The Link Between Cancer and Mitochondria:

Restoring Mitochondrial Function to Fight Cancer


by Michael Karlfeldt, ND, PhD

The role of mitochondria in the initiation and progression of cancer has long been debated, but it is generally accepted that mitochondria play an important role in cancer through replication and energy production. Identifying the important roles that mitochondria play in cancer development and progression can possibly help identify ways in which repairing mitochondrial function may be used for therapeutic benefit. Many cancer researchers tend to seek a reductionist approach in their research: the theory that condenses complex biological phenomena into their many parts, so we can understand a single cause and devise a cure. However, once reduction is done, there may be incentive for unification of theories to create a more holistic approach to cancer treatment. The mitochondria may be the gateway for this alternative approach. 
      
This article will review the history of mitochondrial-cancer research as well as various, promising, non-toxic approaches to altering mitochondrial function in cancer cells, such as low-carbohydrate diet and fermented wheat germ extract nutrition.

The Mitochondria

The mitochondria, home of the Krebs cycle or tricarboxylic acid cycle (TCA), are maternally-inherited, cytoplasmic organelles having evolved from symbiotic bacteria.(1)  Containing only 37 genes, they are known as the powerhouse of the cell for their role in producing chemical energy or adenosine triphosphate (ATP). By oxidizing (losing an electron) the fat, protein, and carbohydrates we consume through food and drink, they create energy-abundant molecules for the cell. These biochemical processes are known as cellular respiration. Within the TCA, substrates such as oxygen and glucose are converted, through enzymatic processes, first into pyruvate, then acetyl-CoA and ultimately lead to the production of an ATP molecule, water, and carbon dioxide. 
      
Researchers at the United Mitochondrial Disease Foundation have reported that only three percent of genetic material per mitochondrion (one hundred in every three thousand) is required to produce up to 90% of the body's ATP.(2)  This efficiency apportions more than ninety-five percent of the mitochondrion to play other roles in regulating metabolic pathways. The mitochondria are genetically independent from the nucleus of the cell and communicate via nuclear transport and messenger proteins. Mitochondria are responsible for building and encoding nucleic acids and proteins responsible for cellular respiration, communicating with the nucleus, causing the cell to grow, function, and recycle its molecular building blocks through regulation of apoptosis pathways.(3)

421-2KarlfeldtFig1_0818.jpg

Figure 1: Vander Heider MG et al. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009. 324(5930):1029–1033.6  This image shows normal cell respiration via OXPHOS, Anaerobic glycolysis, when oxygen is not available, and the cancer cell's energy cycle termed as the Warburg effect or 'Aerobic glycolysis'.

Mitochondria and the Warburg Effect 

Normal cells produce energy through mitochondrial oxidative phosphorylation (OXPHOS). When oxygen is not available, they produce energy via the less efficient route of anaerobic glycolysis. In the 1920s, Otto Warburg observed that cancer cells do not produce energy in the efficient way that normal cells do. Rather, cancer cells produce most of their energy through an inefficient, high rate of glycolysis and glutaminolysis(4) followed by fermentation of lactate into lactic acid. Glucose and glutamine metabolites are then diverted from producing ATP to a process to promote cell proliferation. This process was coined by Warburg himself as aerobic fermentation, which has been adapted to 'aerobic glycolysis', and commonly known as the Warburg Effect. Since lactate production is considered an indicator of respiratory insufficiency in biological systems,(5)  Warburg assessed aerobic production of lactate in cancer cells as a gauge of respiratory insufficiency. (Differentiated cells produce large amounts of lactate only under anaerobic conditions.) This observation, as we will see is a controversial one, not so much as to the involvement of the mitochondria in cancer, but at what point they become involved in the process, and whether they are functioning. 
      
Biology professor, contemporary Warburg devotee, and cancer researcher, Dr. Thomas Seyfried outlines the key points of Warburg very well when he states that (i) insufficient respiration initiates tumorigenesis and ultimately cancer, (ii) energy through glycolysis gradually compensates for insufficient energy through respiration, (iii) cancer cells continue to ferment lactate in the presence of oxygen and (iv) respiratory insufficiency eventually becomes irreversible.(5)

The mitochondrion theory appears to be the only cancer initiation theory that relates to all cancers

