#174: Angela Poff, PhD: Cancer as a Metabolic Disease, the Ketogenic Diet & Warburg Effect

 

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About Angela Poff, PhD

Angela is a Research Associate at the University of South Florida, studying non-toxic metabolic-targeted therapies for cancer and neurological diseases. She specialize in studying low carbohydrate and ketogenic nutrition, including ketogenic diets and exogenous ketone supplements. She has a B.A. in Biochemistry and Molecular Biology from Hendrix College, and a M.S. and Ph.D. in Medical Sciences with a concentration in Molecular Pharmacology and Physiology from the University of South Florida.

Angela is not a medical doctor. No information found here should be considered medical advice. Always consult a licensed medical professional prior to initiating any new dietary or other treatment. This is especially important if you have a known medical condition.

Connect

http://Ketonutrition.org

Books and Resources Discussed

Optimal Electrolyte | Berry Flavor | 30 Single-Serving Packets | Provides Key Nutrients In An Easy-To-Use Powder Form To Support Peak Physical Performance | Physician Formulated | Seeking Health

Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer

The Ketogenic Kitchen: Low carb. High fat. Extraordinary health.

Show Notes

02:08 Metabolism and Cancer: There are certain hallmarks of cancer. Cancer cells need to keep dividing. The cells do not go through apoptosis, programmed cell death. The idea was that these are conferred through genetic mutations in the nucleus of the cancer cell.

02:54 The Warburg Effect: Almost 100 years ago Otto Warburg showed that cancer cells don’t undergo normal energy metabolism.  He started the idea that in most cancers, cancer cell activities are actually downstream of a metabolic problem. This refers to metabolic pathways that regulate energy production and biomass synthesis in the cell. Cancer cells have dysregulated metabolism. Across cancer types, cancer cells have a high upregulation of glucose intake and lactate production, instead of sending glucose to the mitochondria. It is the Warburg Effect.

04:36 Oxygen and the Warburg Effect: This process occurs whether oxygen is present or not. In normal cells, we utilize lactate fermentation when oxygen is limited. Cancer cells do this even when oxygen is present. When genetic mutations within the cells were discovered, the idea that metabolism was the cause of cancer fell by the wayside.

05:42 Mitochondrial Dysfunction: There is widespread mitochondrial dysfunction in cancer. When mitochondrial dysfunction occurs, you have a great increase in the amount of oxidative stress. Mitochondria make free radicals. The free radicals and oxidative stress, coupled with and energy failure by the dysfunctional mitochondria, limits DNA repair mechanisms, is a prime environment for genetic mutations in the nuclear genome.

09:04 Cell Division: Every time your cell divides, it has to copy its DNA. Mistakes will be made, but we have repair mechanisms that survey and fix mutations. This is a viable possibility in the cause of cancer.

09:47 Lactic Acid and Cancer: The cancer field views aerobic glycolysis, or the Warburg Effect, as a beneficial adaptation of tumors. Lactate is an acid that is exported into the extra cellular environment of the tumor. It dramatically increases the invasive capacity of the tumor and the ability to metastasize. If you are not taking glucose carbons all the way into the Krebs cycle in the mitochondria, you lose the carbons as CO2 and they are shunted toward biomass synthesis to build new tumor.

12:45 Fat Consumption and Cancer: Fatty acids and ketone bodies are converted into acetyl-coA to enter the metabolic pathways at the level of the Krebs cycle.  It bypasses glycolysis and fermentation. Thus, you are not supplying energy substrates for cancer and there is no net carbon gain to be converted into glucose.

14:03 Hypoxia-inducible factor 1-alpha (HIF1 Alpha): Tumors grow under chaotic abnormal signaling properties. In order to grow past a certain size, the tumor needs to make its own new blood vessels. The chaos makes the blood vessel network abnormal and inadequate. With the deficient blood vessels, there are areas within the tumor that do not receive enough oxygen or nutrients from the blood. They are hypoxic areas. Oddly, it benefits the tumor in many ways. One is the activation of hypoxia-inducible factor, which is a transcription factor that is activated by hypoxia. HIF1 will directly regulate about 60 genes’ expression, influencing hundreds of genes. Some of which are pro-survival, pro-proliferative, anti-apoptotic, increasing invasive capacity of the tumor and reprogramming metabolism to make it more glycolytic.

16:30 Hyperbaric Oxygen Therapy: At sea level, we breathe 20% oxygen. In HBOT, oxygen intake is increased to 100%. It increases the amount of oxygen that dissolves in the plasma of your blood, diffusing into the tumor. Theoretically, this shuts off HIF1 signaling. This therapy works best in conjunction with ketosis as a ketogenic diet and with exogenous ketone supplements.

19:02 Oxygen Free Radical Production: In some parts of the tumor there may be no oxygen and parts of the tumor may die. Radiation therapy and a lot of chemotherapies work because they cause oxygen free radical production. When hypoxic areas are hit with radiation therapy, it will not respond to the treatment. Oxygenating the tumor is a potential way to restore sensitivity to radiation therapy.

