Chronic Dietary Administration of 2-Deoxy-D-Glucose Does Not Compromise Neurobehavioral Functions at Tumor Preventive Doses in Mice

Abstract

Beneficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have been well established. Given that DER is difficult to implement in humans due to practical constraints, development of energy restriction mimetics (ERMs) is considered as a suitable alternative. Our recent studies have established the anti-tumor effects of the dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose, a potential ERM, an alternative to DER; without any adverse effects on general physiology. Since functioning of the brain is critically dependent on glucose, we investigated the effects of chronic dietary 2-DG administration on the behavioural outcome in mice. Our findings based on a battery of neuro-behavioural tests clearly suggest that the chronic dietary administration of 2-DG that appreciably impairs the process of tumorigenesis has no adverse effect on the cognitive, affective and sensory-motor functions. Together with the maintenance of normal physiology reported by us earlier, these observations strengthen the potential of dietary 2-DG as a safe cancer preventive strategy.

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Singh, S. , Kumar, M. , Manda, K. , Haridas, S. , Bhatt, A. , Saluja, D. and Dwarakanath, B. (2015) Chronic Dietary Administration of 2-Deoxy-D-Glucose Does Not Compromise Neurobehavioral Functions at Tumor Preventive Doses in Mice. Journal of Behavioral and Brain Science, 5, 381-393. doi: 10.4236/jbbs.2015.59037.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Ingram, D.K., Zhu, M., Mamczarz, J., Zou, S., Lane, M.A., Roth, G.S. and DeCabo, R. (2006) Calorie Restriction Mimetics: An Emerging Research Field. Aging Cell, 5, 97-108.
http://dx.doi.org/10.1111/j.1474-9726.2006.00202.x
[2] Heilbronn, L.K. and Ravussin, E. (2003) Calorie Restriction and Aging: Review of the Literature and Implications for Studies in Humans. The American Journal of Clinical Nutrition, 78, 361-369.
[3] Barger, J.L., Kayo, T., Vann, J.M., Arias, E.B., Wang, J., Hacker, T.A., Wang, Y., et al. (2008) A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice. PLoS ONE, 3, e2264.
http://dx.doi.org/10.1371/journal.pone.0002264
[4] Lin, J.N., Lin, V., Rau, K.M., Shieh, P.C., Kuo, D.H., Shieh, J.C., Chen, W.J., et al. (2010) Resveratrol Modulates Tumor Cell Proliferation and Protein Translation via SIRT1-Dependent AMPK Activation. Journal of Agricultural and Food Chemistry, 58, 1584-1592.
http://dx.doi.org/10.1021/jf9035782
[5] Thompson, H., Zhu, Z., Thompson, M., Jiang, W. and McGinley, J. (2011) Metformin as an Energy Restriction Mimetic Agent for Breast Cancer Prevention. Journal of Carcinogenesis, 10, 17.
http://dx.doi.org/10.4103/1477-3163.83043
[6] Lane, M.A., Ingram, D.K. and Roth, G.S. (1998) 2-Deoxy-D-Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction. Journal of Anti-Aging Medicine, 1, 327-337.
http://dx.doi.org/10.1089/rej.1.1998.1.327
[7] Zhu, Z., Jiang, W., McGinley, J.N. and Thompson, H.J. (2005) 2-Deoxyglucose as an Energy Restriction Mimetic Agent: Effects on Mammary Carcinogenesis and on Mammary Tumor Cell Growth in Vitro. Cancer Research, 65, 7023-7030.
http://dx.doi.org/10.1158/0008-5472.CAN-05-0453
[8] Warburg, O., Wind, F. and Negelein, E. (1927) The Metabolism of Tumors in the Body. The Journal of General Physiology, 8, 519-530.
http://dx.doi.org/10.1085/jgp.8.6.519
[9] Warburg, O. (1956) On the Origin of Cancer Cells. Science, 123, 309-314.
http://dx.doi.org/10.1126/science.123.3191.309
[10] Woodward, G.E. and Carmer, F.B. (1952) 2-Deoxy-D-Glucose as an Inhibitor of Anaerobic Glycolysis in Tumor Tissues. Journal of the Franklin Institute, 254, 259-260.
http://dx.doi.org/10.1016/0016-0032(52)90482-1
[11] Wan, R., Camandola, S. and Mattson, M.P. (2003) Intermittent Fasting and Dietary Supplementation with 2-Deoxy-D-Glucose Improve Functional and Metabolic Cardiovascular Risk Factors in Rats. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 17, 1133-1134.
