Ketogenic Diet and Cancer

Ketogenic diets and mechanism of action

The ketogenic diet is a carbohydrate-restricted eating pattern, with a moderate amount of protein and a high fat content. Its objective is to reduce the amount of circulating insulin and force the body to produce ketone bodies.

Glucose normally stimulates pancreatic β cells to release insulin, which allows glucose to enter the cells and provide energy. With a high intake of carbohydrates and glucose, the pancreas secretes more and more insulin, which promotes the interaction of growth hormone receptors and growth hormones to produce insulin-like growth factor 1 (IGF-1) in the liver – promoting cell growth and proliferation, which can be harmful to cancer patients.

In 1922, Braunstein observed that glucose disappeared from the urine of patients with diabetes after a cancer diagnosis, suggesting that glucose is recruited to cancerous areas where it is consumed at higher rates than normal. During this same period, Nobel laureate Otto Warburg discovered that cancer cells produce high amounts of lactate from glucose, even in the presence of abundant oxygen. Warburg conducted many in vitro and animal experiments demonstrating this result, known today as the Warburg effect [2].

Overexpression of glucose transporters 1 and 3 (Glut-1, Glut-3) also occurs in many cancers and corresponds to the degree of glucose uptake in aggressive tumors as seen on positron emission tomography (PET).

When glucose is scarce, the body feels the need to produce an alternative form of energy for the cells. The liver then produces ketones and fatty acids, which provide energy for healthy cells but generally do not benefit cancer cells. Cancer cells have dysfunctional mitochondria and possibly defects in the electron transport chain, which disrupt the mitochondria’s normal production of adenosine triphosphate (ATP). The result is that cancer cells become heavily dependent on ATP from the less efficient process of lactic acid production, through fermentation.

Overexpression of hexokinase, the rate-limiting enzyme of glycolysis, further drives the production of pyruvate and lactate, showing a degree of mitochondrial dysfunction and increased production of free radicals in patients with cancer. Translocation of the rate-limiting enzyme hexokinase from the cytosol to the outer mitochondrial membrane, can suppress the apoptotic pathways of cancer cells, making them more resistant to chemotherapy.

Excessive lactate production, which is part of the Warburg effect, compensates for defects in ATP production caused by dysfunctional mitochondrial oxidative phosphorylation. Ketogenic diets delay cancer by inhibiting insulin/IGF and downstream intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR).

Ketogenic diets also amplify adenosine monophosphate-activated protein kinase (AMPK), which inhibits aerobic glycolysis and suppresses tumor proliferation, invasion, and migration.

Source of image: Tan-Shalaby, 2017

Benefits of ketones in cancer

Ketone bodies have several modulating effects on gene expression and end up stimulating the generation of new mitochondria, then improving cellular bioenergetics. Furthermore, ketone bodies protect the nervous system, act as antioxidants, help preserve lean mass and reduce the number of cancer cells.

For now, research shows that the patients who appear to respond best to the ketogenic diet are those diagnosed with glioblastoma, the most common and aggressive type of brain cancer. But it is reported that ketone bodies also reduce the side effects of chemotherapy drugs used to treat some types of breast cancer. Ketogenic diet tends to benefit cardiometabolic health in patients with different types of cancer [2][3]. 

There is, though, some research showing that patients with pancreatic and colorectal cancer can worsen cachexia, characterized by loss of appetite, loss of weight and muscle mass, changes in taste, weakness and atrophy of visceral organs. Therefore, researchers are studying strategies so that these patients can benefit from the positive effects of ketone bodies, without the side effects. Corticosteroids appear to prevent cachexia, at least in mice with cancer following the ketogenic diet.

Cachexia is a cascade process. Biological systems gradually collapse, causing a decline in health. Diets with a lot of polyunsaturated fat (from soybean oil, corn, canola, sunflower, etc.) generate more toxic lipid byproducts, which can accumulate in cancer cells. This slows down tumor growth, but also causes early cachexia. When the researchers gave the mice the corticosteroid, the ketogenic diet continued to reduce the tumors but did not initiate cachexia. Of course, before starting any treatment, consult your oncologist and a dietitian specialized in metabolic therapies for cancer treatment.

Bibliography:

[1] Dowis, K.; Banga, S. The Potential Health Benefits of the Ketogenic Diet: A Narrative Review. Nutrients 2021, 13, 1654. https://doi.org/10.3390/nu13051654 

[2] Tan-Shalaby J. Ketogenic Diets and Cancer: Emerging Evidence. Fed Pract. 2017 Feb;34(Suppl 1):37S-42S. PMID: 30766299; PMCID: PMC6375425.

[3] Doaa N. Al-Jada, Hamed R. Takruri & Wamidh H. Talib. (2023) From antiepileptic therapy to promising adjuvant in medical oncology: A historical view of the ketogenic diet. PharmaNutrition 24, pages 100340.

[4] Patikorn, C., Saidoung, P., Pham, T. et al. Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials. BMC Med 21, 196 (2023). https://doi.org/10.1186/s12916-023-02874-y