Co-supplementation of Omega-3 Fatty Acids and Vitamin D in Cancer Development – A Potential for Cancer Immunotherapy

By Hung-Hsi (Chelsea) Chen 

Taking supplements like vitamin D for bone health, and omega-3 fatty acids for eye health has become a popular trend in society. Current research has suggested that there is a potential premise to implement these supplements into cancer treatment and be used as a potential future immunotherapy? 

Omega-3 fatty acids include Docosahexaenoic acid (DHA) and ei-cosapentaenoic acids (EPA). They are mainly found in fishes like salmon, sardines, herring, tuna, lake trout, mackerel and  sturgeon. There is another type of fatty acid, called alpha-linolenic acid (ALA), which is commonly found in plant-based fat sources like nuts, seeds and avocados. Traditionally, Omega-3 fatty acids are found to lower the clotting of arteries and blood triglycerides, which results in lowering and individual’s risk of developing heart diseases. However, omega-3 is not synthesized by the body itself, therefore, it must be obtained from external sources like marine plants and animals. 

Currently, the molecular mechanisms for the inhibition of tumor growth by omega-3 fatty acids is still unknown and under investigation. A few suggested outcomes of omega-3 fatty acid supplementation in cancer prevention is via decreased cell proliferation, decreased angiogenesis and tumor endothelial cell adhesion and increased apoptosis (Manson et al., 2012). 

One of the hallmarks of cancer evading the immune system, is the target for omega-3 fatty acids. Tumor cells achieve this hallmark via a mechanism called immune tolerance (Ali et al. 2014). It is established by promoting immunosuppressive cytokines, like interleukin-10 (IL-10), and transforming growth factor-ß, which are secreted to inhibit dendritic cells and T-cells maturation and function, respectively (Ali et al. 2014). This is achieved by the catalysis of tryptophan to kynurenine by indoleamine 2,3-dioxygenase 1 (IDO) via the Akt/mTOR signaling pathway. Luckily, omega-3 fatty acids have been found to downregulate IDO expression, as well as phospho-protein kinase B (p-Akt), phospho-mammalian targets of rapamycin (p-mTOR) and kynurenine levels and subsequently an increase in the survival of T-cells. In another study done by Fiala showed supplementation of omega-3 fatty acids in a patient with metastatic prostate cancer had natural killer cells with higher cytotoxicity (Fiala, 2015).  

Vitamin D, a fat-soluble vitamin with a role in maintaining skeletal health, with its receptor present in most tissues, has a role in regulating calcium level in cells (Haidari et al., 2020). The binding of vitamin D to its receptor causes a series of signaling events that lead to inhibition of proliferation, angiogenesis, and apoptosis in tumor cells (Haidari et al., 2019). Low serum vitamin D levels and decreased vitamin D receptor expression in patients has been reported in various cancer types, and has been associated with increased cancer risks, especially towards a more aggressive tumor growth. Calcitriol, an active form of vitamin D, usually made in the kidney, has been found to inhibit cancer cell-proliferation and contains anti-inflammatory properties (Manson et al., 2011, MacLean et al., 2006). It exerts its anti-inflammatory effects via the inhibition of three pathways: the prostaglandin pathway, the p38/MAPK-mediated proinflammatory signaling pathway and lastly, the nuclear factor kappa B signaling pathway (Jeon et al., 2018). 

The two supplements have one thing in common, their anti-inflammatory properties, which is why they’re commonly used together to supplement chemotherapy. Inflammation is a common feature in most cancers as it supports tumor growth by producing an inflammatory tumor microenvironment (Haidari et al., 2020). The inflammatory microenvironment can promote the secretion of immunosuppressive cytokines to suppress the host’s immune system while supporting cell proliferation, angiogenesis, and metastasis (Haidari et al., 2020). Therefore, the co-supplementation of vitamin D and Omega-3 fatty acids can potentially be used as a form of tumor immunotherapy together with the traditional chemotherapy to improve therapy resistance and increase therapy efficacy, or it can be used on its on as prevention therapy. 