http://dx.doi.org/10.1096/fj.02-0996fje
[12] Wan, R., Camandola, S. and Mattson, M.P. (2004) Dietary Supplementation with 2-Deoxy-D-Glucose Improves Cardiovascular and Neuroendocrine Stress Adaptation in Rats. American Journal of Physiology-Heart and Circulatory Physiology, 287, H1186-H1193.
http://dx.doi.org/10.1152/ajpheart.00932.2003
[13] Pelicano, H., Martin, D.S., Xu, R.H.H. and Huang, P. (2006) Glycolysis Inhibition for Anticancer Treatment. Oncogene, 25, 4633-4646.
http://dx.doi.org/10.1038/sj.onc.1209597
[14] Dwarakanath, B. and Jain, V. (2009) Targeting Glucose Metabolism with 2-Deoxy-D-Glucose for Improving Cancer Therapy. Future Oncology, 5, 581-585.
http://dx.doi.org/10.2217/fon.09.44
[15] Gupta, S., Farooque, A., Adhikari, J.S., Singh, S. and Dwarakanath, B.S. (2009) Enhancement of Radiation and Chemotherapeutic Drug Responses by 2-Deoxy-D-Glucose in Animal Tumors. Journal of Cancer Research and Therapeutics, 5, S16-S20.
http://dx.doi.org/10.4103/0973-1482.55135
[16] Singh, D., Banerji, A.K., Dwarakanath, B.S., Tripathi, R.P., Gupta, J.P., Mathew, T.L., et al. (2005) Optimizing Cancer Radiotherapy with 2-Deoxy-D-Glucose: Dose Escalation Studies in Patients with Glioblastoma Multiforme. Strahlentherapie und Onkologie, 181, 507-514.
http://dx.doi.org/10.1007/s00066-005-1320-z
[17] Pina, Y., Houston, S.K., Murray, T.G., Boutrid, H., Celdran, M., Feuer, W., Shi, W., et al. (2010) Focal, Periocular Delivery of 2-Deoxy-D-Glucose as Adjuvant to Chemotherapy for Treatment of Advanced Retinoblastoma. Investigative Ophthalmology and Visual Science, 51, 6149-6156.
http://dx.doi.org/10.1167/iovs.09-5033
[18] Raez, L., Papadopoulos, K., Ricart, A., Chiorean, E., DiPaola, R., Stein, M., Lima, C., et al. (2012) A Phase I Dose-Escalation Trial of 2-Deoxy-D-Glucose Alone or Combined with Docetaxel in Patients with Advanced Solid Tumors. Cancer Chemotherapy and Pharmacology, 71, 523-530.
http://dx.doi.org/10.1007/s00280-012-2045-1
[19] Farooque, A., Singh, N., Adhikari, J.S., Afrin, F. and Dwarakanath, B.S.R. (2014) Enhanced Antitumor Immunity Contributes to the Radio-Sensitization of Ehrlich Ascites Tumor by the Glycolytic Inhibitor 2-Deoxy-D-Glucose in Mice. PLoS ONE, 9, e108131.
http://dx.doi.org/10.1371/journal.pone.0108131
[20] Stein, M., Lin, H., Jeyamohan, C., Dvorzhinski, D., Gounder, M., Bray, K., Eddy, S., et al. (2010) Targeting Tumor Metabolism with 2-Deoxyglucose in Patients with Castrate-Resistant Prostate Cancer and Advanced Malignancies. Prostate, 70, 1388-1394.
http://dx.doi.org/10.1002/pros.21172
[21] Mohanti, B.K., Rath, G.K., Anantha, N., Kannan, V., Das, B.S., Chandramouli, B.A., Banerjee, A.K., et al. (1996) Improving Cancer Radiotherapy with 2-Deoxy-D-Glucose: Phase I/II Clinical Trials on Human Cerebral Gliomas. International Journal of Radiation Oncology, Biology, Physics, 35, 103-111.
http://dx.doi.org/10.1016/S0360-3016(96)85017-6
[22] Dwarakanath, B.S., Singh, D., Banerji, A.K., Sarin, R., Venkataramana, N.K., Jalali, R., Vishwanath, P.N., et al. (2009) Clinical Studies for Improving Radiotherapy with 2-Deoxy-D-Glucose: Present Status and Future Prospects. Journal of Cancer Research and Therapeutics, 5, S21-S26.
http://dx.doi.org/10.4103/0973-1482.55136
[23] Goldstein, D.S., Breier, A., Wolkowitz, O.M. and Pickar, D. (1992) Plasma Levels of Catecholamines and Corticotrophin during Acute Glucopenia Induced by 2-Deoxy-D-Glucose in Normal Man. Clinical Autonomic Research, 2, 359- 366.
http://dx.doi.org/10.1007/BF01831392
[24] Lin, X., Zhang, F., Bradbury, C.M., Kaushal, A., Li, L., Spitz, D.R., Aft, R.L., et al. (2003) 2-Deoxy-D-Glucose-Induced Cytotoxicity and Radiosensitization in Tumor Cells is Mediated via Disruptions in Thiol Metabolism. Cancer Research, 63, 3413-3417.
