Petra Davelaar Dorfsman, ND
The importance of scientific arguments behind metabolic therapies for cancer with the understanding of underlying mechanisms to assess their efficacy, or lack thereof, cannot be overstated. There are many basic biochemical misunderstandings being promoted as facts, which are unfortunately based on incorrect theories and cherry-picking data. This causes confusion for patients, their families, and practitioners alike. The lack of understanding basic biochemistry wastes valuable time and resources aside from adding to the confusion that already exists about the cancer process, where clarity is key.
The theory I am referring to involves glutamine. It has been promulgated that glutamine plays a critical role in cancer metabolism, given its importance in the synthesis and energetics of biologically active molecules, especially that in cancer cells1-3. This does not match what we know about glutamine, which is the following:
- Glutamine, a conditionally essential amino acid, is present at low levels in tissues and the circulation compared to glycogenic (storage form) and glucogenic substrates (both are various forms of glucose reserves).
- Although glutamine is the most abundant free amino acid in the bloodstream, it is only 1/5th or much less than circulating glucose.
- Glutamine is neither maintained nor replenished through metabolic pathways when it is used up. Glutamine cannot substitute for the central role of glucose in metabolism, which is readily being replenished via gluconeogenesis and hepatic glucose production. In fact, there are no glutamine-replenishing or regulating metabolic pathways in any species we know of.
- There is no regulation of glutamine in human metabolism. In contrast, glucose is tightly regulated by insulin, glucagon, somatostatin and others.
- This makes glutamine a conditionally essential amino acid, as mentioned above. This means that the body cannot produce sufficient amounts of glutamine in instances of stress, or when demands step up due to uncontrolled cancer growth.
- Glutamine can only come from the diet which makes it non-critical for continuous and uncontrolled cell proliferation or tumor growth and has limited direct roles as an anabolic or anaplerotic carbon source during cancer proliferation.
- Glutamine has only 5 carbons, glucose has 6. This has far-reaching consequences in medical biochemistry, which I will not detail here.
- Glutamine has to go through reductive carboxylation (adding a carbon) in mitochondria by reversing the TCA cycle to become a 6-carbon molecule (citrate) to be an efficient energy source4.
- To summarize, glutamine is a low (or zero) concentration unreliable substrate without regulation in human metabolism. For these reasons, glutamine cannot participate in new molecule synthesis to serve tumor growth or its energetic requirements to any significance as detailed below.
The research literature doesn’t match the “glutamine fuels cancer” theory either. 13C tracer substrate-based metabolic profiling studies confirm that glutamine is a non-player in tumor progression. In this study,5 the researchers compared substrate uptake into tumor cell nucleic acid RNA from either 13C-labeled glucose or 13C-labeled glutamine under 21% oxygen (normoxia) or under 1% oxygen (hypoxia). See table below for results.
This means that glucose was taken up into tumor cell nucleic acids at a rate of 487 times greater than glutamine was in the 21% O2 environment. In a hypoxic environment, glucose was taken up 700 times greater as compared to glutamine, which practically dismisses glutamine as a significant source of nucleic acid carbons in rapidly dividing transformed cells.
If glutamine is a non-participant in tumor cell nucleic acid synthesis and turnover, which are hallmarks of progression, how did we arrive at this notion that glutamine fuels cancer progression? If this is the reality, it makes little sense to avoid glutamine containing foods or oral supplementation when depleted; or more drastically, use glutaminase [EC 3.5.1.2] or glutamine synthetase [EC 6.3.1.2] inhibitors?
The discussions, publications, and presentations6 concerning glutamine, all seem to point to Harry Eagle’s 1955 paper in science7. He performed an elegant set of experiments examining the differences in cell culture requirements for growth between single-cell lines of fibroblasts and human uterine carcinoma cells (HeLa). Here is where the cherry picking is apparent. Of the thirteen amino acids tested, eight besides glutamine were required in two or three times the quantity in the HeLa cell vs. the fibroblast, not just the requirement for glutamine increased. Additionally, ions essential for the survival and growth for both were Na+, K+, Mg++, Ca++, Cl-, and H2PO4 -. There were also minimum requirements for B-vitamins and neither cell line would grow despite all of the previous components without adding a small amount of serum protein. It goes without saying that both cell lines grew very well in a medium that just contained glucose as its carbon source. To conclude from this paper that “cancer cells need an excessive amount of glutamine”8 is a very far stretch. In fact, all dividing cells require some glutamine, not just cancer cells. Gastrointestinal cells and white blood cells turn over every one to five days, on average. Besides, the chemistry of the minimal essential medium (MEM) the authors used, was not shown.
It is important to distinguish between key anabolic substrates and processes before drawing conclusions about the sluggish control properties of flux of glutamine in support of transformed and rapidly proliferating tumor cells. There is also a big difference among net availability from the diet and circulation, new synthesis in organs, versus intracellular exchange via intermediary metabolism. Additionally, the metabolic state and energetic demands of tumor cells all have to be taken in consideration.
In July of 2023, a team from Princeton & Yale universities published new insights regarding the metabolic fate of glutamine in the hypometabolic (hypoxic) state in sepsis9. They analyzed tissue-specific, organ, and systemic metabolomics and found significant upregulation of isotopically labeled glutamine’s contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis in the liver. This confirms that targeting glutamine in a hypometabolic state is reductionist, failing to see the body as a whole organism, especially in the light of glucose homeostasis, cachexia, and cancer.
