Home Uncategorized Ketogenic Diets for Cancer III. More background and the Warburg Effect.

Ketogenic Diets for Cancer III. More background and the Warburg Effect.

This series of posts is a followup to the job that Dr. Eugene Fine and that I described in our campaign at Experiment.com. As followup to Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and the in vitro projects that we’re carrying out in parallel.

The last post explained the two major processes in energy metabolism, (anaerobic) glycolysis and respiration. Pyruvate is the product of glycolysis and has many fates. (Recall pyruvate and pyruvic acid refer to the same chemical). For cells which rely largely on glycolysis, pyruvate is converted to several final products such as ethanol, lactic acid and a whole lot of other stuff that microorganisms make in the fermentation of glucose. (The exceptional smell of butter, e.g., is due to acetoin and other condensation products of pyruvate).

The sudden interest in the metabolic approach to cancer originates from the work of Otto Warburg whose laboratory in the 1930’s was a centre for the study of metabolism.  (Hans Krebs was an Assistant Professor in the laboratory ). Warburg’s landmark observation was that cells from cancer tissue showed a higher ratio of lactate to CO2 than normal cells, that is, the cancerous tissue was metabolizing glucose via glycolysis to a greater degree than normal although oxygen was present. The Coris (Carl and Gerty of the Cori cycle) demonstrated what’s now called the Warburg effect in a whole animal. Finally, Warburg refined the result by comparing the ratio of lactate:CO2 at a cannulated artery to that in the vein for a normal forearm muscle. He compared that to the ratio in the forearm of the same patient  that contained a tumor. Warburg claimed that this greater dependence on glycolysis was a general characteristic of all cancers and for a long time it was presumed that there was a defect in the mitochondrion in cancer cells. These are both exaggerations but aerobic glycolysis appears as a characteristic of several cancers and defects in mitochondria, where they exist, are more subtle than gross structural damage. The figure shows current comprehension of the Warburg Effect.


What about this mechanism makes us believe that  ketone bodies are going to work against cancer? We need an additional step in biochemical background to explain what we believe is going on. Acetyl-CoA represents another large player in metabolism and functions as the actual substrate for aerobic metabolism. If you have taken general chemistry, you may recognize acetyl-CoA as a a derivative of acetic acid.

The reaction acetyl-CoA ➛ 2CO2 is the main transformation from that we get energy. Under conditions of starvation, or a low-carbohydrate diet, the liver assembles two acetyl-CoA’s to ketone bodies (β-hydroxy butyrate and acetoacetyl-CoA). The ketone bodies are transported to other cells where they are disassembled back to acetyl-CoA and are processed in the cell for energy. The liver is a sort of metabolic control center and ketone bodies are a way for the liver to deliver acetyl-CoA to other cells. kdforca_blog-iii_dec_4

Now we’re at the point of asking how a cell knows what to do if presented with a choice of fuels? Specifically, how does the input from fat dial down glycolysis so that pyruvate, which could be used for something else (in starvation or low carb, It’ll Be substrate for gluconeogenesis), is not used to make acetyl-CoA.   It turns out that acetylCoA (that is, fat or ketone bodies) govern their own use by feeding back and directly or indirectly turning off glycolysis (in other words: do not process pyruvate into acetyl-CoA because we have a lot). The feedback system is referred to as the Randle cycle and looks (roughly) as the dotted line in our expanded metabolic procedure.

robin_map_2012-2Where we are going. In our earlier work Dr. Fine and I and our assistant, Anna Miller, found that if we grow cancer cells in culture, acetoacetate (one of the ketone bodies) will inhibit their development and will reduce the amount of ATP that they can generate. Normal cells, however, are not inhibited by ketone bodies and the cells may even be using them. Now, normal cells can maintain energy, that is compensate for the Randle cycle, by conducting the TCA cycle (in fact, that’s the purpose of the Randle cycle: to change fuel sources). The cancer cells, however, have some kind of  defect in aerobic metabolism and can’t compensate.  How can this happen? That’s what we’re looking for out but we have a fantastic guess. (A good guess in science means that when we find out it’s wrong we’ll probably see a better idea). We think that’s a player. To be discussed in Part IV.


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