Although the idea of using supplements to combat cancer seems idealistic, we are still at the early stages of research. Most results reported were conducted in cell cultures and in laboratory conditions, meaning physiological conditions in patients will be different, causing inconsistency in results reported. Results were inconsistent when patients with breast, colorectal, pancreatic and prostate cancer were treated (Haidari et al., 2019). Individual cases are also different, which makes the dosage and absorption of omega-3 fatty acids and vitamin D supplements hard to standardise and measure. Furthermore, one limitation of using supplements as potential therapy is the issue with overdosing. Vitamin D overdose can lead to hypercalcemia, and omega-3 overdose can lead to hyperglycaemia and bleeding (Jeon et al., 2018). Consequently, further research has yet to be done for this to be a promising treatment in the future. 

References:

Ali, K., Soond, D.R., Piñeiro, R., Hagemann, T., Pearce, W., Lim, E.L., Bouabe, H., Scudamore, C.L., Hancox, T., Maecker, H., Friedman, L., Turner, M., Okkenhaug, K. & Vanhaesebroeck, B. 2014, “Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer”, Nature (London), vol. 510, no. 7505, pp. 407-411.

Fiala, M. 2015, “Curcumin and omega-3 fatty acids enhance NK cell-induced apoptosis of pancreatic cancer cells but curcumin inhibits interferon-γ production: benefits of omega-3 with curcumin against cancer”, Molecules (Basel, Switzerland), vol. 20, no. 2, pp. 3020-3026.

Haidari, F., Abiri, B., Iravani, M., Ahmadi-Angali, K. & Vafa, M. 2020, “Effects of Vitamin D and Omega-3 Fatty Acids Co-Supplementation on Inflammatory Factors and Tumor Marker CEA in Colorectal Cancer Patients Undergoing Chemotherapy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial”, Nutrition and cancer, vol. 72, no. 6, pp. 948-958.

Haidari, F., Abiri, B., Iravani, M., Seyed-Mohsen Razavi, Sarbakhsh, P., Kambiz Ahmadi-Angali & Vafa, M. 2019a, “Effects of vitamin D and omega-3 fatty acids co-supplementation on inflammatory biomarkers, tumor marker CEA, and nutritional status in patients with colorectal cancer: a study protocol for a double blind randomized controlled trial”, Trials, vol. 20, no. 1, pp. 1-7.

Haidari, F., Abiri, B., Iravani, M., Seyed-Mohsen Razavi, Sarbakhsh, P., Kambiz Ahmadi-Angali & Vafa, M. 2019b, “Effects of vitamin D and omega-3 fatty acids co-supplementation on inflammatory biomarkers, tumor marker CEA, and nutritional status in patients with colorectal cancer: a study protocol for a double blind randomized controlled trial”, Trials, vol. 20, no. 1, pp. 1-7.

Jeon, S. & Shin, E. 2018, “Exploring vitamin D metabolism and function in cancer”, Experimental & molecular medicine, vol. 50, no. 4, pp. 20-14.

MacLean, C.H., Newberry, S.J., Mojica, W.A., Khanna, P., Issa, A.M., Suttorp, M.J., Lim, Y., Traina, S.B., Hilton, L., Garland, R. & Morton, S.C. 2006, “Effects of Omega-3 Fatty Acids on Cancer Risk: A Systematic Review”, JAMA : the journal of the American Medical Association, vol. 295, no. 4, pp. 403-415.

Manson, J.E., Bassuk, S.S., Lee, I., Cook, N.R., Albert, M.A., Gordon, D., Zaharris, E., MacFadyen, J.G., Danielson, E., Lin, J., Zhang, S.M. & Buring, J.E. 2012, “The VITamin D and OmegA-3 TriaL (VITAL): Rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease”, Contemporary clinical trials, vol. 33, no. 1, pp. 159-171.

Manson, J.E., Mayne, S.T. & Clinton, S.K. 2011, “Vitamin D and Prevention of Cancer — Ready for Prime Time?”, The New England journal of medicine, vol. 364, no. 15, pp. 1385-1387.

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