M-E. 2011. Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med. 51:1106–1115.
   PubMed Web of Science ®Google Scholar
• Marcu L, Bezak E, Allen BJ. 2012. Biomedical physics in radiotherapy for cancer. 1st ed. Collingwood VIC3066, Australia: CSIRO Publishing.
   Google Scholar
• Marini C, Bianchi G, Buschiazzo A, Ravera S, Martella R, Bottoni G, Petretto A, Emionite L, Monteverde E, Capitanio S, et al. 2016. Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer. Sci Rep. 6:19569.
   PubMed Web of Science ®Google Scholar
• Martuscello RT, Vedam-Mai V, McCarthy DJ, Schmoll ME, Jundi MA, Louviere CD, Griffith BG, Skinner CL, Suslov O, Deleyrolle LP, et al. 2016. A supplemented high-fat low-carbohydrate diet for the treatment of glioblastoma. Clin Cancer Res. 22:2482–2495.
   PubMed Web of Science ®Google Scholar
• Maurer GD, Brucker DP, Bähr 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.
   PubMed Web of Science ®Google Scholar
• Meijer TWH, Kaanders JHAM, Span PN, Bussink J. 2012. Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res. 18:5585–5594.
   PubMed Web of Science ®Google Scholar
• Meister A. 1983. Selective modification of glutathione metabolism. Science. 220:472–477.
   PubMed Web of Science ®Google Scholar
• Miller AC, Rivas R, McMahon R, Miller K, Tesoro L, Villa V, Yanushkevich D, Lison P. 2017. Radiation protection and mitigation potential of phenylbutyrate: delivered via oral administration. Int J Radiat Biol. 93:907–919.
   PubMed Web of Science ®Google Scholar
• Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A. 2016. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 66:271–289.
   PubMed Web of Science ®Google Scholar
• Morscher RJ, Aminzadeh-Gohari S, Feichtinger RG, Mayr JA, Lang R, Neureiter D, Sperl W, Kofler B. 2015. Inhibition of neuroblastoma tumor growth by ketogenic diet and/or calorie restriction in a CD1-Nu mouse model. PLoS One. 10:e0129802.
   PubMed Web of Science ®Google Scholar
• Morscher RJ, Aminzadeh-Gohari S, Hauser-Kronberger C, Feichtinger RG, Sperl W, Kofler B. 2016. Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model. Oncotarget. 7:17060–17073.
   PubMed Web of Science ®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. 10:5622–5629.
   PubMed Web of Science ®Google Scholar
• Mukherjee P, Sotnikov AV, Mangian HJ, Zhou J, Visek WJ, Clinton SK. 1999. Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J Natl Cancer Inst. 91:512–523.
   PubMedGoogle Scholar
• Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, Ismail S, Stevens C, Meyn RE. 2005. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res. 11:4912–4922.
   PubMed Web of Science ®Google Scholar
• Nagao M, Toh R, Irino Y, Mori T, Nakajima H, Hara T, Honjo T, Satomi-Kobayashi S, Shinke T, Tanaka H, et al. 2016. β-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes. Biochem Biophys Res Commun. 475:322–328.
   PubMed Web of Science ®Google Scholar
• Newman JC, Verdin E. 2014. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 25:42–52.
   PubMed Web of Science ®Google Scholar
• O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. 2017. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 15:106.
   PubMed Web of Science ®Google Scholar
• Ogura A, Oowada S, Kon Y, Hirayama A, Yasui H, Meike S, Kobayashi S, Kuwabara M, Inanami O. 2009. Redox regulation in radiation-induced cytochrome c release from mitochondria of human lung carcinoma A549 cells. Cancer Lett. 277:64–71.
   PubMed Web of Science ®Google Scholar
• Oike T, Ogiwara H, Amornwichet N, Nakano T, Kohno T. 2014. Chromatin-regulating proteins as targets for cancer therapy. J Radiat Res. 55:613–628.
   PubMed Web of Science ®Google Scholar
• Otto C, Klingelhöffer C, Biggermann L, Melkus G, Mörchel P, Jürgens C, Gahn S, Kämmerer U. 2014. Analysis of the metabolism of ketone bodies and lactate by gastrointestinal tumor cells in vitro. Aktuel Ernahrungsmed. 39:51–59.
   Google Scholar
• Pawlik TM, Keyomarsi K. 2004. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 59:928–942.
   PubMed Web of Science ®Google Scholar
• Petersen C, Eicheler W, Frömmel A, Krause M, Balschukat S, Zips D, Baumann M. 2003. Proliferation and micromilieu during fractionated irradiation of human FaDu squamous cell carcinoma in nude mice. Int J Radiat Biol. 79:469–477.
   PubMed Web of Science ®Google Scholar
• Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T, et al. 2016. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell. 30:147–160.