[25] Singh, S., Pandey, S., Bhatt, A.N., Chaudhary, R., Bhuria, V., Kalra, N., Soni, R., et al. (2015) Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich’s Ascites Tumor in Mice. PLoS ONE, 10, e0132089.
http://dx.doi.org/10.1371/journal.pone.0132089
[26] Singh, S., Oberoi, R., Khanna, S., Bhatt, A., Saluja, D. and Dwarakanath, B. (2012) Energy Restriction Caused by the Glycolytic Inhibitor, 2-Deoxy-D-Glucose Inhibits Chemical Induced Carcinogenesis in Mice. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, March 31-April 4 2012.
[27] Stafstrom, C., Ockuly, J., Murphree, L., Valley, M., Roopra, A. and Sutula, T. (2009) Anticonvulsant and Antiepileptic Actions of 2-Deoxy-D-Glucose in Epilepsy Models. Annals of Neurology, 65, 435-447.
http://dx.doi.org/10.1002/ana.21603
[28] Ockuly, J., Gielissen, J., Levenick, C., Zeal, C., Groble, K., Munsey, K., Sutula, T., et al. (2012) Behavioral, Cognitive, and Safety Profile of 2-Deoxy-2-Glucose (2DG) in Adult Rats. Epilepsy Research, 101, 246-252.
http://dx.doi.org/10.1016/j.eplepsyres.2012.04.012
[29] Eikelis, N. and Buuse, V.M. (2000) Cardiovascular Responses to Open-Field Stress in Rats: Sex Differences and Effects of Gonadal Hormones. Stress, 3, 319-334.
http://dx.doi.org/10.3109/10253890009001137
[30] Carola, V., D’Olimpio, F., Brunamonti, E. and Mangia, F. (2002) Evaluation of the Elevated Plus-Maze and Open-Field Tests for the Assessment of Anxiety-Related Behaviour in Inbred Mice. Behavioural Brain Research, 134, 49-57.
http://dx.doi.org/10.1016/S0166-4328(01)00452-1
[31] Dawson, G.R. and Tricklebank, M.D. (1995) Use of the Elevated Plus Maze in the Search for Novel Anxiolytic Agents. Trends in Pharmacological Sciences, 16, 33-36.
http://dx.doi.org/10.1016/S0165-6147(00)88973-7
[32] Porsolt, R.D., Pichon, L.M. and Jalfre, M.L. (1977) Depression: A New Animal Model Sensitive to Antidepressant Treatments. Nature, 266, 730-732.
http://dx.doi.org/10.1038/266730a0
[33] Morris, R., Garrud, P., Rawlins, J. and O’Keefe, J. (1982) Place Navigation Impaired in Rats with Hippocampal Lesions. Nature, 297, 681-683.
http://dx.doi.org/10.1038/297681a0
[34] Vorhees, C. and Williams, M. (2006) Morris Water Maze: Procedures for Assessing Spatial and Related Forms of Learning and Memory. Nature Protocols, 1, 848-858.
http://dx.doi.org/10.1038/nprot.2006.116
[35] Ennaceur, A. and Delacour, J. (1988) A New One-Trial Test for Neurobiological Studies of Memory in Rats.1: Behavioral Data. Behavioural Brain Research, 37, 47-59.
http://dx.doi.org/10.1016/0166-4328(88)90157-X
[36] Bevins, R.A. and Besheer, J. (2006) Object Recognition in Rats and Mice: A One-Trial Non-Matching-to-Sample Learning Task to Study Recognition Memory. Nature Protocols, 1, 1306-1311.
http://dx.doi.org/10.1038/nprot.2006.205
[37] Kehl, L.J., Trempe, T.M. and Hargreaves, K.M. (2000) A New Animal Model for Assessing Mechanisms and Management of Muscle Hyperalgesia. Pain, 85, 333-343.
http://dx.doi.org/10.1016/S0304-3959(99)00282-1
[38] Duan, W. and Mattson, M.P. (1999) Dietary Restriction and 2-Deoxyglucose Administration Improve Behavioral Outcome and Reduce Degeneration of Dopaminergic Neurons in Models of Parkinson’s Disease. Journal of Neuroscience Research, 57, 195-206.
