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Growth of Human Colon Cancer Cells in Nude Mice is Delayed by Ketogenic Diet With or Without Omega-3 Fatty Acids and Medium-chain Triglycerides

  • Hao, Guang-Wei (Department General Surgery, Zhongshan Hospital, Fudan University) ;
  • Chen, Yu-Sheng (Department General Surgery, Zhongshan Hospital, Fudan University) ;
  • He, De-Ming (Department Pathology, Zhongshan Hospital, Fudan University) ;
  • Wang, Hai-Yu (Department General Surgery, Zhongshan Hospital, Fudan University) ;
  • Wu, Guo-Hao (Department General Surgery, Zhongshan Hospital, Fudan University) ;
  • Zhang, Bo (Department General Surgery, Zhongshan Hospital, Fudan University)
  • Published : 2015.03.18

Abstract

Background: Tumors are largely unable to metabolize ketone bodies for energy due to various deficiencies in one or both of the key mitochondrial enzymes, which may provide a rationale for therapeutic strategies that inhibit tumor growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat. Materials and Methods: Thirty-six male BALB/C nude mice were injected subcutaneously with tumor cells of the colon cancer cell line HCT116. The animals were then randomly split into three feeding groups and fed either a ketogenic diet rich in omega-3 fatty acids and MCT (MKD group; n=12) or lard only (LKD group; n=12) or a standard diet (SD group; n=12) ad libitum. Experiments were ended upon attainment of the target tumor volume of $600mm^3$ to $700mm^3$. The three diets were compared for tumor growth and survival time (interval between tumor cell injection and attainment of target tumor volume). Results: The tumor growth in the MKD and LKD groups was significantly delayed compared to that in the SD group. Conclusions: Application of an unrestricted ketogenic diet delayed tumor growth in a mouse xenograft model. Further studies are needed to address the mechanism of this diet intervention and the impact on other tumor-relevant parameters such as invasion and metastasis.

