Glutamine and Cancer

Have you ever wondered what role amino acids play in cell growth? Do you know how important amino acids are in the formation of cancer? Can we regulate amino acids to target cancer and improve treatment side effects? The key to answering these questions is the amino acid glutamine.

This amino acid is responsible for normal cell function and the immune system and is produced by the body naturally. Depleting levels due to surgery, injury or chemotherapy can lead to diseases related to a poor immune system and inflammation. Many cancer cells use glutamine as an energy source, reducing glutamine concentration. L-glutamine supplements are suggested to be beneficial to reduce side effects in a range of cancers and gastrointestinal-related issues.

What is Glutamine?

Glutamine is the most abundant amino acid found in the human body. An amino acid is an organic compound involving both an NH2 and COOH functional group. Glutamine comprises around 20%  of all plasma amino acids and is a building block for proteins and an important energy source.1 

Glutamine affects processes involved in cell function and cell proliferation (cell growth), such as protein synthesis and controlling the pH of cells. Under normal conditions, enough glutamine is produced naturally in the muscles and is broken down rapidly by metabolism. 

Glutamine is essential for the body’s lymphocytes and ‘T cells’, which are important white blood cells that fight off infections and diseases. The rate of glutamine consumption in immune cells is similar to that of glucose which explains amino acid’s importance. Glutamine is used by the T cells for cell proliferation and the production of cytokines. When the body is stressed from a disease or injury, the body needs more glutamine for cells to function normally, and as a result, can lead to a deficiency when glutamine is not produced quickly enough to replenish what is lost. 

Glutamine and Cancer: a Closer Look

Cancer is the uncontrolled growth and division of abnormal cells that form tumours. Glutamine dependence is a key trait of cancerous cells, and this is because glutamine is important for cancer cell survival and growth. 

  • Cancerous cells grow uncontrollably by ‘reprogramming’ cells to increase glutamine uptake to increase the speed of cell and tumour growth. 
  • The importance of glutamine in cancer has been studied and found that cancerous cells break glutamine down for energy and use it as a source of nitrogen to produce proteins.2

Glutamine can be metabolised into glutamate by mitochondrial glutaminase, which is an enzyme that operates within your cells. The rate of this enzyme’s metabolism can be increased by tumorigenic cells. Cancer must synthesise nitrogenous compounds such as nucleotides in order to grow, and a source of nitrogen is required for nucleotide synthesis. Glutamic acid is the most common source of nitrogen, and glutamic acid is a derivative of glutamine. This means the glutamine will be broken down into glutamic acid by the cancer cells and cause glutamine deprivation which has some important factors to consider:

  • Glutamine concentration in tumours is lower than in normal healthy tissue as more is used, and glutamine can be used as a target to regulate cancer growth.
  • Cancer research has found that glutamine starvation can decrease the growth of cancerous cells and has potential use as a treatment.

These findings show that glutamine is used by cancer cells to support tumour growth. This is because glutamine can be used in an energy production pathway called glutaminolysis that provides the cancer cells with enough energy and nutrients to divide quickly. Especially in prostate and human lymphoid tumours cancer cell lines, these cancers use more glutamine for energy, so the body no longer has enough to function normally.

Glutamine has been found to ease the side effects of radiation and chemotherapy cancer treatments and is used as a supplement. Chemotherapy, which is used to kill cancerous cells, can lead to immunosuppression. This is the increased susceptibility to disease due to the immune system working poorly as chemotherapy destroys immune cells, specifically  T-cells and can make patients ill.

Glutamine Deprivation / Starvation

Glutamine deprivation and starvation are used interchangeably in the literature but overall mean a decrease in glutamine concentration available in the cells. 

This decrease is often due to severe stress or injury to the body. In healthy cells, glutamine is necessary for cell proliferation and the development of tissues, so glutamine depletion can disrupt the progression of the cell cycle and the generation of antioxidants. Deprivation of antioxidants in the cells causes tissue damage and can lead to cell death as antioxidants prevent free radicals from attacking and destroying cells. 

But what causes a glutamine deficiency?

The most common causes are as follows: 

  • Severe stress
  • Shock 
  • Major infections (such as sepsis)
  • Cancer treatments (Chemotherapy and Radiotherapy)
  • Lack of L-glutamine in the diet
  • HIV and other immune disorders
  • Chronic intestinal diseases

Particularly, the main cancer treatments causing glutamine deficiency are radiotherapy and chemotherapy. Maintaining adequate glutamine levels is important as glutamine contributes primarily to normal intestinal function, and therefore glutamine deprivation can cause and aggravate some related intestinal diseases such as Crohn’s disease and diarrhoeal diseases, which further increase glutamine deficiency.

Glutamine Supplementation

Glutamine is most commonly taken as an oral supplement, and the duration of treatment and daily dose will depend on the disease or condition being treated. There is some research suggesting the health benefits of glutamine supplements to prevent or treat specific conditions. 

There are two types of glutamine: L-glutamine and D-glutamine. The most common form is L-glutamine, which is found in common foods such as:

  • Meats
  • Beans and lentils 
  • Tofu 
  • Green leafy vegetables. 

L-glutamine is important for cell and body functions and therefore is available as a supplement in this form most often. Oral glutamine supplements may be needed when experiencing a severe illness, injury or condition that caused the glutamine deficiency. This is because stress can increase cortisol release, which decreases the L-glutamine concentrations in the muscles over time.