Mitochondria and Cancer

Given the complexity of a disease, such as cancer, medical science might consider withholding its insistence on reductionism. With cancer, seeking out a single cure may be an over-simplification, as may claiming it to be one disease, or that there is only one cause. Depending on one's point of reference, cancer types differ broadly in such ways as the primary site, histopathology of cells, solid or liquid, genes involved, staging criteria, level of evidence, and perhaps, at what point the mitochondria become involved.(7-14)  Despite inconsistencies in the understanding of biochemical processes, cancer has been hailed for decades and supported by thousands of clinical trials by the somatic mutation theory (SMT), which cites that the initiating disease process is the result of nuclear mutations in oncogenes and tumor suppressor gene.(9,15)  This view is responsible for the ongoing development of cancer drugs that block specific genetic mutations, with some promise that one day a single drug could potentially treat all tumor types that share the same mutation.(10)
      
The mitochondrion theory appears to be the only cancer initiation theory that relates to all cancers, which, up to recently, has generally been explained in contrast with the SMT. Even genetics researchers Hanselmann and Welter, who wrote the highly cited paper Origin of Cancer: An Information, Energy, and Matter Disease,(7) have been gathering evidence for and against alternative cancer etiology theories. In addition to the 1) SMT, these other theories are 2) microenvironment, 3) mitochondrion , and 4) aneuploidy categories, characterized by Hanselmann and Welter as each having 'supporting' and 'contradicting' evidence for the validity of the category itself. The Warburg Effect is detectable in all tumors, whereas the research shows that the microenvironment can cause cancer, or most cancer cells show mutations and most tumors show aneuploidy.(7)  However, this article will not debate reductionist theories and pit them against one another as the issue may not be in choosing the right one but in unifying them properly.(5)
      
All evidence supports the Warburg effect - whether causal or not - as constant in the initiation and/or progression of cancer. Some research argues against a reductionist model, while still upholding the majority view that cancer begins with the SMT, progresses to the microenvironment and then to the mitochondrion.(9) It has been elucidated that cancer will select against the genes with the highest consumption of free energy. An alternate holistic model suggests that the underlying mechanisms of deregulated cellular metabolism are associated with, but not necessarily caused by, mitochondrial dysfunction, and that mitochondrial dysfunction can promote cancer progression to an apoptosis-resistant or invasive phenotype through a variety of mechanisms.(12) Seyfried's holistic model is in accordance with the somatic mutation as an event that follows mitochondrion disruption. This research allows him to conclude that respiratory insufficiency is the origin of cancer, and that the other initiation theories, including the SMT, arise either directly or indirectly from insufficient respiration.(12)  In later research Seyfried postulates that a major weakness in the effort to cure cancer is due to the confusion surrounding the initiation theories. He believes that without a unifying agreement of how cancer arises, it becomes difficult to formulate a successful plan for effective treatment and prevention.(5)  Considering the aforementioned statistic of cancer initiation, from a reductionist perspective, it would be most appropriate to address the mitochondrion theory.

Mechanisms of Mitochondrial Disruption Provide Therapeutic Opportunities

Many vital cellular parameters are controlled by mitochondria. These include regulation of energy production, modulation of oxidation–reduction (redox) status, generation of reactive oxygen species (ROS), contribution to cytosolic biosynthetic precursors such as acetyl-CoA and pyrimidines, and initiation of apoptosis through the activation of the mitochondrial permeability transition pore and Cytochrome C. Changes in these parameters can shift the cell from a dormant state of differentiation to a proliferation state.(1)  Below, the mitochondrial disruptions are categorized but bear in mind that they overlap and should be considered a locus in the greater process or state of cancer initiation. There are many thorough investigations and positions on the role of mitochondrial dysfunction in cancer(1,10,11,16,17) and following is a summary.
      
Genetic Mutations
. Cancer cells have been shown to display genetic and epigenetic mutations that activate irregular programs that are important in development, stress response, wound healing and nutritional status.(2)  Cancer cells optimize the cancer cell environment by reprogramming adjacent cells for their benefit, using retrograde signaling.(1)  Some research claims that functional mitochondria are essential for the cancer cell.(1,8,9)  When mutations in mitochondrial genes are present, which is often in cancer cells, they alter the mitochondrial bioenergetic (i.e. oxygen rate and extracellular acidification rate) and biosynthetic state (i.e. cell proliferation), rather than inactivating mitochondrial energy metabolism (i.e. glycolysis, glutaminolysis, ATP). 
      
