Ketogenic Diets for Cancer-2. Background on why ketone bodies might help.

by Drs. Eugene J. Fine and Richard D. Feinman

Posted on 9/2/20

To follow up on the last post on the potential of the ketogenic diet for cancer, we address the change in basic outlook from the genetic approach to the metabolic approach. Although, in terms of biochemical mechanisms, we can’t really separate the two, but there has definitely been a change in focus in basic research. In our original discussion on experiment.com, several people thought that the explanation of the metabolism was too technical. Here we try to present a somewhat simplified version that may allow easier access to the main ideas.

 Energy exchange in biochemistry is represented in the interconversion of the molecules known as ADP and ATP, the former identified as a “low energy” form and the latter, the "high energy" form. In essence, it costs you energy to make ATP from ADP and, if you have ATP, the energy from going back to ADP can be used to do work, usually chemical work, making something new like protein or DNA.  We speak of coupled reactions, the downhill conversion of ATP to ADP is coupled to the uphill production of some product (the quotation marks reminding 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 level of ATP.

Two major processes, glycolysis and respiration, provide ATP. Glycolysis, common to almost 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 does not require oxygen and is referred to as anaerobic metabolism. Pyruvate is a key metabolite and can be converted to many substances. Some cells — rapidly exercising muscle, red blood cells, and some microorganisms — are restricted to anaerobic metabolism and the final product from pyruvate in these cases is lactate (lactic acid).

The second process in energy generation, respiration, is aerobic (requires oxygen) and can convert all the carbons in pyruvate to CO2 . Most mammalian cells carry out respiration and process the resultant pyruvate acid aerobically. Respiration is more efficient, producing more ATP than glycolysis, although glycolysis is faster (related to its role in rapidly exercising muscle). Respiration is dependent on oxygen and produces most of the ATP in aerobic cells. You probably know the punch line here: cancer cells are more likely to rely on glycolysis than the normal cells of which they are variants, even if there is oxygen present. What Warburg originally measured was the ratio of lactic acid to CO2 and he assumed that the higher than normal ratio of  lactate to CO2 presented a good indication of the cancerous state.

The Warburg effect calls attention to the choice of fuel for cellular metabolism as a key in understanding the cancerous state. Closing in on the question of why we think ketone bodies are important, we have to look at other inputs to energy metabolism. Fat is obviously the major contributor. The fatty acids supplied by ingested and stored lipid can go directly into respiration. Under conditions of starvation or of carbohydrate restriction, the fatty acids can also provide 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 mostly in the liver and are transported to other cells, notably the brain, for energy. (Looking ahead to more detailed explanation, the derivative of acetic acid, acetyl-CoA is the actual input to respiration; the ketone bodies supply acetyl-CoA to other cells). The figure summarizes the basic ideas on energy metabolism.

We found that if you grow cancer cells in culture, ketone bodies will inhibit their growth and the amount of ATP that they can generate. Next post will describe the experiments and how we think they might be explained by the metabolic pathway in the figure.