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Sugar and Cancer Glycolysis; Mitochondria and the Pentose Phosphate Pathway “The one statistic that EXPOSES what an abysmal failure the war on cancer has been is this: the death rates from cancer today, are the SAME as they were in 1950.” Robbwolf.com/2013/09/19 “The Origin of Cancer” Dr. Kieron Rooney [email protected] @kieron_rooney QuickTime™ and a decompressor are needed to see this picture. What have we missed? › For the past 50 or so years, conventional wisdom in cancer research has followed the “somatic mutation theory of cancer” / Cancer is a disease of “Genetics” - Caused by mutations that render certain biological systems dysfunctional (apoptosis) - Most likely triggered by a genetic mutation or exposure to an environmental toxin (such as smoking) - This theory wasn’t always the case however › 90 years ago German Biochemist - Otto Warburg (among others) viewed cancer as a metabolic disease. - The environmental toxin that caused cancer was sugar. - This theory is experiencing a renaissance, a shift in focus from random DNA mutations that cause cells to proliferate uncontrollably to specific metabolic disturbances that provide the energy and metabolites for proliferation - Thomas Seyfried, Dominic D’Agostino, Peter Pedersen, Mina Bissell, Lewis Cantley Cell Energetics - All About “ATP” Nutrient Transporters (Sugars or Fats) Cell Membrane (Fat and Phosphate and some proteins) Cell Signal Receptors (Growth Hormone, Insulin) Glucose Glucose Glycolysis ATP (108) NAD NADH (2) Lactate Fat Proteins / Amino Acids Fat ATP (2) Pyruvate (2) Acetyl CoA TCA KREBS Mitochondria ATP (30) Oxygen NAD NADH (lots) E T C Warburg’s Cancer Cell Energetics - All About “ATP” (from glycolysis only) Glucose Glucose Glycolysis 400x (Mina Bissell) NAD NADH (2) Lactate Fat Proteins / Amino Acids Warburg Hypothesis: The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by the fermentation of sugar Fat ATP (2) Pyruvate (2) ? Although Glycolysis is a relatively inefficient fuel supply in regard to ATP production - It can happen really really fast (up to 200x the rate of normal cells) Mitochondrial Respiration is observed to be normal in certain cancers and glucose restriction doesn’t always stop cancer growth › Vander Heiden MG et al. “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation”. Science 324, 1029 (2009). › Kim HH etal. “The Mitochondrial Warburg Effect: A Cancer Enigma” Interdiscinplinary Bio Central doi: 10.4051/ibc.2009.2.0007 (2009). › Roderiguez-Enriquez S et al. “The Warburg Hypothesis and the ATP Supply in Cancer Cells is Oxidative Phosphorylation Impaired in Malignant Neoplasias?” Curr Pharm Biotechnol (2012). › Ma L et al. “Control of Nutrient Stress-Induced Metabolic Reprogramming by PKC in Tumorigenesis. Cell 152, 599 (2013). › So is the Warburg Hypothesis Wrong? A Hypothesis is Never Wrong - Just in Need of Refinement › While the Warburg Hypothesis may need refining, The Warburg Effect is proving to be highly reproducible across cancer cell types That is: - A CONSISTENT FEATURE OF CANCER CELLS IS AEROBIC GLYCOLYSIS › Of particular interest then is the how / why this occurs in the presence of relatively normal functioning mitochondria that would be a more efficient energy source? - CELL METABOLISM IS NOT JUST ABOUT ENERGY Cell Energetics - All About “Making New cells” Pentose Phosphate Pathway Glucose Glucose Glycolysis Fructose Lactate (100s) Pyruvate (100s) NADPH DNA Acetyl CoA ATP (100s) Oxygen Acetyl CoA Glutamine Ribose-5Phosphate FAT NADPH NAD NADH TCA KREBS Mitochondria Cell Membrane (Fat and Phosphate and some proteins) NAD NADH (lots) E T C Conclusions? › Glucose does appear to be a vital fuel for cancer cell growth. It is used by proliferating cells to provide: - Energy as ATP via glycolysis at rates far in excess to that of normal cells and mitochondrial respiration - An essential component of DNA synthesis in Ribose - 5 - Phosphate via the Pentose Phosphate Pathway - An essential component of Fat Synthesis in both NADPH from the PPP as well as Acetyl CoA via glycolysis › Could sugar restriction be a treatment plan for cancer? - Cell Cultures and small animal studies tend to give mixed results depending on the type of cancer - Published Human studies are few with varied designs but the literature base is growing - It is likely that diet and drug treatment together will provide the most immediate, positive effects - Previously reported associations between sugar intake, metabolic disease and cancer are now being supported by basic science mechanisms - Sugar restriction is an achievable low risk option for consideration Human Studies of carbohydrate restriction and cancer: › Nebeling LC et al “Effects of a ketogenic diet on tumor metabolism and nutritional stauts in pediatric oncology patients: Two Case Reports J. Am. Coll. Nutr. 14(2), 202-208 (1995). › Zuccoli G et al “Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr & Metab 7:33 (2010). › Schmidt M et al “Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot Trial. Nutr & Metab 8:54 (2011). › Champ CE et al “Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme” J Neurooncol doi: 10.1007/s11060-014-1362-0 (2014). › Reviewed in: › Klement RJ and Kammerer U “Is there a role for carbohydrate restriction in the treatment and prevention of cancer?” Nutr & Metab 8: 75 (2011).