Mitochondria regulate the transcription factor Hypoxia-Inducible Factor 1 (HIF-1), which induces glycolysis under hypoxic conditions allowing cancer to thrive. HIF-1 is increasingly studied because it allows for survival and proliferation of cancerous cells due to its angiogenic properties thus inhibition of HIF-1 potentially could prevent the spread of cancer.(1,4)
      
Enzyme Defects
. Cancer cells require altered metabolism to efficiently incorporate nutrients into biomass and support abnormal proliferation. In addition, the survival of tumor cells outside of normal tissue context requires adaptation of metabolism to different microenvironments. Warburg theorized that to treat cancer is not to target mutated genes but enzymes that cancer cells depend upon more than normal cells for tumor cell growth, survival and proliferation. They are present in virtually all cancers.(18)  There are several metabolic enzyme defects that give way to some existing treatments targeting these enzymes.(13)  However, long-term success with this approach may depend on understanding why specific metabolic pathways are important for cancer cells and which patients are likely to respond.(19
      
Redox Reactions and Glycolysis
. Reactions involving electron transfers are known as oxidation-reduction reactions or redox reactions for which OXPHOS is the metabolic pathway. A redox reaction occurs as a result of two smaller reactions; one molecule loses one or more electrons, and simultaneously gains an oxygen atom, to become oxidized and another molecule gains an electron and loses an oxygen atom to become reduced. Cancer cells have an amazing tendency to reprogram their metabolic capability by inhibiting OXPHOS to elevate glycolytic metabolism. There is a therapeutic opportunity for inhibiting glycolysis to shift cellular metabolism to OXPHOS(20) oxidizing NADH to ATP instead.
      
Reactive Oxygen Species and Antioxidants
. The increase of ROS in cancer cells is linked to many irregularities in cellular functions such as cell proliferation, migration, differentiation and apoptosis.(21)  The increased promotion of ROS in tumor cells with mitochondrial dysfunction may make them more liable to further oxidative stress, compared to normal cells with lower ROS yield. High production of mitochondrial ROS in hypoxic cells has been shown to link cancer to ischemic disorders.(21
      
NADPH is required for the reduction of hydroperoxides by glutathione and glutathione peroxidases by the mitochondria. When mitochondrial ROS production is too high, it is toxic to the cell and can induce apoptosis or necrosis as well as contribute to new abnormal tissue. The tumor suppressor p53 can arrest growth and initiate apoptosis. Inactivation of p53 should decrease OXPHOS in favor of glycolysis, increase ROS production and inhibit apoptosis. In other contexts, p53 activation can also induce cellular deterioration. Excessive shortening of chromosomal telomeres activates p53, which results in mitochondrial dysfunction, increased ROS levels, and deterioration.1

Ketogenic diets could be rapidly implemented to correct inherent oxidative metabolic differences between cancer cells and normal cells and to improve standard therapeutic outcomes.

Lactic Acid and the Microenvironment. It has been debated whether cancer cells opt for fermentation to proliferate, or if they must choose this path over cellular respiration due to mitochondrial damage.(8,12)  In fact, some researchers state that the Warburg effect is common to all cancers,(7,9,12) and that regardless of the availability of oxygen, the cancer cells convert most glucose to lactic acid. Studies have shown that lactic acid is not merely a byproduct but that it informs a predictive role in the proliferation of cancerous cells, metastasis of cancer and patient survival. Acidosis generated from lactic acid impedes the function of normal immune cells, including loss of T-cell function, thereby suppressing the anti-cancer immune response and enhancing tumor cell survival.(4)

Cytochrome C and Apoptosis. Just as mitochondria are descendants of bacteria, cytochrome c molecules in human, yeast, and plant cells cannot be distinguished from one another. In normal cells and in the presence of oxygen, Cytochrome C acts like a shuttle to move electrons from glucose to ATP production. Cytochrome C also plays the opposite function signaling the cell to begin the process of apoptosis or programmed cell death. When there is a bad climate for the cell, Cytochrome C initiates one or more cascades of signaling proteins that spread the message through the cell and ultimately self-destruct. While apoptosis is part of healthy growth and development, if the system is malfunctioning the growth of cancers can be propagated and the system corrupted causing calamitous results, leading to degenerative diseases when overactive and allowing the growth of cancers when obstructed.(22)