20:10 Radiation Therapy and Oxygen: Radiation causes the formation of free radicals. Because they are oxygen radicals, you need to have oxygen present. The area of the tumor that escaped treatment survives and is able to repopulate the tumor and it will be much more aggressive, because hypoxia promotes aggressiveness of the tumor.

21:11 Oxygen Therapies for Treatment and Prevention: The efficacy of lower levels of oxygen as therapy are being explored. So far, the data is mixed.

22:38 Mitochondria Membranes: Healthy functioning mitochondria act as tumor suppressors. By preserving mitochondrial membrane, in turn helps to preserve mitochondrial function.  A well formulated ketogenic diet helps with cell membrane integrity.

25:21 Insulin Signaling and Cancer: Insulin is a potent growth factor in cancers. Many cancer types upregulate insulin receptors and IGF receptors. Insulin promotes tumor growth. High glucose and high insulin are promoters for cancer growth. Diet is a great way to suppress glucose and insulin.

26:20 Ketogenic Diet and Glucose: We don’t always get a remarkable drop in circulating blood glucose. However, with a ketogenic diet you don’t get the insulin spikes caused by carbohydrates meals. These spikes potently drive tumor growth.

27:33 Pro-Oxidant Therapies:  Oxidative stress is a double edged sword for cancer. Cancer cells at a basal level operate under more free radicals and more oxidative stress than our healthy tissues. It stimulates growth factor signaling and the aggressiveness of the tumor. It can aid in the acquisition of new genetic mutations in the tumor. It is thought that cancer cells are selectively vulnerable to further increasing oxidative stress at a certain threshold. We can manipulate this by providing pro-oxidant therapies to push them over the threshold. If you are receiving pro-oxidant therapies and you are taking antioxidants, you could be undermining the efficacy of the therapy. However, the antioxidant ketogenic diet, as well as the pro-oxidant HBOT, create a synergistic effect with oxidative therapies.

31:11 The Effects of Ketones: Ketones have anticancer effects. They have very important signaling and functional roles in our cells that have nothing to do with their role as energy metabolites. Ketones are histone deacetylase inhibitors, altering what genes are being expressed in the cell. It has been shown that the ketogenic diet influences/normalizes gene expression in the tumor.

33:09 Inflammation: It is a huge component in cancer origination and progression. Ketosis is anti-inflammatory. Beta hydroxybutyrate inhibits the assembly of the NLRP3 inflammasome that is activated during cancer, ageing and many chronic illnesses that incite inflammation.

35:56 Ketones and the Alterations in Oxidative Stress: Ketone metabolism decreases free radical production, reducing oxidative stress and increasing antioxidant capacity. Ketones are taken into the cells by the same transporters that export lactate. Dr. Poff wonders if this has an impact upon the inhibition of the cancer’s ability to get rid of its lactate and perhaps reduce lactate availability.

37:17 Ketones and Glycolysis:  Some data suggests that ketones can inhibit glycolysis, an important pathway in cancer. Ketones are anti-catabolic in a catabolic state, serving as a fat-derived energy substrate and suppressing muscle breakdown during starvation. Cancer patients experience damaging cachexia, the loss of lean body mass.  Being in ketosis may potentially slow this.

41:31 Restoring Anti-Tumor Immunity: The ketogenic diet restores anti-tumor immunity. It increases our immune cells ability to attack the cancer and reduces the ability of cancer cells to hide from our immune systems. Our immune systems have the ability to detect and eliminate cancer. Tumors are only a problem when this ability is lost.

44:14 Ketogenic Cancer Benefits: There is not a lot of human data on the ketogenic diet and cancer. There are 12 clinical trials registered now.

46:44 Dr. Poff’s Morning Routine: She awakens early and spends quality time with her husband and pets. She has coffee with MCT or coconut oil or butter and tries to workout. She takes some exogenous ketones as needed. She does intermittent fasting a few days a week.

48:27 Exogenous Ketones: The study of exogenous ketones is new. They have had a therapeutic effect in a wide variety of seizure models. Exogenous ketones are something that you consume that is either already a ketone or is converted into ketones in your body, or releases ketones. Ketone salts are simple compounds that release ketones in to the blood. Ketone esters have an ester bond in them. The form that Dr. Poff uses contains acetoacetate and a molecule that goes to the liver and is converted to beta hydroxybutyrate. It elevates in both of the primary ketone bodies. In her model, the ketone ester had the same benefits as the ketogenic diet.

51:26 Dr. Poff’s Favorite Ketogenic Food: Coconut oil is her choice. She uses it daily. It is an easy way to elevate your blood ketones naturally.

52:10 Dr. Poff’s Elevator Speech: The quality of pre-clinical evidence is encouraging and more funding is desperately needed. Often ketogenic diet is not funded through traditional funding mechanisms. It deserves more attention and more funding. Research is expensive. Human trials are very expensive. Even a phase 1 trial is a minimum of a million dollars. There is no monetary return on investing in this research.