Taking glutamine can improve symptoms and the quality of life of some cancer patients. One potential way glutamine can help is by fuelling lymphocytes and T-cells to increase the lymphocyte count and continue to fight off infection. This prevents the development of common chemotherapy side effects such as the gut and oral inflammation known as mucositis, which is very painful and caused by a poor immune response. 

Chemotherapy can cause other GI effects such as nausea, vomiting and malnutrition. Glutamine supplements can improve the effectiveness of chemotherapy by decreasing the ability of tumours to resist chemotherapy treatment. Glutamine can also help to maintain functional immune cells during chemotherapy and can even increase antioxidant levels that can improve the effects of chemotherapy and reduce tumour growth for some cancers.

There are other uses for glutamine supplementation in development. L-glutamine is used by sufferers of IBS or stress-related IBS, as glutamine is essential for intestinal function and boosts the immune cell activity of the intestine mucosal lining. However, there is no concrete evidence to support this.

On the other hand, there are some people that should avoid taking L-glutamine supplements: 

  • Kidney and liver disease sufferers are advised not to take L-glutamine 
  • Cancer patients also are advised not to take L-glutamine unless otherwise advised (for reducing chemotherapy side effects). 

This is because some cancer cells ‘feed’ on L-glutamine to survive and grow, which will be explained in the next section.

As always, please consult your GP before taking any glutamine supplements.

Glutamine Dependence & Addiction

Even though glutamine is not an essential amino acid, tumour cells continue to use glutamine in glutaminolysis to provide the energy for cell division and subsequent tumour growth. In most cancers, the tumour or cancer cells become ‘addicted’ to glutamine to maximise the speed of biosynthesis for cell proliferation and tumour growth. This means the tumours can no longer survive without an exogenous source of glutamine (from outside the body) and explains why glutamine starvation can be particularly effective at combatting cancer growth. 

Not only is glutamine required as an energy source for cancer, but is also involved in:

  • The uptake of highly essential amino acids that the cancer cells need to survive. 
  • Biochemical reactions: glutamine is the primary substance used by the mitochondria, a cell organelle that generates the chemical energy for biochemical reactions of the cell. 

These important uses of glutamine help us understand why cancers rely on this amino acid for their function and growth. As glutamine metabolism and dependence are so great, analysing glutamine metabolism could become an effective diagnostic imaging tool in cancers.

Purposefully starving the cancerous cells of glutamine could pose a potential therapeutic treatment for cancer, especially for patients with a current poor prognosis and those that are unresponsive to other cancer therapies. New cancer research is attempting to target specific cell lines of breast cancers, specifically triple-negative breast cancer, which are extremely sensitive to glutamine levels.3 

Human myeloma cell lines involved in multiple myeloma (MM) are also highly sensitive to glutamine, affecting the rate of MM cell growth. 

Some pharmacological progress has been made in devising glutamine metabolic inhibitors. These work by preventing enzymes from breaking glutamine down so its metabolites cannot be used as an energy source in cancer cells, thereby preventing glutamine starvation. This strategy, alongside glutamine-based imaging, could be implemented into cancer treatment plans in the future.

Conclusion

Glutamine is a key amino acid involved in maintaining healthy cells and tissues, and its metabolism affects many other processes linked with cell production. 

When these levels are depleted, cellular processes can go wrong and lead to intestinal diseases. 

As different glutamine concentrations have different effects on the body, manually changing glutamine levels in the body could be an important strategy for many diseases where glutamine is heavily involved. 

By increasing glutamine levels using supplements for patients undergoing chemotherapy:

  • Immunosuppression can be avoided 
  • Inflammatory side effects are reduced (mucositis)

L-glutamine is considered to be a safe supplement; however, before taking it, always consult your doctor and ensure you are taking the correct dosage.

Glutamine starvation in particularly glutamine-sensitive tumours can slow or prevent further tumour growth. Recent developments using glutamine as a biomarker in cancer imaging techniques could play an important role in cancer monitoring.

References

  1. Anderson PM, Lalla RV. Glutamine for amelioration of radiation and chemotherapy associated mucositis during cancer therapy. Nutrients [Internet]. 2020 Jun 4 [cited 2022 Aug 6];12(6):1675. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352314/
  2. Cluntun AA, Lukey MJ, Cerione RA, Locasale JW. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer [Internet]. 2017 Mar [cited 2022 Aug 6];3(3):169–80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383348/
  3. Gwangwa MV, Joubert AM, Visagie MH. Effects of glutamine deprivation on oxidative stress and cell survival in breast cell lines. Biological Research [Internet]. 2019 Mar 27 [cited 2022 Aug 6];52(1):15. Available from: https://doi.org/10.1186/s40659-019-0224-9
  4. Labow, B.I. and Wiley, W.S. Glutamine. World J. Surg, 24(12) [pdf] 2000 1503-1513. Available from: https://link.springer.com/content/pdf/10.1007/s002680010269.pdf [Accessed 22/02/22]
  5. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci [Internet]. 2010 Aug [cited 2022 Aug 6];35(8):427–33. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917518/
  6. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest [Internet]. 2013 Sep 3 [cited 2022 Aug 6];123(9):3678–84. Available from: https://www.jci.org/articles/view/69600

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Laura Preece

BSc Pharmaceutical Sciences and MRes Pharmacy and Pharmaceutical Sciences
I am a researcher and medical writer with a passion for pharmaceutics, disease and biological sciences. I am currently researching cellular and molecular biology, investigating the use of vitamin C as an adjunctive therapy for diabetes mellitus.

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