Ketogenic diet and cancer: Fad or fabulous?
Corresponding Author
Manpreet S. Mundi MD
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
Manpreet S. Mundi, MD, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Email: [email protected]
Search for more papers by this authorOsman Mohamed Elfadil MBBS
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorIshani Patel MBBS
Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorJalpan Patel MBBS
Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorRyan T. Hurt MD, PhD
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorCorresponding Author
Manpreet S. Mundi MD
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
Manpreet S. Mundi, MD, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Email: [email protected]
Search for more papers by this authorOsman Mohamed Elfadil MBBS
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorIshani Patel MBBS
Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorJalpan Patel MBBS
Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorRyan T. Hurt MD, PhD
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorAbstract
As the prevalence of smoking continues to decline, dietary factors are rapidly becoming the leading preventable cause of disease. Diet and obesity are also leading to a shift in cancer prevalence with increases noted in breast, liver, pancreas, and uterine cancers. Once cancer is detected, obesity is also associated with poorer outcomes with therapy as well as higher morbidity and mortality. Key factors are associated with the link between obesity and cancer including chronic inflammation, change in sex hormones, alteration in insulin-IGF-1 axis, alteration in adipokines, as well as cancer stem cells that are derived from adipose tissue. Because of these associations, a great deal of effort is being placed in implementing lifestyle changes that mitigate obesity-associated factors that contribute to development of cancer, reduce side effects of treatment, and improve survival. Ketogenic diet is emerging as an attractive option in countering obesity-related tumor-promoting factors, as it is associated with weight loss as well as a reduction in insulin resistance and inflammation. Ketogenic diet can also deprive cancer cells of glucose, a fuel source that is predominantly used by many cancer lines through aerobic glycolysis in the setting of dysregulated mitochondria. Current manuscript reviews the theoretical benefits for use of ketogenic diet in cancer as well as the data available from clinical trials.
CONFLICT OF INTEREST
None declared.
REFERENCES
- 1Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer J Clin. 2018; 68(1): 7-30.
- 2Mariotto AB, Enewold L, Zhao J, Zeruto CA, Yabroff KR. Medical care costs associated with cancer survivorship in the United States. Cancer Epidemiol Biomarkers Prev. 2020; 29(7): 1304-1312.
- 3Laviana AA, Luckenbaugh AN, Resnick MJ. Trends in the cost of cancer care: beyond drugs. J Clin Oncol. 2019; 38(4): 316-322.
- 4Ligibel JA, Alfano CM, Courneya KS, et al. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol. 2014; 32(31): 3568-3574.
- 5Shah M, Hurt RT, Mundi MS. Phenotypes of obesity: how it impacts management. Curr Gastroenterol Rep. 2017; 19(11): 55.
- 6Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied Cohort of U.S. adults. N Engl J Med. 2003; 348(17): 1625-1638.
- 7Chan DSM, Vieira AR, Aune D, et al. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014; 25(10): 1901-1914.
- 8Efstathiou JA, Bae K, Shipley WU, et al. Obesity and mortality in men with locally advanced prostate cancer. Cancer. 2007; 110(12): 2691-2699.
- 9Li D, Morris JS, Liu J, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA. 2009; 301(24): 2553-2562.
- 10Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer—mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014; 10(8): 455-465.
- 11Galvão DA, Newton RU. Review of exercise intervention studies in cancer patients. J Clin Oncol. 2005; 23(4): 899-909.
- 12Goodwin PJ, Segal RJ, Vallis M, et al. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: The LISA Trial. J Clin Oncol. 2014; 32(21): 2231-2239.
- 13Thomson CA, Stopeck AT, Bea JW, et al. Changes in body weight and metabolic indexes in overweight breast cancer survivors enrolled in a randomized trial of low-fat vs. reduced carbohydrate diets. Nutr Cancer. 2010; 62(8): 1142-1152.
- 14Blanchard CM, Courneya KS, Stein K. Cancer survivors’ adherence to lifestyle behavior recommendations and associations with health-related quality of life: results from the American Cancer Society's SCS-II. J Clin Oncol. 2008; 26(13): 2198-2204.
- 15Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tissue and adipocytes supports tumorigenesis and metastasis. Biochim Biophys Acta. 2013; 1831(10): 1533-1541.
- 16Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne). 2016; 7:30.
- 17Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013; 19(10): 1338-1344.
- 18Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature. 2008; 453(7196): 783-787.
- 19Giordano A, Murano I, Mondini E, et al. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res. 2013; 54(9): 2423-2436.
- 20Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013; 93(1): 1-21.
- 21Jernås M, Palming J, Sjöholm K, et al. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J. 2006; 20(9): 1540-1542.
- 22Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112(12): 1796-1808.
- 23Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011; 29(1): 415-445.
- 24Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol. 2015; 208(5): 501-512.
- 25Mardilovich K, Pankratz SL, Shaw LM. Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal. 2009; 7(1): 14.
- 26Tsujimoto T, Kajio H, Sugiyama T. Association between hyperinsulinemia and increased risk of cancer death in nonobese and obese people: a population-based observational study. Int J Cancer. 2017; 141(1): 102-111.