http://dx.doi.org/10.1002/(SICI)1097-4547(19990715)57:2<195::AID-JNR5>3.0.CO;2-P
[39] Yao, J., Chen, S., Mao, Z., Cadenas, E. and Brinton, R. (2011) 2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer’s Disease. PLoS ONE, 6, e21788.
http://dx.doi.org/10.1371/journal.pone.0021788
[40] Wei, J., Cohen, D.M. and Quast, M.J. (2003) Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats. Journal of Cerebral Blood Flow and Metabolism, 23, 556-564.
http://dx.doi.org/10.1097/01.WCB.0000056061.18772.72
[41] Levay, E.A., Govic, A., Penman, J., Paolini, A.G. and Kent, S. (2007) Effects of Adult-Onset Calorie Restriction on Anxiety-Like Behavior in Rats. Physiology and Behavior, 92, 889-896.
http://dx.doi.org/10.1016/j.physbeh.2007.06.018
[42] Geng, Y.Q., Guan, J.T. and Xu, M.Y. (2007) Behavioral Study of Calorie-Restricted Rats from Early Old Age. Proceedings of the 29th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Lyon, 22-26 August 2007, 2393-2395.
http://dx.doi.org/10.1109/iembs.2007.4352809
[43] Geng, Y., Li, T., Liu, X., Li, Z. and Fu, Y. (2011) SIRT1 and SIRT5 Activity Expression and Behavioral Responses to Calorie Restriction. Journal of Cellular Biochemistry, 112, 3755-3761.
http://dx.doi.org/10.1002/jcb.23315
[44] Wadden, T.A. and Stunkard, A.J. (1986) Controlled Trial of Very Low Calorie Diet, Behavior Therapy, and Their Combination in the Treatment of Obesity. Journal of Consulting and Clinical Psychology, 54, 482-488.
http://dx.doi.org/10.1037/0022-006X.54.4.482
[45] Jahng, J.W., Kim, J.G., Kim, H.J., Kim, B.T., Kang, D.W. and Lee, J.H. (2007) Chronic Food Restriction in Young Rats Results in Depression-and Anxiety-Like Behaviors with Decreased Expression of Serotonin Reuptake Transporter. Brain Research, 1150, 100-107.
http://dx.doi.org/10.1016/j.brainres.2007.02.080
[46] Wooley, S.C. and Garner, D.M. (1991) Obesity Treatment: The High Cost of False Hope. Journal of the American Dietetic Association, 91, 1248-1251.
[47] Bellush, L.L., Wright, A.M., Walker, J.P. and Kopchick, J. (1996) Caloric Restriction and Spatial Learning in Old Mice. Physiology and Behavior, 60, 541-547.
http://dx.doi.org/10.1016/S0031-9384(96)80029-1
[48] Mamczarz, J., Bowker, J.L., Duffy, K., Zhu, M., Hagepanos, A. and Ingram, D.K. (2005) Enhancement of Amphetamine-Induced Locomotor Response in Rats on Different Regimens of Diet Restriction and 2-Deoxy-D-Glucose Treatment. Neuroscience, 131, 451-464.
http://dx.doi.org/10.1016/j.neuroscience.2004.11.019
[49] Rosenzweig, E. and Barnes, C. (2003) Impact of Aging on Hippocampal Function: Plasticity, Network Dynamics, and Cognition. Progress in Neurobiology, 69, 143-179.
http://dx.doi.org/10.1016/S0301-0082(02)00126-0
[50] Nehlig, A. and de Vasconcelos, A.P. (1993) Glucose and Ketone Body Utilization by the Brain of Neonatal Rats. Progress in Neurobiology, 40, 163-221.
http://dx.doi.org/10.1016/0301-0082(93)90022-K
[51] Zhou, W., Mukherjee, P., Kiebish, M., Markis, W., Mantis, J. and Seyfried, T. (2007) The Calorically Restricted Ketogenic Diet, an Effective Alternative Therapy for Malignant Brain Cancer. Nutrition and Metabolism, 4, 5.
http://dx.doi.org/10.1186/1743-7075-4-5
[52] Cao, D., Lu, H., Lewis, T. and Li, L. (2007) Intake of Sucrose-Sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer Disease. Journal of Biological Chemistry, 282, 36275-36282.
http://dx.doi.org/10.1074/jbc.M703561200
[53] Breier, A., Crane, A.M., Kennedy, C. and Sokoloff, L. (1993) The Effects of Pharmacologic Doses of 2-Deoxy-D-Glucose on Local Cerebral Blood Flow in the Awake, Unrestrained Rat. Brain Research, 618, 277-282.
http://dx.doi.org/10.1016/0006-8993(93)91276-X

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