The series of posts Ketogenic Diets for Cancer follows from the experiment.com Effort run by Dr. Eugene J. Fine and myself. The effort is now over and we were most grateful for the support and wished to keep the conversation going. Currently on this site we will attempt to summarize and organize some of the exchanges. We expect the discussion to be broad but the two key papers are Dr. Fine’s pilot study with ten advanced cancer patients which, though a little study, may be the only prospective human study, and a related in vitro research.
Acetoacetate reduces growth and ATP concentration in cancer cell lines that over-express uncoupling protein 2 Cancer Cell Int.
To follow up on the previous post, the potential of the ketogenic diet derives from a change in fundamental outlook from the genetic approach to the metabolic approach. In our original discussion on experiment.com, several people thought that the explanation of the metabolism was overly technical. Here wepresent a simplified variant that may allow easier access to the main ideas.
Energy exchange in biochemistry is represented in the interconversion of these molecules called ADP and ATP, the former the”low energy” form and the latter, the “high energy” form. Essentially, it costs you energy to generate ATP from ADP and, if you have ATP, the energy from going back to ADP can be employed to perform work, usually chemical work, making something fresh like protein or DNA. (The quote marks remind us that the energy is in the reaction not in the molecules as such). In a rough sort of way then the energy charge of the cell is identified with the amount of ATP.
Two big processes, glycolysis and respiration, provide energy as ATP. Glycolysis, common to nearly all living cells, converts glucose into a three carbon compound pyruvic acid (or pyruvate — acids have two different forms and the names are used interchangeably in biochemistry). Glycolysis doesn’t need oxygen and is called anaerobic metabolism. Pyruvate is a key metabolite and can be converted to many substances. Some cells, quickly exercising muscle, red blood cells and some germs are restricted to anaerobic metabolism and the final product from pyruvate is lactate (lactic acid).
The next method, respiration is aerobic and may convert all the carbons in pyruvate to CO2 and water. Most mammalian cells carry our respiration and procedure pyruvic acid aerobically. Respiration is more effective, produces more ATP than glycolysis, although glycolysis is faster — related to its role in rapidly exercising muslce. Respiration depends on oxygen and produces the majority of the ATP in aerobic cells. You probably know the punch line here: cancer cells are more likely to rely on glycolysis compared to cells of which they are variations even when there is oxygen present. What Warburg original measured was that the ratio of lactic acid to COtwo and this represents a good sign of the cancerous state.
Closing in on the question of why we believe ketone bodies are important, we must appear at other inputs to energy metabolism. Fat is obviously the significant contributor. The fatty acids provided by ingested and stored lipid goes directly into respiration. Under conditions of starvation or of carbohydrate restriction, the fatty acids can also supply the material for synthesis of ketone bodies. Ketone bodies, in turn, derived from fats provide an alternative fuel in place of glucose for many cells. Ketone bodies are made in the liver and transported to other cells, especially the brain, for energyy. (Looking forward to more detailed explanation, the derivative of acetic acid, acetyl-CoA is the true input signal to respiration; the ketone bodies provide acetyl-CoA to other cells). The figure summarizes the basic ideas on energy metabolism.
We found that in the event that you develop cancer cells in culture, ketone bodies will inhibit their development and the amount of ATP that they can generate. Next post will explain the experments and how we believe they might be explained by the metabolic pathway in the figure.