The term “aerobic glycolysis” is confusing to biochemists because it is inherently contradictory. Aerobic refers to reactions that require oxygen, and anaerobic refers to reactions that take place without the need for oxygen. Glycolysis is a biochemical pathway that does not need or use oxygen, therefore it is anaerobic. The definitions of aerobic and anaerobic shed no light on why glycolysis is described as aerobic.
Where did this concept of aerobic glycolysis come from? Interestingly, it arose from early studies of Otto Warburg in the metabolism of cancer cells. He found that cancer cells appeared to metabolize glucose in the same manner as free-living anaerobic single- celled organisms. But he noted an important difference. In the presence of oxygen, the rate of glycolysis by microorganisms slowed, but in cancer cells the rate of glycolysis was unaffected by the presence of oxygen. This was the origin of the term aerobic glycolysis, which is intended to mean anaerobic metabolism in the presence of oxygen.
Reflection on this definition of cancer metabolism led to speculation about the vulnerabilities of cancer cells that might reveal a passageway to a cure. But first, before discussing an outline for a cancer cure, some background information based strictly on biochemical science, not on epidemiology (known as observational studies), is appropriate.
All known forms of life derive metabolic energy either from glycolysis alone, which is a ubiquitous pathway in all forms of life, or a combination of anaerobic glycolysis and the aerobic Krebs cycle, also known as the Citric Acid cycle or the Tricarboxylic Acid (TCA) cycle. Glycolysis is the more primitive pathway and produces less energy than the Krebs cycle (two net ATPs from glycolysis versus 36 ATPs from the Krebs cycle). Plants use both glycolysis and the Krebs cycle for energy production, but also use reverse glycolysis in photosynthesis to convert airborne CO2 to glucose.
Life forms that have only glycolysis as their energy provider are primarily single-cell organisms. These single-celled organisms may be obligatory anaerobes, for which oxygen is lethal, or facultative anaerobes, which can tolerate the presence of oxygen.
Fermentation: Long before the chemistry by which yeast turned sugar into alcohol was known, the products of the process, in the form of beers and wines, were a part of ancient civilization’s cultural life. The process was labeled fermentation by Louis Pasteur in the mid-1800s. By the early to mid-1900s, the biochemical reactions of fermentation were identified and its biochemical pathway was named glycolysis after the Greek words that connote “the splitting of sugar.”
Glycolysis: Since glycolysis is common to all forms of life, it is appropriate to consider what it does. Although it is a primitive pathway, is not reserved as a default pathway used only for rapid energy demand. Glycolysis has two important roles. One is to metabolize glucose in a series of ten biochemical reactions to form pyruvate; the second is to produce two ATPs. In anaerobes, both roles are required; glucose must be metabolized to pyruvate in order to obtain the needed ATPs. In human metabolism, the two ATPs from glycolysis are of little value relative to the need for pyruvate to supply substrate for the Krebs cycle and its 36 ATPs.
Pyruvate: Pyruvate is a three-carbon molecule formed from the splitting up of six- carbon glucose; one glucose molecule yields two pyruvate molecules. Before leaving the subject of glycolysis, the behavior of pyruvate must be explained. There is a rule in biochemistry that when the product of a reaction is not withdrawn as it is made and its concentration is permitted to build up, the reaction will stop. Pyruvate is the end point of glycolysis. At this point, it has two electrons that it must be passed on to another biochemical so that it is free to accept the two electrons that are being continually being passed down to it along the glycolytic reaction chain. If it cannot get rid of its two electrons, the reaction stops and the organism dies.
In glycolysis, pyruvate solves the problem by using the two electrons to make a product that can then be removed or isolated. Depending on the organism, the product is ethanol, CO2, acetic acid, lactic acid, or another organic acid. In obligate anaerobes, an appropriate element from the periodic table, such as sulfur, iron, manganese, or cobalt, is used to accept pyruvate’s two electrons.
Lactic Acid: A very interesting example of the use of anaerobic fermentation in human metabolism can be found in muscle tissue. When the oxygen supply to muscle tissue is not sufficient to permit entry of pyruvate into the Krebs cycle, as can occur during heavy exercise, pyruvate holds on to its own two electrons and converts itself to lactic acid leaving the pyruvate slot open for continued glycolysis.