   PubMed Web of Science ®Google Scholar
• Poff AM, Ari C, Seyfried TN, Agostino DPD. 2013. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One. 8:e65522.
   PubMed Web of Science ®Google Scholar
• Poff AM, Ward N, Seyfried TN, Arnold P, D’Agostino DP. 2015. Non-toxic metabolic management of metastatic cancer in VM mice: novel combination of ketogenic diet, ketone supplementation, and hyperbaric oxygen therapy. PLoS One. 10:e0127407.
   PubMed Web of Science ®Google Scholar
• Powolny AA, Wang S, Carlton PS, Hoot DR, Clinton SK. 2008. Interrelationships between dietary restriction, the IGF-I axis, and expression of vascular endothelial growth factor by prostate adenocarcinoma in rats. Mol Carcinog. 47:458–465.
   PubMed Web of Science ®Google Scholar
• Prasad V. 2016. Perspective: The precision-oncology illusion. Nature. 537:S63.
   PubMed Web of Science ®Google Scholar
• Puchalska P, Crawford PA. 2017. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25:262–284.
   PubMed Web of Science ®Google Scholar
• Qin L, Fan M, Candas D, Jiang G, Papadopoulos S, Tian L, Woloschak G, Grdina DJ, Li JJ. 2015. CDK1 enhances mitochondrial bioenergetics for radiation-induced DNA repair. Cell Rep. 13:2056–2063.
   PubMed Web of Science ®Google Scholar
• Quennet V, Yaromina A, Zips D, Rosner A, Walenta S, Baumann M, Mueller-klieser W. 2006. Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice. Radiother Oncol. 81:130–135.
   PubMed Web of Science ®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. 105:8215–8220.
   PubMed Web of Science ®Google Scholar
• Richardson RB, Harper M. 2016. Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy. Oncotarget. 7:21469–21483.
   PubMed Web of Science ®Google Scholar
• Richtsmeier WJ, Dauchy R, Sauer LA. 1987. In vivo nutrient uptake by head and neck cancers. Cancer Res. 47:5230–5233.
   PubMed Web of Science ®Google Scholar
• Rodrigues LM, Uribe-Lewis S, Madhu B, Honess DJ, Stubbs M, Griffiths JR. 2017. The action of β-hydroxybutyrate on the growth, metabolism and global histone H3 acetylation of spontaneous mouse mammary tumours: evidence of a β-hydroxybutyrate paradox. Cancer Metab. 5:4.
   PubMed Web of Science ®Google Scholar
• Rojas-Morales P, Tapia E, Pedraza-Chaverri J. 2016. β-Hydroxybutyrate: a signaling metabolite in starvation response? Cell Signal. 28:917–923.
   PubMed Web of Science ®Google Scholar
• Roś-Mazurczyk M, Wojakowska A, Marczak Ł, Polański K, Pietrowska M, Jelonek K, Domińczyk I, Hajduk A, Rutkowski T, Składowski K, et al. 2017. Ionizing radiation affects profile of serum metabolites: increased level of 3-hydroxybutyric acid in serum of cancer patients treated with radiotherapy. Acta Biochim Pol. 64:189–193.
   PubMed Web of Science ®Google Scholar
• Rossi-Fanelli F, Franchi F, Mulieri M, Cangiano C, Cascino A, Ceci F, Muscaritoli M, Seminara P, Bonomo L. 1991. Effect of energy substrate manipulation on tumour cell proliferation in parenterally fed cancer patients. Clin Nutr. 10:228–232.
   PubMed Web of Science ®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:e44603.
   PubMed Web of Science ®Google Scholar
• Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. 2009. Fasting and cancer treatment in humans: a case series report. Aging (Albany Ny). 1:988–1007.
   PubMedGoogle Scholar
• Saleh AD, Simone BA, Savage J, Sano Y, Jin L, Champ C, Zhao S, Lim M, Sotgia F, Camphausen K, et al. 2013. Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle. 12:1955–1963.
   PubMed Web of Science ®Google Scholar
• Sattler UGA, Mueller-Klieser W. 2009. The anti-oxidant capacity of tumour glycolysis. Int J Radiat Biol. 85:963–971.
   PubMed Web of Science ®Google Scholar
• Sattler UGA, Meyer SS, Quennet V, Hoerner C, Knoerzer H, Fabian C, Yaromina A, Zips D, Walenta S, Baumann M. 2010. Glycolytic metabolism and tumour response to fractionated irradiation. Radiother Oncol. 94:102–109.
   PubMed Web of Science ®Google Scholar
• Scherer E. 1995. 100 Jahre Röntgenstrahlung. Bemerkungen zur Historie, Gegenwart und Zukunft ihrer therapeutischen Anwendung. Strahlenther Onkol. 171:709–714.