Expanding Opportunities for Nutrition Treatment

Cancer is a genetic disorder and yet the common denominator may be controlled by mitochondria function.(5)  Since the mitochondria have so few parts to them, are such a major role in tumorigenesis or so scientists believe, they are an obvious target for therapeutic opportunities. New drugs are being developed to inhibit mitochondrial respiration of cancer cells and induce mitochondrial structural damage.(13)  Nutrition may offer a successful holistic therapeutic opportunity for cancer treatment by 1) providing targeted TCA cycle intermediates, 2) affecting whole body biochemistry and improving quality of life, 3) offering more than one mechanism of action or 4) acting as adjuvants for medical treatments. By focusing on the needs of the mitochondria to regulate energy production by oxidizing the fats,carbohydrates and proteins we consume, nutrients may recreate the therapeutic energy required to inhibit cancer proliferation. In many cancers the damage on normal cells seems irreversible, but there maybe a nutritional vista to advance cancer treatments by rescuing the mitochondrial function of cancer cells. 
      
Ketogenic Diet (KD). 
In 1921, Dr. R.M. Wilder at the Mayo Clinic initially proposed a diet in which most calories were derived from fat to mimic the biochemical effects of fasting.(23)  The now popular KD is to swap one's intake of carbohydrates with fat, as the main source of fuel and push the whole-body metabolism into ketosis, thereby avoid fueling the cancer cells with available glucose. Some research has suggested taking a broader view of the overall organism in which cancer growth and progression can be managed by following an individualized nutritional protocol, so the TCA cycle will shift the whole body from fermentable metabolites, mostly glucose and glutamine, to respiratory metabolites, primarily ketones. A pilot study has shown that it is safe even for late stage cancer patients.(14)
      
It has been proposed that the KD may be supportive to first line cancer treatments by two different mechanisms that both increase the oxidative stress inside cancer cells. The first is that lipid metabolism obliges the cells to generate energy from mitochondrial metabolism instead of anaerobic glycolysis as the glucose is not available for that process. This reduction in the availability of glucose, limits glycolysis, and controls the formation of pyruvate which can form the NADPH. Because dysfunctional mitochondria lead to ROS production, cancer cells will be selected relative to normal cells to experience oxidative stress, when glucose metabolism is restricted. Protein metabolism may not lead to the same levels of increased cancer cell oxidative stress as fat metabolism because energy production from proteins and amino acids may undergo gluconeogenesis to produce NADPH.(23)
      
In 2017, a systematic review was done on the KD in animal models. Of 13 articles included in the study, all articles indicated that KD had an inhibitory effect on tumor growth and nine articles expressed that KD could enhance survival time.(24) There are over 11 trials assessing ketogenic diets as an adjuvant cancer therapy. In the University of Würzburg, Germany, patients having failed traditional cancer therapy and who were able to continue the ketogenic diet therapy for over three months showed improvement with a stable physical condition, tumor shrinkage, or slowed growth.(23)  It is recommended to eat broccoli family vegetables when following the KD because they are low in carbohydrate value but there is an additional reason. A beneficial compound found in cruciferous vegetables called phenethyl isothiocyanate (PI) has been shown to exhibit a potent anticancer ability to disable the glutathione antioxidant system, which results in severe ROS accumulation in cancer cells. Consequently, the oxidative damage initiates death of the cancer cell.(23)  Ketogenic diets could be rapidly implemented to correct inherent oxidative metabolic differences between cancer cells and normal cells and to improve standard therapeutic outcomes by selectively enhancing oxidative stress and ROS in cancer cells.(23)  Studies of ketogenic diets in adults show a small percentage experiencing minor adverse effects including 1) an increase in low-density lipoprotein (LDL) cholesterol levels, shakiness, and uneasiness 2) kidney stones. While the potential exists for ketoacidosis, it has not occurred in study patients to date.(23)
      
Fermented Wheat Germ Extract (FWGE). 
Nobel laureate Dr. Albert Szent-Györgyi initially proposed that the use of FWGE as an anticancer agent could address cellular metabolism.(25)  Szent-Györgyi hypothesized that halting replication of cancer cells may be possible with high redox potential quinones naturally occurring in wheat germ.(25)  Results from more than two dozen in vitro and in vivo studies show that FWGE has strong anticancer, anti-metastatic, and immunomodulatory effects, including tumor-inhibiting effects in human breast adenocarcinoma cells equal to or better than tamoxifen,(26) exhibited significant antiproliferative effects against 12 human OVCA cell lines, and potentiated cisplatin-induced apoptosis.(27)
      
