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

Posted: December 4, 2016 in Cancer, Cell Signaling, energy metabolism, gluconeogenesis, glycolysis, ketogenic diet, low-carbohydrate diet, Warburg effect
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This series of posts is a followup to the project that Dr. Eugene Fine and I described in our campaign at Experiment.com. as follow-up to Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and the in vitro projects that we are carrying out in parallel.

The last post described the two major processes in energy metabolism, (anaerobic) glycolysis and respiration. Pyruvate is the product of glycolysis and has many fates. (Remember pyruvate and pyruvic acid refer to the same chemical). For cells that rely largely on glycolysis, pyruvate is converted to several final products like ethanol, lactic acid and a bunch of other stuff that microorganisms make in the fermentation of glucose. (The unique smell of butter, e.g., is due to acetoin and other condensation products of pyruvate). Rapidly exercising muscles also produce lactic acid.

The sudden interest in the metabolic approach to cancer stems from the work of Otto Warburg whose lab in the 1930’s was a center for the study of metabolism. (Hans Krebs was an Assistant Professor in the lab). 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 even though oxygen was present. The Coris (Carl and Gerty of the Cori cycle) demonstrated what is now called the Warburg effect in a whole animal. Ultimately, Warburg refined the result by comparing the ratio of lactate:CO2 in 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 feature of all cancers and for a long time it was assumed that there was a defect in the mitochondrion in cancer cells. These are both exaggerations but aerobic glycolysis appears as a feature of many cancers and defects in mitochondria, where they exist, are more subtle than gross structural damage. The figure shows current understanding of the Warburg Effect.

kdforca_blog_iii_warburg_figure

What about this mechanism makes us think that  ketone bodies are going to be effective against cancer? We need one more step in biochemical background to explain what we think is going on. In normal aerobic cells, pyruvate is converted to the compound acetyl-CoA.  Acetyl-CoA represents another big player in metabolism and functions as the real substrate for aerobic metabolism. If you have taken general chemistry, you will recognize acetyl-CoA as a a derivative of acetic acid.

The reaction acetyl-CoA ➛ 2CO2 is the main transformation from which we get energy. Acetyl-CoA provides the building block for fatty acids and for ketone bodies. Conversely, fatty acids are a fuel for cells because they can be broken down to acetyl-CoA. Under conditions of starvation, or a low-carbohydrate diet, the liver assembles 2 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 kind of metabolic command center and ketone bodies are a way for the liver to deliver acetyl-CoA to other cells.kdforca_blog-iii_dec_4

Now we are at the point of asking how a cell knows what to do when presented with a choice of fuels? In particular, 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 will be substrate for gluconeogenesis), is not used to make acetyl-CoA.  It turns out that acetylCoA (that is, fat or ketone bodies) regulate their own use by feeding back and directly or indirectly turning off glycolysis (in other words: don’t process pyruvate to acetyl-CoA because we already have a lot). The feedback system is known as the Randle cycle and appears (roughly) as the dotted line in our expanded metabolic scheme.

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 growth 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. Our working explanation is that the ketone bodies are inhibiting the cancer cell through the Randle cycle. Now, normal cells can maintain energy, that is compensate for the Randle cycle, by running the TCA cycle (in fact, that is the purpose of the Randle cycle: to switch fuel sources). The cancer cells, however, have some kind of  defect in aerobic metabolism and can’t compensate.  How does this happen? That’s what we’re trying to find out but we have a good guess. (A good guess in science means that when we find out it’s wrong we’ll probably see a better idea). We find that our cancer cells in culture over-express a protein called uncoupling protein-2 (UCP2). We think that’s a player. To be discussed in Part IV.

Comments
  1. Alfonzo Luz says:

      ´´¯`·.¸ >`·.¸¸.·´¯`·>´¯`·.¸¸.·´¯`·.¸¸.·´¯`·.¸ >     ~•$*>  ~  

    Dear Dr. Feinman,Long time.Ducks’ weather here in Oregon.You are on a good path; keep it up. Apparently, Dr. Warburg was not particularly impressed by Budwig’s work.Neither was Dr. Pauling. After all, she was a woman and that was not in style.Nevertheless, her discoveries and accomplishments complement the work of both…and yours. I ommitted the citations in the reference below because of a plethora of links. Curing Cancer: Nobel Laureate Otto Warburg