This reaction is probably a remnant from pre-Krebs-cycle times in evolutionary history. Lactic acid is also an endpoint biochemical, but it has no other role in human metabolism, thus it must be removed. The least costly way is to recycle it back to glucose via the Cori cycle.
The Cori cycle: As lactic acid builds up in the muscle, it is removed by the blood stream and transported to the liver. There it is reduced back to pyruvate, metabolized back to glucose by reverse glycolysis, and then sent back to blood stream. The Cori cycle is often referred to as a gluconeogenic pathway but it actually is a glucogenic pathway; it does not make new glucose but rather regenerates old glucose for reuse.
The Krebs Cycle: The ability to further metabolize the pyruvate end point of glycolysis by an oxidative pathway (Krebs cycle) provided the added energy required for evolutionary development of higher life forms. All scientific evidence indicates that although cancer cells live in an environment supported by and bound to aerobic metabolism, they do not seem to be participants in the system. The biochemistry of the Krebs cycle is well described in biochemistry texts. Its relevance for discussion of a cancer cure is only to the extent that its biochemistry benefits the cancer. The reality of this possibility is suggested in the second recommendation in the next section.
A Cancer Cure
The discussion and recommendations for curing cancer presented below are based on the Hickey Roberts hypothesis2 that cancer cells follow the same microevolution that free- living single-celled organisms follow.
The “aerobic glycolysis” label for cancer cell metabolism, as noted above, had its origin in the observations of Otto Warburg3 almost 100 years ago. Warburg noticed that cancer cells obtained energy (ATP) from glucose by fermentation to lactic acid (recall muscle physiology?) independent of the presence of oxygen. The fact that cancer cells preferred anaerobic metabolism over aerobic metabolism was considered not to be natural for human cells led to a conclusion that cancer cells have a metabolic quirk.
The Hickey Roberts hypothesis would say that there is no quirk; cancer cells are merely human cells that have lost their identity as human and have returned to the primitive state of single-celled anaerobic metabolism; they are not human anymore. Why they lose their identity to begin with is another issue, but having done so they are merely behaving as normal anaerobic cells would behave in the same situation. The key here is their situation: Cancer cells are unique among anaerobic organisms in that they are totally confined in a human body and figuratively (if not literally) awash in an oxygen environment.
The cancer cells referred to in the recommendations below are either obligate or facultative anaerobes. If they are obligate, they would have to find an electron acceptor for pyruvate in the oxygen environment in the human body. If facultative, they are already tolerant of oxygen. All anaerobes obtain their requirements from their environments, whether obligate or facultative. What do cancer cells want or need from their human host besides glucose?
The work of Warburg and later colleagues found that cancer had a voracious appetite for glucose and that it preferred an oxidizing environment. The human host provides cancer cells with glucose, but its redox (reducing–oxidizing) environment varies and depends on the host’s diet. An important question is why do cancer cells, which do not use oxygen, prefer an oxidizing environment? Logically, it would be because the oxidizing environment of the host makes something they need that they cannot make on their own.
What does the human body give to cancer cells besides glucose? Does it provide ATP from its own Krebs cycle? Does it regenerate glucose from lactate using its own Cori cycle? Do cancer cells piggyback on any other function of human cells? Regardless of the details of the relationship between a cancer cell and it human host, the Hickey Roberts theory of microevolution of cancer cells would predict the outcomes of the following steps.
Starve the Cancer: The first step in a cancer cure is to stop feeding the cancer. Dr. Seyfried and associates are using a ketogenic diet4 with good results in cancer patients to achieve this goal. Ketogenic nutrition is the hope for not only curing cancer5 but also in preventing it.
However, further dietary modifications should be augmented if ketogenesis is to be more uniformly effective. The research of Serhan6; 7; 8 and colleagues in the biochemistry of the lipid mediator endpoints of polyunsaturated fatty acids has demonstrated that eicosanoids regulate inflammation and that resolution of disease is not automatic. Resolution requires dietary omega-3 and omega-6 fatty acids, namely eicosapentaenoic (EPA), docosahexaenoic (DHA), and gamma linolenic (GLA) acids. Without control of inflammation and active resolution, the benefits of ketogenic nutrition could be limited or negated.
