The promising action of DHA as a tumour killer

By Lucia Friscioni

Essential fats, such as dietary omega-3 fatty acids (n-3 FAs), have considerable health benefits. These alleged “good FAs” are much pursued by the nutritiously conscious. However, the human body cannot produce these fats naturally and is reliant on an appropriate diet. Specifically, docosahexaenoic acid (DHA) is a well-studied omega-3, essential for brain development, vision and regulation of inflammatory processes. Interestingly, it is known to exhibit anti-cancerous properties such as reducing tumour growth. Researchers at the University of Louvain (UCLouvain) have assessed the role of FAs and, for the first time, have identified how DHA exerts its anti-cancer effects. The findings of this study could lead to a major breakthrough in cancer therapeutics, further highlighting the importance of keeping a good diet.

DHA is one of the most important n-3 polyunsaturated fats (PUFAs) found in most seafood and certain types of algae. It is crucial during pregnancy and the beginning of infancy as it has roles in brain tissue growth and function.1 This FA is an integral component of cell membranes throughout the body. Its main function is allowing membrane fluidity to aid communication between cells and their receptors. It is mainly found in the grey matter of the frontal lobes of the brain which is responsible for processing information, memory and emotions. These FAs are also important in regulating blood clotting and vasoconstriction of blood vessels – so are closely associated with the prevention of heart disease, stroke and inflammation. DHA-deficiency has been associated with visual/learning disabilities and certain behavioural disorders such as ADHD or aggressiveness.

Tumour acidosis results from the high metabolic demand that is characteristic of cancer cells. These cells rapidly outgrow their blood supply and need to adapt to their environment by changing their metabolic requirements. One of these adaptations involves bioenergetics. Cancer cells can rapidly produce energy, which sustains their growth. However, the increase in energy production is accompanied by an accumulation of lactate and H+ ions in their tumour microenvironment. This creates an acidic environment that contributes to disease progression via the stimulation of FAs.2

Previous studies have reported that exogenous uptake of FAs supports the accumulation of triglycerides into lipid droplets (LDs), fulfilling the cellular needs of the tumour.3 Storing FAs into these LDs protects them from oxidation. Research has mainly focused on how blockage of FAs can induce tumour cell death2,4, based on the idea that depriving the tumour of major nutrients limits cancer progression. Dierge et al. (2021), however, examined the anti-tumour effects resulting from excessive FA uptake and found that n-3 and n-6 PUFAs selectively induced cell death via ferroptosis in acidic tumours.5 Ferroptosis is a type of non-apoptotic iron-dependent programmed cell death characterised by lipid peroxidation, triggering oxidative cell death.6

Storage of excess FAs into triglycerides was suggested as the mechanism for inducing peroxidation. This increased cytotoxic effect in acidic cells correlated with long-chain (LC) n-3 and n-6 PUFA peroxidation and consecutive ferroptosis. Therefore, the anti-tumour effect is a result of ferroptosis, triggered by acidic cancer cells failing to cope with increased FAs. In other words, the increased presence of DHA overwhelms tumour cells, oxidising them and killing them. In vivo experiments were also carried out to further support these observations. Tumour growth was significantly decreased in mice following the DHA-rich diet compared to mice on a conventional diet. With the concomitant weight loss recorded, it was concluded DHA delays tumour development.6,7 More importantly, both in vitro- and in vivo-observed anti-cancer effects were amplified when treated with a lipid metabolism inhibitor (diacylglycerol acetyltransferase inhibitor, DGATi) which prevents PUFAs from accumulating in LDs.

Overall, these findings highlight the importance of pharmacological approaches aimed at increasing intracellular PUFAs rather than blocking their uptake. The lack of data on n-3-related cancer incidence, LC-PUFA-mediated ferroptosis and from randomised trials causes uncertainty around the effects of dietary LC-PUFAs supplements.8 However, recent findings do suggest they might be more suited for specific subsets of chemo-resistant or highly invasive tumour cells. Moreover, other studies documented the association of higher intake of marine n-3 PUFAs with lower colorectal cancer deaths and longer disease-free survival,9 and also found that cancer cells metastasising through lymph resist ferroptosis by decreasing oxidative stress.10 Altogether, these observations suggest PUFAs, especially marine FAs such as DHA, directly participate in cancer proliferation in acidic, drug-resistant and pro-invasive cells, even if they may not exert global anti-tumour effects.

DHA represents a different approach to targeting cancer, exploiting the altered metabolism distinctive of tumour cells. The key is focusing on the vulnerability of tumour cells (such as the increase of LC-PUFAs) instead of considering their lipid metabolism as a target to inhibit. It is worth noting that the aforementioned role of n-3 PUFAs has been observed during tumour acidosis in an acidic environment. This specificity towards prompting ferroptosis in tumour cells (acidic pH) compared to other body tissues (neutral pH) supports the safe and selective use of dietary LC-PUFA supplements. There is enough evidence to indicate DHA is a potential new anti-cancer agent or tumour killer, thus paving the way for new strategies and treatment combinations aimed at eradicating cancer.11

References:

  1. Corbet C., Bastien E., Santiago de Jesus J.P., et al. (2020) TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nature Communications. 11(1): 454. doi: 10.1038/s41467-019-14262-3
  2. Corbet C., Feron O. (2017) Tumour acidosis: from the passenger to the driver’s seat. Nature Reviews Cancer. 2017; 17: 577-593. doi: 10.1038/nrc.2017.77
  3. Butler LM, Perone Y, Dehairs J, (2020) et al. Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention. Advanced Drug Delivery Reviews. 159: 245-293
  4. Eilander A., Hundsheid D.C., Osendarp S.J., et al. (2007) Effects of n-3 long chain polyunsaturated fatty acid supplementation on visual and cognitive development throughout childhood: a review of human studies. Prostaglandins Leukotrienes Essential Fatty Acids. 76 (4): 189-203. doi: 10.1016/j.plefa.2007.01.003
  5. Dierge E., Debock E., Guilbaud C., et al. (2021) Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metabolism. doi: 10.1016/j.cmet.2021.05.016
  6. Li J., Cao F., Yin H., et al. (2020) Ferroptosis: past, present and future. Cell Death and Disease. 2020; 11, 88. doi: 10.1038/nrc.2017.77
  7. Dierge E., Larondelle Y., Feron O. (2020) Cancer diets for cancer patients: Lessons from mouse studies and new insights from the study of fatty acid metabolism in tumors. Biochimie 178: 56-68. doi: 10.1016/j.biochi.2020.08.020
  8. Hanson S., Thorpe G., Winstanley L., et al. (2020) Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials. British Journal of Cancer. 122(8): 1260-1270. doi: 10.1038/s41416-020-0761-6
  9. Van Blarigan E.L., Fuchs C.S., Niedzwiecki D., et al. (2018) Marine ω-3 Polyunsaturated Fatty Acid and Fish Intake after Colon Cancer Diagnosis and Survival. Cancer Epidemiology Biomarkers. 27(4): 438-445. doi: 10.1158/1055-9965.EPI-17-0689
  10. Ubellacker J.M., Tasdogan A., Ramesh V., et al. (2020) Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 585 (7823): 113-118. doi: 10.1038/s41586-020-2623-z
  11. Serini S., Vasconcelos R.O., Fasano E., et al. (2016) How plausible is the use of dietary n-3 PUFA in the adjuvant therapy of cancer? Nutrition Research Reviews. 29(1): 102-125. doi:10.1017/S0954422416000044

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