Carbohydrate restriction and cancer control

Ketogenic diets promote metabolic health and confer protection against cancer through multiple processes, including: lowering insulin levels; improving mitochondrial substrate oxidation; and beneficially modulating ketone-driven anti-inflammatory and antioxidative effects (1).

In addition, in the majority of preclinical tumor studies, ketogenic diets have been shown to inhibit cancer cell glycolysis and proliferation, with clinical results evidencing anti-tumor benefits in children (1-3).

Cancer cells preferentially feed on glucose due to an overactive glycolytic process (4). It is established that cancer cells do not go through a normal process of glycolysis, the citric acid cycle or the electron transport chain (4).

Specifically, it has been demonstrated that aggressive tumors’ high glycolytic rate leads to resistance to radiation therapy and progression of cancer via a number of different molecular and physiologic mechanisms (5). Many of these mechanisms use the same molecular channels that are modified through carbohydrate restriction (5).

Their energy preference for glycolysis instead of oxidative phosphorylation is known as the “Warburg Effect” (6).

 

Glucose and carbohydrate restriction

There is evidence that glucose restriction, through application of a ketogenic diet, serves to selectively starve tumor cells of the glucose on which they are dependent (7).

In addition, research also shows that a carbohydrate-restricted diet decreases tumor progression, as well (7).

In 2012, researchers suggested that the optimal anti-cancer dietary approach may include “limiting carbohydrates and, counter to traditional recommendations, replacing those dietary sources” with fat (8).

 

Carbohydrate restriction: Effects on breast cancer and prostate cancer

Overall, a body of evidence shows that carbohydrate-restricted diets reduce breast-cancer recurrence and improve outcomes (8).

In fact, in a prospective cohort study from the Framingham Offspring Cohort of 3,184 men and women, diets with the highest glycemic load were associated with a 78 percent increased risk of prostate cancer (9).

Conversely, consumption of low-glycemic-index (GI) foods was associated with a 69 percent reduction in breast cancer risk (9).

 

Ketones or a ketogenic diet: Effects on tumor cells

Ketone production has been shown, in ex vivo studies, to make cancer cells increasingly vulnerable to reactive oxygen species (ROS)-induced oxidative stress and cell damage (10-12).

This heightened vulnerability to tumor damage and cytotoxicity from ROS may enhance the DNA-damaging and oxidative effects of chemotherapy and radiotherapy against cancerous cells (7), which is supported by experimental research (13).

 

Pathways in which a ketogenic diet operates

It is known that cancerous cells are dependent on the insulin pathway, which is down-regulated when the body is deprived of carbohydrates, as demonstrated in a dietary trial of 10 patients with advanced cancer that evaluated the insulin-inhibiting effects of β-hydroxybutyrate (14).

In addition, there is evidence that a ketogenic diet upregulates AMPK (5′ adenosine monophosphate-activated protein kinase), which has been shown to be helpful against cancer (7) and may downregulate mTOR (mammalian target of rapamycin), a protein kinase that is implicated in cancer cell growth and angiogenesis (15).

An early animal cell culture study established that administration of acetoacetate can significantly inhibit the growth of neuroblastoma cells (16).

Research has also shown that carbohydrate restriction, overall, inhibits malignant cells’ ability to adapt and enhances both cancer cell DNA fragmentation and apoptosis (7).

References

  1. Klement R and Pzzienza V. “Impact of different types of diet on gut microbiota profiles and cancer prevention and treatment.” Medicina (Kaunas). 2019;55(4). pii: E84. doi: 10.3390/medicina55040084
  2. Klement RJ, et al. “Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation.” Med Oncol. 2017;34(8):132. doi: 10.1007/s12032-017-0991-5
  3. Weber DD, et al. “Ketogenic diet in cancer therapy.” Aging (Albany NY). 2018;10(2):164-165.
  4. Tan-Shalaby J. “The ketogenic diet─defining a role in cancer therapy.” Integr Food Nutr Metab. 2018;5(2):1-2.
  5. Klement RJ and Champ CE. “Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation.” Cancer Metastasis Rev. 2014 Mar;33(1):217-229.
  6. Liberti MV and Locasale JW. “The Warburg Effect: How does it benefit cancer cells?” Trends Biochem Sci. 2016; 41(3): 211–218.
  7. Simone BA, et al. “Selectively starving cancer cells through dietary manipulation: methods and clinical implications.” Future Oncol. 2013;9(7):959-976.
  8. Champ CE, et al. “Weight gain, metabolic syndrome, and breast cancer recurrence: Are dietary recommendations supported by the data?” Int J Breast Cancer. 2012; 2012: 506868. doi: 10.1155/2012/506868
  9. Makarem N, et al. “Dietary carbohydrate Intake, glycemic index and glycemic load in relation to adiposity-related cancer risk: Results from the Framingham Offspring Cohort (1991–2013).” Presented at the American Society for Nutrition’s Scientific Sessions & Annual Meeting, San Diego, California, April 2016. Abstract No. 417.7
  10. Dwarkanath BS, et al. “Heterogeneity in 2-deoxy-D-glucose-induced modifications in energetics and radiation responses of human tumor cell lines.” Int J Radiat Oncol Biol Phys. 2001;50(4):1051-1061.
  11. Aykin-Burns N, et al. “Increased levels of superoxide and hydrogen peroxide mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation.” Biochem J. 2009;418(1):29-37.
  12. Simons AL, et al. “Enhanced response of human head and neck cancer xenograft tumors to cisplatin combined with 2-deoxy-D-glucose correlates with increased 18F-FDG uptake as determined by PET imaging.” Int J Radiat Oncol Biol Phys. 2007;69(4):1222-1230.
  13. Abdelwahab MG, et al. “The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma.” PLoS One. 2012;7(5):e36197. doi: 10.1371/journal.pone.0036197.
  14. Fine EJ, et al. “Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients.” Nutrition. 2012;28(10):1028-1035.
  15. Conciatori F, et al. “Role of mTOR signaling in tumor microenvironment: An overview.” Int J Mol Sci. 2018; 19(8): 2453.
  16. Patel MS, et al. “Ketone-body metabolism in glioma and neuroblastoma cells.” Proc Natl Acad Sci U S A. 1981;78(11):7214-7218.

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