Creatine Part 2 - role in cancer and as antioxidant

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What is an antioxidant?

Antioxidants are crucial for maintaining health because they protect the body from oxidative stress, which is caused by an imbalance between the production of reactive oxygen species and the body’s ability to neutralize them. Oxidative stress can lead to cell and tissue damage and is linked to various chronic diseases.

Health Benefits and Conditions:

  1. Cancer Prevention: Antioxidants help prevent cellular damage that can lead to cancer. They neutralize ROS, reducing DNA mutations and the risk of cancerous cell growth.

  2. Cardiovascular Health: They reduce the risk of heart disease by preventing the oxidation of LDL cholesterol, which is a key step in the development of atherosclerosis (plaque buildup in the arteries).

  3. Neurodegenerative Diseases: Antioxidants protect against neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease by reducing oxidative damage to brain cells.

  4. Aging and Skin Health: They slow the aging process and improve skin health by combating oxidative stress that leads to wrinkles and other signs of aging.

  5. Immune Function: Antioxidants enhance immune function by protecting immune cells from oxidative damage, thereby improving the body’s defense mechanisms against infections and illnesses.

Creatine as an antioxidant

There are multiple mechanisms by which creatine acts as an antioxidant 1 2.

  • Direct scavenging of reactive oyxgen species (ROS)
  • Mitochondrial membrane integrity
  • Mitochondrial ATP production
  • Reduction of lipid peroxidation
  • Modulation of antioxidant enzymes
  • Reduced inflammatory markers

Creatine’s role as an antioxidant may explain some of its benefit in preventing primary tumor formation, but more research needs to be done on this topic before the link and mechanisms are fully understood.

Creatine’s Role in Cancer and Metastasis

Along with the concern about contaminants introduced during manufacturing, the ambiguous role that creatine plays in the formation and spread of cancer is one of the more concerning possibilities about supplementation.

An unfortunate reality about cancer is that many primary tumors are present without symptoms, and only become apparent after they spread (metastasize). What role might creatine play in this process, considering its capacity as an antioxidant and its essential role in cell energetics?

There are several studies looking at this topic, and so far the weight of the evidence suggests that creatine may have an effect in preventing primary tumor formation, but may assist metastatic cells in surviving adverse conditions like hypoxic/ischemic events.

  • The NHANES study was analyzed for associations between creatine intake and cancer, finding that cancer-free individuals consumed more creatine than those with cancer, but the difference between groups was small (11.7 vs 10.6). It suggested a possible association but provided weak evidence 3. Note that this study only looked at dietary, not supplemental, creatine.

  • In orthotopic mouse models, dietary and de novo synthesized creatine promote metastasis of colorectal cancer and breast cancer 4.

  • In rats, creatine inhibits growth of multiple tumors 5.

  • Human colon adenocarcinoma tumor growth when xenografted into mice was inhibited by creatine supplementation 6.

  • Exogenous creatine uptake by prostate cancer cells drives progression 7.

  • Creatine enhances CD8 cytotoxic T cell activity 8, which are involved in killing cancer cells.

  • Creatine mediates crosstalk between fat cells and breast cancer cells 9.

Overall, it is apparent that creatine plays roles in cancer development and progression. The total extent and the specific scenarios where it is best taken or avoided are yet to be fully investigated, especially in humans. The findings in mice and rats may not apply.

Closing Thoughts

One final thought before closing would be to consider also the indirect effects of creatine supplementation in allowing greater work capacity and improved recovery, and the effects this might have in other areas. Some might find it easier to exercise when the recovery time is shorter, or more motivating to do so when the progress is slightly faster. And, we know that exercise itself is one of the best ways to prevent cancer directly, as well as the other indirect and long term effects of an active lifestyle like preventing metabolic syndrome, diabetes, obesity, improving mental health, and reducing inflammation.

There is little in life that comes without any tradeoffs, and so it likely goes with creatine. We are all looking for the perfect supplement to enhance our performance, make us live longer and healthier, without any risks. Creatine is well studied and seemingly safe for most people in the short term, but there are still risks and long term data is not available currently. It stands to reason that the mechanism by which creatine enhances our muscle cells and exercise performance could also apply to a cancer cell that is under its own unique kinds of stress.

Everybody will have to make their own choice about whether the benefits are worth the risks, with the advice of their physicians.

References

  1. Arazi, H., Eghbali, E. and Suzuki, K. (2021) ‘Creatine Supplementation, Physical Exercise and Oxidative Stress Markers: A Review of the Mechanisms and Effectiveness’, Nutrients, 13(3), p. 869. Available at: https://doi.org/10.3390/nu13030869. ↩︎

  2. Clarke, H. et al. (2020) ‘The Evolving Applications of Creatine Supplementation: Could Creatine Improve Vascular Health?’, Nutrients, 12(9), p. 2834. Available at: https://doi.org/10.3390/nu12092834. ↩︎

  3. Ostojic, S.M., Grasaas, E. and Cvejic, J. (2023) ‘Dietary creatine and cancer risk in the U.S. population: NHANES 2017–2020’, Journal of Functional Foods, 108, p. 105733. Available at: https://doi.org/10.1016/j.jff.2023.105733. ↩︎

  4. Zhang, L. et al. (2021) ‘Creatine promotes cancer metastasis through activation of Smad2/3’, Cell Metabolism, 33(6), pp. 1111-1123.e4. Available at: https://doi.org/10.1016/j.cmet.2021.03.009. ↩︎

  5. Miller, E.E., Evans, A.E. and Cohn, M. (1993) ‘Inhibition of rate of tumor growth by creatine and cyclocreatine.’, Proceedings of the National Academy of Sciences, 90(8), pp. 3304–3308. Available at: https://doi.org/10.1073/pnas.90.8.3304. ↩︎

  6. Kristensen, C.A. et al. (1999) ‘Creatine and cyclocreatine treatment of human colon adenocarcinoma xenografts: 31P and 1H magnetic resonance spectroscopic studies’, British Journal of Cancer, 79(2), pp. 278–285. Available at: https://doi.org/10.1038/sj.bjc.6690045. ↩︎

  7. Patel, R. et al. (2022) ‘Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression’, Cancer Research, 82(14), pp. 2565–2575. Available at: https://doi.org/10.1158/0008-5472.CAN-21-1301. ↩︎

  8. Di Biase, S. et al. (2019) ‘Creatine uptake regulates CD8 T cell antitumor immunity’, Journal of Experimental Medicine, 216(12), pp. 2869–2882. Available at: https://doi.org/10.1084/jem.20182044. ↩︎

  9. Maguire, O.A. et al. (2021) ‘Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer’, Cell Metabolism, 33(3), pp. 499-512.e6. Available at: https://doi.org/10.1016/j.cmet.2021.01.018. ↩︎