Deprive the Cancer of any Benefit Provided by Host: The long-known preference of cancer cells for an oxidizing environment should be exploited. Oxidative stress is an important consideration in the causation and the prevention inflammatory diseases including cancer. Oxidative stress produces harmful isoprostanes that destroy AA, EPA and DHA1, p. 197.
The biosynthesis of isoprostanes is not catalyzed by enzymes; the oxygen free radicals in the body simply react with any fatty acids having three or more double bonds. Isoprostane levels determined by an inexpensive urine test are considered a reliable indicator of oxidative stress in humans. Normal levels in healthy individuals have been accurately defined so that the degree of oxidative stress in patients can be reliably measured1, p. 197.
These data would suggest that an oxidizing environment in the host should be replaced by a reducing one. This would be accomplished, as determined by the attending physician, with appropriate use of antioxidants. However, the recent demonstration by Poff et al.9 that a ketogenic diet combined with hyperbaric oxygen therapy prolonged survival in mice with systemic metastatic cancer gives urgency to the need for understanding the mechanism whereby the redox environment within the body of the host influences the metabolism of cancer cells.
Considerable research has been directed toward understanding the deficiencies of tumor cell energy metabolism but how much of this deficiency is made up by contribution from aerobic respiration and other pathways in healthy cells? What else does the unique environment (the human body) of cancer cells provide in its metabolism that helps (or hinders) cancer cell survival? If these questions have not been asked, there is more work to be done. The answers will provide direction for isolating cancer cells from gifts provided by the body.
Kill Surviving Viable Cancer Cells: The bell-shaped curve is a reality that cannot be ignored. No matter what the issue, there will always be a few outliers at each end of the curve. A few viable cancer cells will remain after the cancer appears to have been conquered. These surviving cells should be eliminated to the extent possible.
Ascorbic acid has been demonstrated to be a very efficient method for selectively killing cancer cells. The biochemical mechanism by which ascorbic acid kills malignant cells1; 3 has been discovered and described. The mechanism in brief is as follows:
When ascorbic acid enters the oxidizing environment of a cancer, it is oxidized to dehydroascorbic acid. Because of structural similarity between dehydroascorbic acid and glucose (cancer’s preferred energy source), cancer cells cannot distinguish between the two. Thus, when dehydroascorbic acid is present in high concentrations it competes effectively with glucose for active transport into cancer cells by glucose pumps.
Once inside, dehydroascorbic acid generates hydrogen peroxide and other oxidants that the cancer cells cannot counter. The very high levels of hydrogen peroxide cause either apoptosis (programmed cell death) or necrosis of cancer cells. Normal cells are protected by catalase, which destroys peroxide. Cancer cells do not contain catalase.
These data on the effectiveness of ascorbic acid in cancer treatment have been either rejected or ignored by the medical establishment. Considering the enormity of rejecting a therapy that is based on valid science and clinical success is unwarranted. Failure to investigate objectively the use of ascorbic acid in cancer therapy is a lapse of moral judgment.
- Ottoboni A, Ottoboni F. The Modern Nutritional Diseases and How to Prevent Them. Fernley, NV: Vincente Books, 2013.
- Hickey S, Roberts H. Cancer: Nutrition and Survival. 2005. self-published, available amazon.com
- Seyfried TN. Cancer as a Metabolic Disease. New York, NY: John Wiley and Sons, 2012
- Klement RJ, Kammerer U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutrition & Metabolism 2011, 8:75, http://www.nutritionandmetabolism.com/content/8/1/75
- Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxins are first lipid mediators of endogenous anti-inflammatory and resolution. Prostaglandins, Leukotrienes, and Essential Fatty Acids.2005;73:141.
- Bannenberg GL. Therapeutic applicability of anti-inflammatory and proresolving polyunsaturated fatty acid-derived lipid mediators. The Scientific World Journal. 2010; 10: 676-712.
- Serhan CN, Chang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. National Review of Immunology. 2008; 8(5): 348-361.
- Poff AM, Ari C, Seyfried TN, D’Agostino DP. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One. 2013 Jun 5;8(6):e65522. doi: 10.1371/journal.pone.0065522. Print 2013.