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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 therapy30;
- 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 patients32;
- Reducing treatment-associated febrile neutropenia in pediatric cancer patients29;
- Breast cancer - FWGE was shown to enhance efficacy of tamoxifen in estrogen receptor positive breast cancer26;
- Ovarian cancer - enhance cisplatin effectiveness in ovarian cancer cell lines27; 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.
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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.