Keywords

Ketogenic diet;colon cancer;${\omega}$-3 fatty acids;MCT;lard

References

  1. Akram M (2013). A focused review of the role of ketone bodies in health and disease. J Med Food, 16, 965-7. https://doi.org/10.1089/jmf.2012.2592
  2. Amin TT, Suleman W, Al Taissan AA, et al (2012). Patients' profile, clinical presentations and histopathological features of colo-rectal cancer in Al Hassa region, Saudi Arabia. Asian Pac J Cancer Prev, 13, 211-6. https://doi.org/10.7314/APJCP.2012.13.1.211
  3. Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC (1999). The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer, 81, 80-6. https://doi.org/10.1038/sj.bjc.6690654
  4. Beck SA, Tisdale MJ (1989). Effect of insulin on weight loss and tumour growth in a cachexia model. Br J Cancer, 59, 677-81. https://doi.org/10.1038/bjc.1989.140
  5. Berquin IM, Min Y, Wu R, et al (2007). Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids. J Clin Invest, 117, 1866-75. https://doi.org/10.1172/JCI31494
  6. Connor KM, SanGiovanni JP, Lofqvist C, et al (2007). Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med, 13, 868-73. https://doi.org/10.1038/nm1591
  7. Fearon K, Strasser F, Anker SD, et al (2011). Definition and classification of cancer cachexia: an international consensus. Lancet Oncol, 12, 489-95. https://doi.org/10.1016/S1470-2045(10)70218-7
  8. Freeman JM, Kossoff EH, Hartman AL (2007). The ketogenic diet: one decade later. Pediatrics, 119, 35-43.
  9. Giordano KF, Jatoi A (2005). The cancer anorexia/weight loss syndrome: therapeutic challenges. Curr Oncol Rep, 7, 271-6. https://doi.org/10.1007/s11912-005-0050-9
  10. Hardman WE (2002). Omega-3 fatty acids to augment cancer therapy. J Nutr, 132, 3508-12.
  11. Hardman WE (2007). Dietary canola oil suppressed growth of implanted MDA-MB 231 human breast tumors in nude mice. Nutr Cancer, 57, 177-83. https://doi.org/10.1080/01635580701277445
  12. Iftikhar S, Bond AR, Wagan AI, Weinberg PD, Bharath AA (2011). Segmentation of endothelial cell boundaries of rabbit aortic images using a machine learning approach. Int J Biomed Imaging, 2011, 270247.
  13. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  14. Jin S, DiPaola RS, Mathew R, White E (2007). Metabolic catastrophe as a means to cancer cell death. J Cell Sci, 120, 379-83. https://doi.org/10.1242/jcs.03349
  15. Jiang YS, Wang FR (2013). Caloric restriction reduces edema and prolongs survival in a mouse glioma model. J Neurooncol, 114, 25-32. https://doi.org/10.1007/s11060-013-1154-y
  16. Kim HS, Masko EM, Poulton SL, et al (2012). Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer. BJU Int, 110, 1062-9. https://doi.org/10.1111/j.1464-410X.2012.10971.x
  17. Kimoto Y, Tanji Y, Taguchi T, et al (1998). Antitumor effect of medium-chain triglyceride and its influence on the selfdefense system of the body. Cancer Detect Prev, 22, 219-24. https://doi.org/10.1046/j.1525-1500.1998.0OA32.x
  18. Kwan HY, Chao X, Su T, et al (2014). Dietary lipids and adipocytes: potential therapeutic targets in cancers. J Nutr Biochem, [Epub ahead of print].
  19. Lu H, Forbes RA, Verma A (2002). Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem, 277, 23111-5. https://doi.org/10.1074/jbc.M202487200
  20. Lu K, Song XL, Han SL, et al (2014). Potential study perspectives on mechanisms and correlations between adiposity and malignancy. Asian Pac J Cancer Prev, 15, 1057-60. https://doi.org/10.7314/APJCP.2014.15.2.1057
  21. Masko EM, Thomas JA, Antonelli JA, et al (2010). Lowcarbohydrate diets and prostate cancer: how low is "low enough"? Cancer Prev Res (Phila), 3, 1124-31. https://doi.org/10.1158/1940-6207.CAPR-10-0071
  22. Mondello P, Mian M, Aloisi C, et al (2015). Cancer cachexia syndrome: pathogenesis, diagnosis, and new therapeutic options. Nutr Cancer, 67, 12-26. https://doi.org/10.1080/01635581.2015.976318
  23. Mukherjee P, Sotnikov AV, Mangian HJ, et al (1999). Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J Natl Cancer Inst, 91, 512-23. https://doi.org/10.1093/jnci/91.6.512
  24. 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, 693-7. https://doi.org/10.1016/S0002-8223(95)00189-1
  25. 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, 202-8. https://doi.org/10.1080/07315724.1995.10718495
  26. Oleksyszyn J (2011). The complete control of glucose level utilizing the composition of ketogenic diet with the gluconeogenesis inhibitor, the anti-diabetic drug metformin, as a potential anti-cancer therapy. Med Hypotheses, 77, 171-3. https://doi.org/10.1016/j.mehy.2011.04.001
  27. Otto C, Kaemmerer U, Illert B, et al (2008). Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and mediumchain triglycerides. BMC cancer, 8, 122. https://doi.org/10.1186/1471-2407-8-122
  28. Paoli A, Cenci L, Grimaldi KA (2011). Effect of ketogenic Mediterranean diet with phytoextracts and low carbohydrates/ high-protein meals on weight, cardiovascular risk factors, body composition and diet compliance in Italian council employees. Nutr J, 10, 112. https://doi.org/10.1186/1475-2891-10-112
  29. Poff AM, Ari C, Arnold P, Seyfried TN, D'Agostino DP (2014). Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. Int J Cancer, 135, 1711-20. https://doi.org/10.1002/ijc.28809
  30. Sawai M, Yashiro M, Nishiguchi Y, Ohira M, Hirakawa K (2004). Growth-inhibitory effects of the ketone body, monoacetoacetin, on human gastric cancer cells with succinyl-CoA: 3-oxoacid CoA-transferase (SCOT) deficiency. Anticancer Res, 24, 2213-7.
  31. Schmidt M, Pfetzer N, Schwab M, Strauss I, Kammerer U (2011). Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr Metab (Lond), 8, 54. https://doi.org/10.1186/1743-7075-8-54
  32. 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, 310-26. https://doi.org/10.1016/j.eplepsyres.2011.06.017
  33. Seyfried TN, Mukherjee P (2005). Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (Lond), 2, 30. https://doi.org/10.1186/1743-7075-2-30
  34. Sharman MJ, Kraemer WJ, Love DM, et al (2002). A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. J Nutr, 132, 1879-85.
  35. Tisdale MJ (1984). Role of acetoacetyl-CoA synthetase in acetoacetate utilization by tumor cells. Cancer Biochem Biophys, 7, 101-7.
  36. 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, 309-19. https://doi.org/10.1016/j.plefa.2003.09.007
  37. Walenta S, Wetterling M, Lehrke M, et al (2000). High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res, 60, 916-21.
  38. Wang W, Zhu J, Lyu F, et al (2014). omega-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer. Prostaglandins Other Lipid Mediat, 113-115, 13-20. https://doi.org/10.1016/j.prostaglandins.2014.07.002
  39. Weidner N, Semple JP, Welch WR, Folkman J (1991). Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med, 324, 1-8. https://doi.org/10.1056/NEJM199101033240101
  40. Xu RH, Pelicano H, Zhou Y, et al (2005). Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res, 65, 613-21.
  41. Yang SP, Morita I, Murota SI (1998). Eicosapentaenoic acid attenuates vascular endothelial growth factor-induced proliferation via inhibiting Flk-1 receptor expression in bovine carotid artery endothelial cells. J Cell Physiol, 176, 342-9. https://doi.org/10.1002/(SICI)1097-4652(199808)176:2<342::AID-JCP12>3.0.CO;2-5

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