    by Carol Faith Walkr Tuesday, January 25, 2011 As SparkFriends and regular readers of my blog know, my sister lost her battle with cancer on Dec 2, 2010 in a hospice, while I held her hand. She was only 51, & left behind a 12 year old son, an 11 year old daughter, husband and other family. Otto Heinrich Warburg, with a doctorate of chemistry, and a second doctorate in medicine, was a physiologist and noted biochemist born in 1883 in Freiburg, Baden, Germany. Dr. Warburg won the Nobel Prize in Physiology or Medicine in 1931, and died in Berlin in 1970. He believed in eating organic. Dr. Warburg was awarded the Nobel prize for his discovery that cancer is caused by weakened cell respiration due to lack of oxygen at the cellular level, and proving cancer thrives in anaerobic (without oxygen), or acidic, conditions. In other words, the main cause for cancer is acidity of the human body. In his Nobel Prize winning study, Dr. Warburg illustrated the environment of the cancer cell. According to Warburg, damaged cell respiration causes fermentation, resulting in low pH (acidity) at the cellular level. Warburg also wrote about oxygen’s relationship to the pH of cancer cells internal environment. Since fermentation was a major metabolic pathway of cancer cells, Warburg reported that cancer cells maintain a lower pH, as low as 6.0, due to lactic acid production and elevated CO2. HE PROVED CANCER CANNOT GROW NOR DEVELOP IN BODY ALKALINITY OF 7.36. He firmly believed that there was a direct relationship between pH and oxygen. Higher pH means higher concentration of oxygen molecules while lower pH means lower concentrations of oxygen. A normal healthy cell undergoes an adverse change when it can no longer take in oxygen to convert glucose into energy. In the absence of oxygen, the cell reverts to a primal nutritional program to nourish itself by converting glucose through the process of fermentation. The lactic acid produced by fermentation lowers the cell pH (acid/alkaline balance) and destroys the ability of DNA and RNA to control cell division. The cancer cells then begin to multiply. The lactic acid simultaneously causes severe local pain as it destroys cell enzymes. Cancer appears as a rapidly growing external cell covering, with a core of dead cells. So we have known the proven cause, prevention & cure of cancer since 1931. It is rumoured Dr. Warburg was awarded a second Nobel prize but was unable to receive it because he was Jewish and Hitler prevented it from being awarded; the Nobel Prize authorities deny this however. The reason given was that Hitler had prevented all Nobel Prizes from being accepted; however several scientists in Dr. Warburg’s laboratory were awarded and did receive the Nobel Prize. In my opinion it’s clear to me Dr. Warburg was awarded at least two Nobel Prizes. Dr. Otto Warburg finished one of his most famous speeches, “The Prime Cause and Prevention of Cancer”, with the following statement: ��nobody today can say that one does not know what cancer and its prime cause is. On the contrary, there is no disease whose prime cause is better known, so that today ignorance is no longer an excuse that one cannot do more about prevention.� Considering fats to be the main contributor to weight gain is a popular misconception that leads to massive confusion and explains why so many overweight people are not succeeding in losing weight. Many people would be shocked to find out that we may gain weight from eating cheese not only because it is rich in fat, but mostly due to its high acidic level. In response to high pH acid, the body creates fat cells to store the acid. Almonds have 70% fat, and pork has only 58%. However, pork has one of the highest acid values, -38, while almonds are alkaline forming, +3. Cucumbers and watermelons are so alkalizing that they can neutralize the acidifying effect of eating beef. This is why it is very important to know the pH index of all foods, showing the food’s ability to alkalize the body. Please see the reference links to pH Food Indexes. The so-called “bad” cholesterol, lipoprotein (LDL) is made by our own liver in order to bind the toxins and deactivate the acidic waste that came from certain food, not to cause arteriosclerosis (3). Food, stress, mood, and music all alter our pH balance. Anything that is stimulating could leave an acidic residue in our body; any activities that are calming and relaxing could make us more alkaline. Dr. Coldwell believes 80+% of cancers are initiated by or caused by STRESS, which alters our pH balance, which makes us acidic. A lack of education about dietary pH balance results in confusion among people who are trying to eat healthy and stay alkaline to lose weight and to avoid cancer. Test your pH with litmus paper and you will discover on days you eat leafy greens (kale, collards, Swiss chard, etc) you will be healthily alkaline; on the days you don’t, you won’t be alkaline, even if you’re eating raw. Here is the pH test strip paper I use: [Source–Swanson Vitamins (q.v.)] Once cancer has gained a foothold, it does not survive well in the presence of an alkaline cellular pH level, nor in the presence of highly oxygenated cells. As Nobel Laureate Otto Warburg discovered, low cellular oxygen is a primary causal factor for cancer. Perhaps you have heard the name, Dr. Joanna Budwig, or, The Budwig Protocol? Dr. Johanna Budwig of Germany, who passed away in 2003, was Dr. Warburg’s proteg� in 1951. She continued Dr. Warburg’s work and found that IN ORDER FOR PROPER CELLULAR UTILIZATION OF OXYGEN TO TAKE PLACE, OUR DIETS MUST CONTAIN ADEQUATE AMOUNTS OF UNSATURATED FATTY ACIDS. Over a 50 year period, Johanna Budwig had a MEDICALLY DOCUMENTED 90% plus cancer cure rate in Germany with 4500 patients. Some cancer victims that she cured with her protocol were considered terminal. See reference link #5 below if interested in more information on The Budwig Protocol. Sources: 1: The Prime Cause and Prevention of Cancer. Dr. Otto Warburg Lecture delivered to Nobel Laureates on June 30, 1966 at Lindau, Lake Constance, Germany

    [Dr. Budwig was also denied the Nobel more than once, and for a similar reason. –Ed.]