- 27Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927; 8(6): 519-530.
- 28Heiden MGV, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324(5930): 1029-1033.
- 29Rigo P, Paulus P, Kaschten BJ, et al. Oncological applications of positron emission tomography with fluorine-18 fluorodeoxyglucose. Eur J Nucl Med. 1996; 23(12): 1641-1674.
- 30Allen BG, Bhatia SK, Anderson CM, et al. Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism. Redox Biol. 2014; 2: 963-970.
- 31Seyfried TN, Arismendi-Morillo G, Mukherjee P, Chinopoulos C. On the origin of ATP synthesis in cancer. iScience. 2020; 23(11):101761.
- 32Winter SF, Loebel F, Dietrich J. Role of ketogenic metabolic therapy in malignant glioma: a systematic review. Crit Rev Oncol Hemato. 2017; 112: 41-58.
- 33Shestov AA, Liu X, Ser Z, et al. Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. Elife. 2014; 3:e03342.
- 34Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016; 41(3): 211-218.
- 35Dong G, Mao Q, Xia W, et al. PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol Lett. 2016; 11(3): 1980-1986.
- 36Chen Q, Kirk K, Shurubor YI, et al. Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab. 2018;27(5): 1007-1025.e5.
- 37Ahmad IM, Aykin-Burns N, Sim JE, et al. Mitochondrial O2*- and H2O2 mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem. 2005; 280(6): 4254-4263.
- 38Evertts AG, Zee BM, DiMaggio PA, Gonzales-Cope M, Coller HA, Garcia BA. Quantitative dynamics of the link between cellular metabolism and histone acetylation. J Biol Chem. 2013; 288(17): 12142-12151.
- 39Estrella V, Chen T, Lloyd M, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013; 73(5): 1524-1535.
- 40Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B. Ketogenic diet in the treatment of cancer—where do we stand? Mol Metab. 2020; 33: 102-121.
- 41Wilder RM, Winter MD. The threshold of ketogenesis. J Biol Chem. 1922; 52(2): 393-401.
- 42Volek JS, Phinney SD, Forsythe CE, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids. 2009; 44(4): 297-309.
- 43Saslow LR, Daubenmier JJ, Moskowitz JT, et al. Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mellitus or prediabetes. Nutr Diabetes. 2017; 7(12): 304.
- 44Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018; 560(7719): 499-503.
- 45Aminzadeh-Gohari S, Feichtinger RG, Vidali S, et al. A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model. Oncotarget. 2017; 8(39): 64728-64744.
- 46Zhang J, Jia P-P, Liu Q-L, et al. Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo. J Lipid Res. 2018; 59(4): 625-634.
- 47Pflanz NC, Daszkowski AW, James KA, Mihic SJ. Ketone body modulation of ligand-gated ion channels. Neuropharmacology. 2019; 148: 21-30.
- 48Trotta MC, Maisto R, Guida F, et al. The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome. PLoS One. 2019; 14(1):e0211005.
- 49Nakamura K, Tonouchi H, Sasayama A, Ashida K. A ketogenic formula prevents tumor progression and cancer cachexia by attenuating systemic inflammation in colon 26 tumor-bearing mice. Nutrients. 2018; 10(2): 206.
- 50Youm Y-H, Nguyen KY, Grant RW, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nat Med. 2015; 21(3): 263-269.
- 51Klement RJ, Brehm N, Sweeney RA. Ketogenic diets in medical oncology: a systematic review with focus on clinical outcomes. Med Oncol. 2020; 37(2): 14.
- 52Champ CE, Palmer JD, Volek JS, et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol. 2014; 117(1): 125-131.
- 53Cohen CW, Fontaine KR, Arend RC, et al. A Ketogenic diet reduces central obesity and serum insulin in women with ovarian or endometrial cancer. J Nutr. 2018; 148(8): 1253-1260.
- 54Cohen CW, Fontaine KR, Arend RC, Soleymani T, Gower BA. Favorable effects of a ketogenic diet on physical function, perceived energy, and food cravings in women with ovarian or endometrial cancer: a randomized, controlled trial. Nutrients. 2018; 10(9): 1187.
- 55Klement RJ, Champ CE, Kämmerer U, et al. Impact of a ketogenic diet intervention during radiotherapy on body composition: III—final results of the KETOCOMP study for breast cancer patients. Breast Cancer Res. 2020; 22(1): 94.
- 56Hayashi A, Kumada T, Nozaki F, Hiejima I, Miyajima T, Fujii T. Changes in serum levels of selenium, zinc and copper in patients on a ketogenic diet using Ketonformula. Article in Japanese. No To Hattatsu. 2013; 45(4): 288-293.
- 57McNally MA, Pyzik PL, Rubenstein JE, Hamdy RF, Kossoff EH. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet. Pediatrics. 2009; 124(2): e300-e304.
- 58Bergqvist AC, Schall JI, Stallings VA, Zemel BS. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr. 2008; 88(6): 1678-1684.
- 59Simm PJ, Bicknell-Royle J, Lawrie J, et al. The effect of the ketogenic diet on the developing skeleton. Epilepsy Res. 2017; 136: 62-66.