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Long-Chain n-3 Fatty Acids and Cancer Risk: What’s the Prognosis?

DSM Pharma Solutions
Long-Chain n-3 Fatty Acids and Cancer Risk: What’s the Prognosis?

Global cancer prevalence continues to grow, accounting for nearly 1 in 6 deaths. The emergence of multi-drug resistance has ushered in a new wave of scientific research. Can long-chain omega 3 fatty acids – eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in particular – impact cancer therapeutics in the future?  

Epidemiologic Trends

Despite recent advances in oncology research and development, global cancer incidence and prevalence continues to grow. By 2030, worldwide cancer cases are expected to increase by 50% (to 21 million), while cancer deaths will likely elevate by 60% (to 13 million).[1]  Meanwhile, the heterogeneity of various oncologic disease states and the complexities of their underlying pathologies often render conventional therapies ineffective.[2]  

The emergence of multiple drug-resistant phenotypes has fueled additional research into the role of long-chain omega 3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as potential therapeutic modulators in the treatment of breast and colorectal cancers.[3]  

Pharmacologic Mechanisms

Cell membranes represent a collection of complex and dynamic protein-lipid structures and microdomains that serve as functional platforms for interacting signaling lipids and proteins.[4] Tumor growth and proliferation often leads to altered membrane fluidity, permeability, and composition.  Thus, membrane lipid therapy encompasses the use of novel compounds designed to modify membrane lipid structures and microdomains as pharmaceutical disease-modifying agents by reversing the malfunction or altering the expression of disease-specific protein or lipid signal cascades.[5,6] 

Various in vitro and pre-clinical in vivo studies have chronicled the impact of  EPA and DHA on membrane structure/function and signaling, making them potentially attractive compounds for targeting neoplasms.[7] Mechanistically, EPA and DHA display inhibitory effects on tumor growth through the induction of cancer cell death via apoptosis, either alone or in combination with conventional anti-neoplastic therapies.[3]  Through preferentially modifying “lipid rafts” within tumor plasma membranes,  EPA and DHA have the potential to modulate the physicochemical properties of various receptors and cytokines essential to tumor signal transduction, growth and proliferation.[8] 

While the exact mechanisms have yet to be elucidated, future applications seem particularly promising, as observed in both pre-clinical and early-stage clinical settings:[3]

1. Increased sensitivity of tumor cells to conventional cytotoxic therapies (i.e. adjuvant therapy)

2. Selective toxicity against tumor cells with little systemic toxicity or effect on otherwise normal cells (i.e. favorable risk-benefit profile)      

Clinical Applications

Breast Cancer

A prospective, open-label phase 2 trial investigating the efficacy and safety of 1.8 g/day of DHA daily as an add-on to anthracycline therapy in patients presenting with metastatic breast cancer demonstrated significantly improved time to progression (TTP) and overall survival (OS). This proof-of-concept trial demonstrated the potential for DHA to convert malignant mammary tumors from resistant to chemo- or radiation therapy-sensitive in specific cohorts, namely those with high levels of DHA plasma lipid incorporation.[9]

A cohort sub-analysis suggested that current Omega 3 use (generally 300 mg EPA + DHA or greater) was associated with a 32% reduction in ductal breast cancer risk (HR 0.68, 95% CI: 0.50-0.92). Participants were female members of the VITamins And Lifestyle (VITAL) Cohort.[10]

Colorectal Cancer

Recent research has highlighted the importance of the gut-brain axis and nutrient-gene interactions in the development of colorectal cancer.[11] A systematic review and meta-analysis of 22 prospective cohort studies and 19 case-control studies demonstrated a 12% reduced risk of colorectal cancer with increased consumption of marine fatty acids (OR, 0.88; 95% CI, 0.80-0.95).[12] Additionally, individuals with high serum levels of EPA and DHA have exhibited a decreased risk of developing colorectal cancer.[13]

Dosing Considerations

To date, there is no one specific dose to utilize for individuals with cancer. Currently, no tolerable upper limit has been set for EPA and DHA supplementation, although the US Food and Drug Administration recognizes doses of up to 3 g/day as safe and the European Safety Union up to 5 g/day as safe [10].  Additional research is required to establish viable dose-response relationships across various disease states and clinical profiles.  

Looking Forward

While promising results have been produced to-date, there is a clear need for large-scale, prospective, randomized clinical trials evaluating the potential role of EPA and DHA supplementation – primarily in combination with chemo- and radio-therapeutic antineoplastic regimens – in the improvement of overall clinical outcomes. 

Consistent use of long-chain omega 3 formulations, with particular attention to EPA/DHA ratios, as well as dose-standardization, may help resolve

discrepancies across various trial designs and will ultimately serve to improve the quality and consistency of forthcoming trial results.[11]

For more information regarding the potential applications of EPA and DHA  in cancer treatment, watch our webinar, ‘Emerging roles of lipids in the modulation of cancer risk and therapy’. Presented by Professors Catherine Field and Robert Chapkin, this webinar  further explores molecular mechanisms by which omega 3s modulate cancer risk and therapy, while addressing both current and future applications of EPA and DHA and their respective roles as bioactive pharmaceutical compounds. 

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References:

[1] National Cancer Institute: Cancer Statistics, January 2018 (https://www.cancer.gov/about-cancer/understanding/statistics).

[2] G. Housman et al. Drug resistance in cancer: an overview. Cancers 2014;6(3):1765-1792. 

[3] D. Eliseo and F. Velotti. Omega-3 fatty acids and cancer cell cytotoxicity: implications for multi-targeted cancer therapy. J Clin Med 2016;5(2):15.

[4] P. Escriba et al. Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment. Prog Lipid Res 2015;59:38-53.

[5] Ibid.

[6] N. Fuentes et al. Emerging role of chemoprotective agents in the dynamic shaping of plasma membrane organization. Biochim Biophys Acta 2017;1859(9):1668-1678.

[7] K. Marshall and R. Winwood. EPA and DHA Omega 3s as a potential adjunct to chemotherapy in the treatment of cancer. Agro Food Ind Hi Tech 2017;28(2):19-22.

[8] R. Chapkin et al. Bioactive dietary long chain fatty acids: Emerging mechanisms of action. Br J Nutr 2008;100(6):1152-1157.

[9] P. Bougnoux et al. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer 2009;101:1978-1985.

[10] C. Fabian et al. Omega-3 fatty acids for breast cancer prevention and survivorship. Breast Cancer Res. 2015;17:62.

[11] T. Hou et al. Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology. Annu Rev Nutr 2016;36:543-70.

[12] S. Wu et al. Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. Am J Med 2012;125:551-9.

[13] M. Kojima et al. Serum levels of polyunsaturated fatty acids and risk of colorectal cancer: a prospective study. Am J Epidemiol 2005;161:462-71.