    [See original page for citations and links.] YrFr,Alfonzo Luz        ∫∫   ~—[*?*]—~

    P.S. I entertain the possibility that ketone bodies are the original nourishment modality of the brain.Since we have adapted to the use of grains, the brain that can use glucose has short-term advantages.My snap diagnosis for you taken from your latest online photo’ is “incipient sub-clinical acidoisis”.Consider prescribing the Budwig Protocol for yourself and let me know how it works out.If you have heard of Ahiflower oil, you are among the very few. See also Gomez-Pinilla UCLA and If you take diet sodas, also consider Budwig’s prescription: Champagne. It’s a refreshing change of pace.I audited Lustig’s latest lecture and found it intellectually stimulating. Hotel food is obviously a scourge. My take away is that Champagne would be better for the grandkids than all that sugar. The Canadians have announced the principal cause of liver injury: acetaminophen. Dr. Lustig might disagree. Have you seen Dr. McDougall’s lecture about the etiology of Steve Job’s “final” illness? AL

    “Freedom of the mind requires not only, or not even especially, the absence of legal constraints but the presence of alternative thoughts. The most successful tyranny is not the one that uses force to assure uniformity, but the one that removes awareness of other possibilities.” — Alan Bloom   Determining tax liability from I.R.S. publications is like mastering immunology from drug company pamphlets.  —Gary Null

    • rdfeinman says:

      A lot of interesting points some of which are not true. I don’t think Warburg received a second Nobel Prize although not being allowed to receive it was the least of your problems if your father was Jewish. It is still bizarre that he was protected, generally assumed to be because of Hitler’s fear of cancer. His ideas on cancer have many exceptions and it is not even clear where lactate fits in. There is the possibility that it is provided by stromal cells and is actually a fuel for cancer cells. On the other hand, champagne in place of diet soda. I’ll drink to that.

  2. Annlee says:

    This seems like a good level of explanation. I know there are several UCPs (from trying to follow Peter’s posts a while back). Is it possible to include a sidebar on the various UCPs and what they do? I for one would appreciate it.

    Thanks for these posts – they are interesting.

  3. james says:

    Professor Feinman what to think of the “reverse of the Warburg effect”? Ketones and lactate “fuel” tumor growth and metastasis Evidence that epithelial cancer cells use oxidative mitochondrial metabolism

    The WordPress page doesn’t let me post this question. Apparently there has been a lot of talk recently about the “Reverse of the Warburg effect” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047616/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040943/

    James

    On 4 December 2016 at 12:27, Richard David Feinman wrote:

    > rdfeinman posted: “The last post described the two major processes in > energy metabolism, (anaerobic) glycolysis and respiration. Pyruvate is the > product of glycolysis and has many fates. (Remember pyruvate and pyruvic > acid refer to the same chemical). For cells that rely la” >

  4. Rune Eliasson says:

    Dear Richard,

    Thank you for sending me the information on ketogenic Diets. A few days earlier I hade received a mail from an old friend, who informed me about her newly discovered cancer. So I sent her your text and hope it will be of help.

    May I take this opportunity to wish you all the Best for the Christmas and New Year events. I will celebrate these recent together with some of my children and grandchildren and I am talen good care of.

    Sincerely yours Rune Rune Eliasson, MD, PhD. rune.eliasson@remcat.se

    comment-reply@wordpress.com 4 dec 2016 kl. 18:27 skrev Richard David Feinman :

  5. Andrew Mortensen says:

    HI. Professor, just came across the following study that appears to indicate that it is fat fueling metastatic cancer in Gliomas. I have been following yours and Dr. Fine’s work as well as Seyfried and others who are investigating the metabolism of cancer. This at least based on the summary appears to run counter to the the view of cancer as a disease fueled by the sugar – insulin axis. Are you familiar with this work. Trying to understand this in the context of everything I have learned about cancer as a metabolic disease. Thank you.

    *Results* We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma

    http://m.neuro-oncology.oxfordjournals.org/content/early/2016/06/29/neuonc.now128

    http://www.sciencealert.com/scientists-just-discovered-we-ve-been-looking-at-cancer-growth-all-wrong

    • rdfeinman says:

      I am not sure that this is inconsistent with the importance of the glucose-insulin axis. I have not read this in detail but the observation that tumors are glucose-avid as seen on the PET scan remains primary and has to be explained. That tumor can utilize other energy sources is known and in fact, Warburg’s original observation (on different tumor) was that he had to starve them for both glucose and oxygen (despite our interpretation that they were anaerobic). I haven’t looked at the details of the paper but we still do not know the degree of heterogeneity of cell type. So, preliminary response is that this is part of the picture which we still need to put together.

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