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 cells^1-3. 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

1. Seyfried TN, Chinopoulos C. Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory? Metabolites. 2021 Aug 25;11(9):572. doi: 10.3390/metabo11090572. PMID: 34564387; PMCID: PMC8467939.

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.

3. Seyfried TN, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P. Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res. 2012 Jul;100(3):310-26. doi: 10.1016/j.eplepsyres.2011.06.017. Epub 2011 Aug 31. PMID: 21885251.

4. Holleran, A.L., Briscoe, D.A., Fiskum, G. et al. Glutamine metabolism in AS-30D hepatoma cells. Evidence for its conversion into lipids via reductive carboxylation. Mol Cell Biochem 152, 95–101 (1995). https://doi.org/10.1007/BF01076071

5. Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, Spasojevic I, Boros LG, Yang SH, Yan H. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem. 2014 Aug 22;289(34):23318-28. https://doi.org/10.1074/jbc.M114.575183. Epub 2014 Jul 1. PMID: 24986863; PMCID: PMC4156049. Supplemental materials: Cell-Metab_Table_S2-IDH1; Cell-Metab_Table_S3-IDH1

6. Gignac, A. M., (2016, February 26). Enteral Glutamine: The “Trojan Horse” of Naturopathic Oncology? [Conference Presentation]. 2016 OncANP Conference, Phoenix Arizona.

7. EAGLE H. Nutrition needs of mammalian cells in tissue culture. Science. 1955 Sep 16;122(3168):501-14. doi: 10.1126/science.122.3168.501. PMID: 13255879.

8. https://www.mskcc.org/news/beyond-sugar-what-cancer-cells-need-grow#:~:text=In%201955%2C%20an%20American%20doctor,other%20known%20requirements%20for%20life.

9. Leitner BP, Lee WD, Zhu W, Zhang X, Gaspar RC, Li Z, Rabinowitz JD, Perry RJ. Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis. PLoS One. 2023 Jul 6;18(7):e0286525. doi: 10.1371/journal.pone.0286525. PMID: 37410734; PMCID: PMC10325078.

10. Hoang G, Nguyen K, Le A. Metabolic Intersection of Cancer and Cardiovascular Diseases: Opportunities for Cancer Therapy. Adv Exp Med Biol. 2021;1311:249-263. doi: 10.1007/978-3-030-65768-0_18. PMID: 34014548; PMCID: PMC9703259.

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.

12. https://www.utmb.edu/surgery/divisions-and-sections/surgical-oncology/breast-melanoma-sarcoma/news/2022/11/07/klimberg-exceptional-woman-medal

13. Kuhn KS, Muscaritoli M, Wischmeyer P, Stehle P. Glutamine as indispensable nutrient in oncology: experimental and clinical evidence. Eur J Nutr. 2010 Jun;49(4):197-210. doi: 10.1007/s00394-009-0082-2. Epub 2009 Nov 21. PMID: 19936817.

14. Kaufmann Y, Todorova VK, Luo S, Klimberg VS. Glutamine affects glutathione recycling enzymes in a DMBA-induced breast cancer model. Nutr Cancer. 2008;60(4):518-25. doi: 10.1080/01635580801956501. PMID: 18584486.

15. Xue H, Sawyer MB, Field CJ, Dieleman LA, Murray D, Baracos VE. Bolus oral glutamine protects rats against CPT-11-induced diarrhea and differentially activates cytoprotective mechanisms in host intestine but not tumor. J Nutr. 2008 Apr;138(4):740-6. doi: 10.1093/jn/138.4.740. PMID: 18356329.

16. Kaufmann Y, Spring P, Klimberg VS. Oral glutamine prevents DMBA-induced mammary carcinogenesis via upregulation of glutathione production. Nutrition. 2008 May;24(5):462-9. doi: 10.1016/j.nut.2008.01.003. Epub 2008 Mar 7. PMID: 18313901.

17. Fahr MJ, Kornbluth J, Blossom S, Schaeffer R, Klimberg VS. Harry M. Vars Research Award. Glutamine enhances immunoregulation of tumor growth. JPEN J Parenter Enteral Nutr. 1994 Nov-Dec;18(6):471-6. doi: 10.1177/0148607194018006471. PMID: 7602720.

18. Klimberg VS, Kornbluth J, Cao Y, Dang A, Blossom S, Schaeffer RF. Glutamine suppresses PGE2 synthesis and breast cancer growth. J Surg Res. 1996 Jun;63(1):293-7. doi: 10.1006/jsre.1996.0263. PMID: 8661213.

19. Johnson AT, Kaufmann YC, Luo S, Todorova V, Klimberg VS. Effect of glutamine on glutathione, IGF-I, and TGF-beta 1. J Surg Res. 2003 May 15;111(2):222-8. doi: 10.1016/s0022-4804(03)00083-0. PMID: 12850466.

20. Kaufmann Y, Klimberg VS. Effect of glutamine on gut glutathione fractional release in the implanted tumor model. Nutr Cancer. 2007;59(2):199-206. doi: 10.1080/01635580701439632. PMID: 18001215.

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.

22. Kaufmann Y, Spring P, Klimberg VS. Oral glutamine prevents DMBA-induced mammary carcinogenesis via upregulation of glutathione production. Nutrition. 2008 May;24(5):462-9. doi: 10.1016/j.nut.2008.01.003. Epub 2008 Mar 7. PMID: 18313901.

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.

24. Matés JM, Campos-Sandoval JA, Santos-Jiménez JL, Márquez J. Dysregulation of glutaminase and glutamine synthetase in cancer. Cancer Lett. 2019 Dec 28;467:29-39. doi: 10.1016/j.canlet.2019.09.011. Epub 2019 Sep 28. PMID: 31574293.

25. Boros, L. G. (2005). Metabolic targeted therapy of cancer: current tracer technologies and future drug design strategies in the old metabolic network. Metabolomics: Official Journal of the Metabolomic Society, 1(1), 11–15. https://doi.org/10.1007/s11306-005-1103-7

26. Noé JE. L-glutamine use in the treatment and prevention of mucositis and cachexia: a naturopathic perspective. Integr Cancer Ther. 2009 Dec;8(4):409-15. doi: 10.1177/1534735409348865. Epub 2009 Nov 25. PMID: 19942578.

27. Boros LG, D’Agostino DP, Katz HE, Roth JP, Meuillet EJ, Somlyai G. Submolecular regulation of cell transformation by deuterium depleting water exchange reactions in the tricarboxylic acid substrate cycle. Med Hypotheses. 2016 Feb;87:69-74. doi: 10.1016/j.mehy.2015.11.016. Epub 2015 Nov 26. PMID: 26826644; PMCID: PMC4733494.

28. Townsend Letter, The Examiner of Alternative Medicine. 2023. https://www.townsendletter.com/1b-deuterium-in-water-and-cancer-risk/

Published November 4, 2023