   PubMedGoogle Scholar
• Schroeder U, Himpe B, Pries R, Vonthein R, Nitsch S, Wollenberg B. 2013. Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutr Cancer. 65:843–849.
   PubMed Web of Science ®Google Scholar
• Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, Kurniali PC, Hord NG, Noel M. 2015. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab. 3:3.
   PubMed Web of Science ®Google Scholar
• Seyfried TN. 2015. Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol. 3:43.
   PubMed Web of Science ®Google Scholar
• Seyfried TN, Flores RE, Poff AM, D’Agostino DP. 2014. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 35:515–527.
   PubMed Web of Science ®Google Scholar
• Seyfried TN, Shelton LM. 2010. Cancer as a metabolic disease. Nutr Metab (Lond). 7:7.
   PubMed Web of Science ®Google Scholar
• Sgantzos M, Tsoucalas G, Laios K, Androutsos G. 2014 The physician who first applied radiotherapy, Victor Despeignes, on 1896. Hell J Nucl Med. 17:45–46.
   PubMed Web of Science ®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:e00038
   PubMed Web of Science ®Google Scholar
• Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, et al. 2013. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 339:211–214.
   PubMed Web of Science ®Google Scholar
• Shukla SK, Gebregiworgis T, Purohit V, Chaika NV, Gunda V, Radhakrishnan P, Mehla K, Pipinos II, Powers R, Yu F, et al. 2014. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab. 2:18.
   PubMedGoogle Scholar
• Shuryak I, Carlson DJ, Brown JM, Brenner DJ. 2015. High-dose and fractionation effects in stereotactic radiation therapy: analysis of tumor control data from 2965 patients. Radiother Oncol. 115:327–334.
   PubMed Web of Science ®Google Scholar
• Simone BA, Champ CE, Rosenberg AL, Berger AC, Anne RP, Monti DA, Dicker AP, Simone NL. 2013. Selectively starving cancer cells through dietary manipulation: methods and clinical implications. Futur Oncol. 9:959–876.
   PubMed Web of Science ®Google Scholar
• Simone BA, Dan T, Palagani A, Jin L, Han SY, Wright C, Savage JE, Lim MK, Palazzo J, Mehta MP, et al. 2016. Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer. Cell Cycle. 15:2265–2274.
   PubMed Web of Science ®Google Scholar
• Skinner R, Trujillo A, Ma X, Beierle EA. 2009. Ketone bodies inhibit the viability of human neuroblastoma cells. J Pediatr Surg. 44:212–216.
   PubMed Web of Science ®Google Scholar
• 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. 899:349–362.
   PubMed Web of Science ®Google Scholar
• Steel GG. 2001. The case against apoptosis. Acta Oncol. 40:968–975.
   PubMed Web of Science ®Google Scholar
• Steel GG, McMillan TJ, Peacock JH. 1989. The 5Rs of radiobiology. Int J Radiat Biol. 56:1045–1048.
   PubMed Web of Science ®Google Scholar
• Stępień K, Ostrowski RP, Matyja E. 2016. Hyperbaric oxygen as an adjunctive therapy in treatment of malignancies, including brain tumours. Med Oncol. 33:101.
   PubMed Web of Science ®Google Scholar
• Storozhuk Y, Hopmans SN, Sanli T, Barron C, Tsiani E, Cutz JC, Pond G, Wright J, Singh G, Tsakiridis T. 2013. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br J Cancer. 108:2021–2032.
   PubMed Web of Science ®Google Scholar
• Strowd RE, Cervenka MC, Henry BJ, Kossoff EH, Hartman AL, Blakeley JO. 2015. Glycemic modulation in neuro-oncology: experience and future directions using a modified Atkins diet for high-grade brain tumors. Neurooncol Pract. 2:127–136.
   PubMed Web of Science ®Google Scholar
• Strunz AM, Peschke P, Waldeck W, Ehemann V, Kissel M. 2002. Preferential radiosensitization in p53-mutated human tumour cell lines by pentoxifylline-mediated disruption of the G2/M checkpoint control. Int J Radiat Oncol. 78:721–732.
   Google Scholar
• Sullivan LB, Chandel NS. 2014. Mitochondrial reactive oxygen species and cancer. Cancer Metab. 2:17.
   PubMedGoogle Scholar
• Szumiel I. 2015. Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: The pivotal role of mitochondria. Int J Radiat Biol. 91:1–12.
   PubMed Web of Science ®Google Scholar
• Tan-Shalaby JL, Carrick J, Edinger K, Genovese D, Liman AD, Passero V. a, Shah RB. 2016. Modified Atkins diet in advanced malignancies – final results of a safety and feasibility trial within the Veterans Affairs Pittsburgh Healthcare System. Nutr Metab (Lond). 13:52.
   PubMed Web of Science ®Google Scholar
• Tisdale MJ, Brennan RA. 1983. Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues. Br J Cancer. 47:293–297.