In the Townsend Letter, Aug/Sept 2016 edition, Dr. Greg Nigh details several potential mechanisms of action for FWGE's anticancer ability, as well as expands clinical research.(25) To review, early evidence shows that FWGE is a holistic and available natural therapeutic with an abundance of mechanisms. FWGE promotes apoptosis directly by increasing levels of Cytochrome C as well as indirectly by cleaving PARP, a family of proteins, which prevent cancer cells from repairing DNA. Second, FWGE influences cancer cell proliferation by inhibiting glycolysis. These metabolic modifications promote cell differentiation to normal cell phenotypes in some cells, whereas in others, promotes apoptosis. FWGE also inhibits the enzyme glucose-6-phosphate dehydrogenase, a metabolic enzyme essential for using glucose carbons to make ribose through the pentose phosphate pathway mentioned above. FWGE may virtually eliminate cancer cell proliferation through inhibition of both major and minor pathways of cancer cell synthesis of ribose. Lastly, FWGE rescues mitochondria, via apoptosis. 
      
The inhibitory effects on glycolysis from FWGE can probably be explained by looking at the effects that FWGE has on mitochondrial function. As with other metabolic therapies, FWGE induces cancer cells to engage in mitochondrial OXPHOS so they produce energy like a normal cell.(25)  Additionally, FWGE delays cell formation and growth associated with impaired glucose utilization, which leads to autophagy, a normal process whereby cancer cell components die in favor of healthy cell formation. During cellular stress the process of autophagy is significantly increased, a discovery that may provide an additional mechanism into the potential therapeutics of FWGE on cancer cell metabolism.(28)  FWGE may show even further therapeutic potential by decreasing lactic acid, increasing oxygen consumption rate, and increasing Cytochrome C disbursement from the cancer cell, leading to apoptosis. 
      
In addition to more than two dozen in vitro and in vivo studies showing that FWGE has anticancer, anti-metastatic, and immunomodulatory effects,(29) data from several human clinical studies indicate its role in improving quality of life as well as playing a further beneficial role in patients with various forms of cancer, such as:

  • Colorectal cancer – 82% reduction in tumor recurrences, a 67% reduction in metastasis and a 62% reduction in deaths as opposed to those who just received conventional therapy(30);

  • Oral cavity cancer – reduced the overall progression of the cancer by 85%(31);

  • Melanoma – 50% increase in overall survival as compared to the control for stage III patients(32);

  • Reducing treatment-associated febrile neutropenia in pediatric cancer patients(29);

  • Breast cancer - FWGE was shown to enhance efficacy of tamoxifen in estrogen receptor positive breast cancer(26);

  • Ovarian cancer - enhance cisplatin effectiveness in ovarian cancer cell lines(27); and

  • Non-Hodgkins Lymphoma – FWGE reduced tumor growth by 50% when used alone and when used in combination with RCHOP, tumor growth was inhibited 100%.(33)

Mitochondria have been an underestimated player in the initiation and progression of cancer, but it is generally accepted that mitochondria play an important role in cancer through macromolecular synthesis and energy production. As indicated in this article, first by acknowledging then identifying the important function that mitochondria play in cancer development and progression, we can discover holistic ways in which repairing mitochondrial function may be used for therapeutic benefit. Two strong nutrition therapies, the ketogenic diet and fermented wheat germ extract were highlighted.

Michael Karlfeldt, ND, PhD

Michael Karlfeldt, ND, PhD

Michael Karlfeldt, ND, PhD, runs a busy Integrative medicine center, The Karlfeldt Center, in Boise, Idaho, focusing on naturopathic oncology, autoimmune disorders, chronic infections, brain and neuroinflammatory conditions, anti-aging, and preventative medicine (www.TheKarlfeldtCenter.com). He was born in Sweden and has been in clinical practice since 1987. He was the host of the Dr. Michael Show, which aired 100 episodes discussing important health-related topics. Currently, he hosts the tv show True Health: Body, Mind, Spirit(www.truehealthshow.com), available on Amazon Prime, and the radio show HealthMade Radio where he connects with international leaders in the integrative health arena. He is also the founder of the health hub HealthMade (www.HealthMade.co), a trusted resource for health education, proven treatments and customized preventative and prescriptive programs for the modern health-minded consumer. Additionally, he is spearheading mobile texting technology for holistic practitioners to educate, connect and interact with their consumers in regard to their treatment plan, therapies available, nutritional supplements, and diet.

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