There is a large body of evidence that supports the beneficial role of glutamine in the cancer state and especially in cardiometabolic disease,10 and more recently in severe COVID-19.11 A great number of papers on glutamine in cancer were published in the late 1990s and early 2000s. The senior author on many (29) of those is surgical oncologist Suzanne Klimberg.12 A 2009 review paper highlights many of these and they provide a great overview table.13 Most significantly, the data shows a paradoxical effect of glutamine on key glutathione recycling enzymes, protecting the host’s healthy cells and down regulating these enzymes in tumor cells.14,15 Other findings include an increase in natural killer (NK) cell activity, reduced tumorigenesis, lower IGF-1and TGF-ß1 levels, increases in glutathione concentration in blood, breast tissue, gut mucosa while lower PGE2 synthesis.16-20 In 2020, metabolomics analysis of melanoma21 revealed that although dietary glutamine increases glutamine concentration in tumors, it does not increase biosynthetic intermediates required for cell proliferation. In fact, they provide evidence that glutamine supplementation “can serve as a potential dietary intervention to block melanoma tumor growth” by downregulating oncogenic pathways.
There is a caveat; most of these findings are based on rodent studies who were fed purified research diets (lacking certain elements) in groups to balance intake. They were subjected to alternate light cycles,22 in some cases, which I suspect was artificial light. We can hypothesize that the benefits could have been greater if the animals were fed differently and if they were kept in natural light environments. Human trials have been shown difficult to execute, for obvious reasons.23
As far as glutaminase and glutamine synthetase specific inhibitors are concerned, the data is underwhelming if not disappointing.24 It’s been known for decades that targeting a single metabolic pathway, or signaling protein or gene for that matter, will not inhibit cancer progression.25 Pathways can and do divert.
In conclusion, glutamine-containing food items are not to be feared. In fact, clinical indications for using supplementation may include maintaining the integrity of the gut lining as well as supporting glutathione levels, low lymphocyte counts and decreased NK cell activity, for inhibiting tumor growth, and in mucositis, stomatitis, and cachexia.26
The data speaks against glutamine fueling cancer growth or cellular transformation. Moving forward, it is my wish that we focus on the real contributors. Submolecular dysregulation due to deuterium accumulation causes cancer initiation and can fuel progression.27,28 This is the science of deutenomics. Once one incorporates the fundamental principles of deuterium regulation in the human body to the approach of chronic diseases, the fog will lift and the mechanisms will become clear. Establishing deutenomics as the foundation for research; the practice of medicine; disease prevention; targeted treatments; sound health policy; as a whole, will create solutions for the chronic disease epidemic and cancer worldwide.
References
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2. Seyfried TN, Arismendi-Morillo G, Mukherjee P, Chinopoulos C. On the Origin of ATP Synthesis in Cancer. iScience. 2020 Nov 2;23(11):101761. doi: 10.1016/j.isci.2020.101761. PMID: 33251492; PMCID: PMC7677709.
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11. Matsuyama T, Yoshinaga SK, Shibue K, Mak TW. Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19. Cell Death Differ. 2021 Dec;28(12):3199-3213. doi: 10.1038/s41418-021-00892-y. Epub 2021 Oct 18. PMID: 34663907; PMCID: PMC8522258.
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21. Ishak Gabra MB, Yang Y, Li H, Senapati P, Hanse EA, Lowman XH, Tran TQ, Zhang L, Doan LT, Xu X, Schones DE, Fruman DA, Kong M. Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth. Nat Commun. 2020 Jul 3;11(1):3326. doi: 10.1038/s41467-020-17181-w. PMID: 32620791; PMCID: PMC7335172.
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23. Pascoe J, Jackson A, Gaskell C, Gaunt C, Thompson J, Billingham L, Steven N. Beta-hydroxy beta-methylbutyrate/arginine/glutamine (HMB/Arg/Gln) supplementation to improve the management of cachexia in patients with advanced lung cancer: an open-label, multicentre, randomised, controlled phase II trial (NOURISH). BMC Cancer. 2021 Jul 12;21(1):800. doi: 10.1186/s12885-021-08519-8. PMID: 34247580; PMCID: PMC8274132.
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Published November 4, 2023
About the Author
Petra Davelaar Dorfsman, is a naturopathic doctor who specializes in Deutenomics.
Deutenomics is a new area in science that explores how water moves inside our body. Essentially humans are electric Beings of water fueled by light. Our food carries hydrogen for metabolic water synthesis and determines the quantity and quality of the water we constantly produce, and therefore the efficiency of our metabolism, our general state of health, our overarching state of mind, our continuous energy supply, our much-needed endurance and performance abilities, the need for sleep, our resiliency, intimacy, it essentially determines everything and beyond.
To learn more about deutenomics, visit https://drpetrad.com/Deutenomics
She completed her naturopathic medical training at Bastyr University and is certified in functional medicine and nutrition. She is an invited reviewer for several scientific periodicals, including Scientific Reports, a Nature group research journal, as well as Medical Oncology, a Springer journal