   PubMed Web of Science ®Google Scholar
• Urits I, Mukherjee P, Meidenbauer J, Seyfried TN. 2012. Dietary restriction promotes vessel maturation in a mouse astrocytoma. J Oncol. 2012:264039.
   PubMedGoogle Scholar
• 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 Fat Acids. 70:309–319.
   PubMed Web of Science ®Google Scholar
• Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. 2017. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 69:305–314.
   PubMed Web of Science ®Google Scholar
• Verschoor ML, Ungard R, Harbottle A, Jakupciak JP, Parr RL, Singh G. 2013. Mitochondria and cancer: past, present, and future. Biomed Res Int. 2013:612369.
   PubMed Web of Science ®Google Scholar
• Vozza A, Parisi G, De Leonardis F, Lasorsa FM, Castegna A, Amorese D, Marmo R, Calcagnile VM, Palmieri L, Ricquier D, et al. 2014. UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proc Natl Acad Sci USA. 111:960–965.
   PubMed Web of Science ®Google Scholar
• Walsh DWM, Siebenwirth C, Greubel C, Ilicic K, Reindl J, Girst S, Muggiolu G, Simon M, Barberet P, Seznec H, et al. 2017. Live cell imaging of mitochondria following targeted irradiation in situ reveals rapid and highly localized loss of membrane potential. Sci Rep. 7:46684.
   PubMed Web of Science ®Google Scholar
• Warburg O. 1956. On the origin of cancer cells. Science. 123:309–314.
   PubMed Web of Science ®Google Scholar
• Warburg O, Posener K, Negelein E. 1924. Über den Stoffwechsel der Carcinomzelle. Biochem Zeitschr. 152:309–343.
   Google Scholar
• Warburg O, Wind F, Negelein E. 1926. Über den Stoffwechsel der Tumoren im Körper. Klin Wochenschr. 5:829–838.
   Google Scholar
• Werner H, Sarfstein R, LeRoith D, Bruchim I. 2016. Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways. Front Oncol. 6:159.
   PubMed Web of Science ®Google Scholar
• Winter SF, Loebel F, Dietrich J. 2017. Role of ketogenic metabolic therapy in malignant glioma: a systematic review. Crit Rev Oncol Hematol. 112:41–58.
   PubMed Web of Science ®Google Scholar
• Wojewodzka M, Kruszewski M, Buraczewska I, Xu W, Massuda E, Zhang J, Szumiel I. 2007. Sirtuin inhibition increases the rate of non-homologous end-joining of DNA double strand breaks. Acta Biochim Pol. 54:63–69.
   PubMed Web of Science ®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:e0130357.
   PubMed Web of Science ®Google Scholar
• Woolf EC, Rossi AP, Silva-Nichols HB, Gardner KD, Syed N, Scheck AC. 2017. Abstract 1125A: β-hydroxybutyrate inhibits histone deacetylase activity and radiosensitizes malignant glioma cells. Cancer Res. 77:7445.
   Web of Science ®Google Scholar
• Woolf EC, Syed N, Scheck AC. 2016. Tumor metabolism, the ketogenic diet and β-hydroxybutyrate: novel approaches to adjuvant brain tumor therapy. Front Mol Neurosci. 9:122.
   PubMed Web of Science ®Google Scholar
• Wouters BG, Begg A. 2009. Irradiation-induced damage and the DNA damage response. In: Joiner MC, van der Kogel AJ, editors. Basic clinical radiobiology. 4th ed. Boca Raton (FL): CRC Press; p. 11–26.
   Google Scholar
• Xia S, Lin R, Jin L, Zhao L, Kang HB, Pan Y, Liu S, Qian G, Qian Z, Konstantakou E, et al. 2017. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 25:358–373.
   PubMed Web of Science ®Google Scholar
• Yakes FM, Van Houten B. 1997. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA. 94:514–519.
   PubMed Web of Science ®Google Scholar
• Zahra A, Fath MA, Opat E, Mapuskar KA, Bhatia SK, Ma DC, III SNR, Snyders TP, Chenard CA, Eichenberger-Gilmore JM, et al. 2017. Consuming a ketogenic diet while receiving radiation and chemotherapy for locally advanced lung cancer and pancreatic cancer: the University of Iowa experience of two phase 1 clinical trials. Radiat Res. 187:743–754.
   PubMed Web of Science ®Google Scholar
• Zhang W, Wu H, Yang M, Ye S, Li L, Zhang H, Hu J, Wang X, Xu J, Liang A. 2016. SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells. Oncotarget. 7:13538–13550.
   PubMed Web of Science ®Google Scholar
• Zhuang Y, Chan DK, Haugrud AB, Miskimins WK. 2014. Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo. PLoS One. 9:e108444.
   PubMed Web of Science ®Google Scholar