Eicosapentaenoic Acid

What Is It?

Eicosapentaenoic acid (EPA) is one of the major dietary omega-3 fatty acids commonly found in fish and fish oils$^{1}$. It is metabolically derived from alpha-linolenic acid (ALA); the health benefits attributed to ALA are physiologically mediated by EPA and another ALA-derived omega-3 fatty acid, called docosahexaenoic acid (DHA). EPA has been investigated in in vitro (cell lines), in vivo (animal models), and clinical studies for its anti-inflammatory$^{2}$, antithrombic$^{2}$ (reduces the risk of harmful blood clots), and antitumour properties$^{3}$, and it is considered to be highly beneficial for our cardiovascular, metabolic, and immunologic health. Furthermore, numerous clinical trials have demonstrated the efficacy of EPA in cancer prevention and treatment, as well as its advantage as a dietary intervention for patients undergoing chemotherapy as it improves treatment-related outcomes like nutritional status$^{4}$, bone resorption$^{5}$, and weight loss$^{6}$. With regards to cancer-fighting activity, EPA has been shown to modulate cancer cell gene expression, inhibit cell cycle progression, and influence cellular pathways$^{7}$, supporting its role as an important anticancer nutrient.

What Are Its Other Names?

Eicosapentaenoic acid is most commonly referred to as EPA, but it may also be referred to as timnodonic acid, icosapentaenoic acid, and C20:5. Its chemical nomenclature is (5E,8E,11E,14E,17E)-icosa-5,8,11,14,17-pentaenoic acid$^{8}$. Studies on omega-3 fatty acids are often referring to EPA, in addition to its precursor ALA and another omega-3 fatty acid called docosahexaenoic acid (DHA).

What Foods Have It?

EPA is typically sourced from fish oil, fish, krill oils, or beef$^{1,9}$. Wild fish is considered a better source of omega-3 fatty acids like EPA, since marine fish feed on plankton rich in omega-3 fatty acids$^{9}$, whereas farmed fish tend to feed on cereals rich in omega-6 fatty acids, which may counteract the health benefits of EPA$^{1}$. Note that a plant-based diet is entirely devoid of EPA—it may be worthwhile to consume fish oils or fish to reap the benefits of this nutrient. The data below has been extracted from the USDA National Nutrient Database for Standard Reference for the EPA content of various foods, arranged in order of EPA concentration$^{9}$.

In the body, ALA can be converted to EPA by the liver, but the conversion rate is only around 8-12%, making it important to directly consume EPA from the sources listed above$^{10}$. Further, EPA from marine sources exhibits better bioactivity than non-marine sources, due to its particular chemical form (as a glycerophospholipid in marine sources, as opposed to its triacylglycerol and ethyl ester forms in non-marine sources)$^{11}$.

What Are Its Main Benefits?

Cancer Prevention & Treatment

Epidemiological and clinical evidence has supported EPA’s role in preventing breast, prostate, lung, and colon cancers, as well as in improving other outcomes of cancer treatment such as weight loss, nutritional status, and bone resorption. Cancer Prevention

Observational studies on Japanese and Swedish men have noted that frequent consumption of fresh fish reduced the risk of developing lung cancer in a dose-dependent manner, regardless of cooking method$^{12}$, as well as of prostate cancer by inhibiting the formation of pro-inflammatory signaling molecules called eicosanoids. Swedish men who ate no fish had double or triple the risk of developing prostate cancer than those who ate moderate or high amounts of fish$^{13}$. Furthermore, numerous clinical trials conducted on healthy volunteers (consuming 4.4 g EPA daily for 2-4 weeks$^{14,15}$), patients who’ve undergone treatment (4 g EPA daily for 6 months$^{16}$), or individuals at risk of colorectal cancer (2.5-4.1 g for 2 weeks to 6 months$^{17,18}$), showed that their respective EPA treatments were effective at inhibiting abnormal colon cell proliferation$^{18,19}$. Note, however, that this effect was not seen in healthy volunteers on a high-fat diet consisting of a low omega-3 to omega-6 ratio$^{15}$, indicating the importance of a diet low in omega-6 fatty acids to reap the benefits of omega-3 fatty acids. In conjunction with DHA, EPA has been reported to decrease the incidence of breast cancer in a dose-dependent manner$^{20}$, and one case-control study found an association between dietary exposure to EPA and a decreased risk of breast fibroadenomas in Chinese women$^{21}$. Cancer Treatment

With regards to cancer treatment, EPA has been shown to improve the efficacy and tolerability of traditional chemotherapy drugs. When used as a supplement for head and neck cancer patients undergoing radiotherapy, EPA improved their quality of life by helping patients better maintain their weight and better tolerate their treatment$^{22}$. Another clinical trial was conducted on 33 patients with inoperable non-small cell lung cancer, investigating the impact of 4 capsules of 510 mg EPA and 340 mg DHA for 66 days$^{23}$. The researchers found a significant improvement in body weight as well as antioxidant and anti-inflammatory status, wherein treatment groups had markedly reduced levels of C-reactive protein and IL-6, two major pro-inflammatory molecules$^{23}$. Furthermore, studies on patients with pancreatic$^{24}$ and lung cancer$^{25}$ found that EPA was highly effective at preventing or reducing loss of lean mass during chemotherapy, especially in patients at risk of cancer cachexia (weight loss$^{26}$). Lastly, a pilot study on 38 postmenopausal breast cancer survivors investigated a treatment of 4 g of EPA and DHA daily for 3 months and found that it could reduce bone resorption (bone loss), although the researchers acknowledged that longer-term studies are needed$^{5}$. Protecting Cardiovascular Health

EPA is most widely known for its critical importance in cardiovascular health, namely reducing the risk of heart attacks, ventricular arrhythmias (abnormal heart rhythms), and dyslipidemia$^{27}$. Observational studies and clinical trials have noted an inverse relationship between diets high in marine-derived fats (such as the Mediterranean and Eskimo diets$^{10}$) and major adverse cardiovascular outcomes$^{28}$. The JELIS study established that 1.8 g of EPA daily in patients with high cholesterol levels (hypercholesterolemia) had reduced the incidence of cardiovascular events, but not arrhythmias$^{29}$. In individuals with blood triglyceride levels above 150 mg/dL, taking 3.4-4 g/day of EPA and/or DHA was shown to reduce these levels by around 29%$^{30}$. Further, in both individuals with normal blood pressure and high blood pressure (hypertension), placebo-controlled trials demonstrated that EPA reduces blood pressure. In individuals with metabolic syndrome, EPA administration alongside DHA for 6 months led to reduced serum levels of LDL-cholesterol and triglycerides$^{31}$. Interestingly, the recent Alpha-Omega trial found that in diabetic patients who have suffered a myocardial infarction, low-dose supplementation of EPA was linked to a reduced incidence of ventricular arrhythmia-related events and future fatal heart attacks$^{32}$. Lastly, women who consumed fish more than once a week had half the age-adjusted risk of having a stroke compared to women who consumed no fish, demonstrating the great potential of EPA (alongside DHA) to protect cardiovascular health$^{33}$. However, it is essential to note that many medications used to treat cardiovascular diseases, such as anti-coagulants, blood thinners, and blood pressure medications, are known to react with fish oil supplements and cause dangerous side effects. Thus, you should always consult a healthcare provider before changing your diet or taking new supplements$^{53}$. Countering Inflammation and Autoimmune Disorders

Central to many of EPA’s biological activities is its ability to suppress inflammation, which is a significant component of several diseases. The global rise in the prevalence of inflammatory disorders, linked to increased consumption of pro-inflammatory omega-6 fatty acids$^{2}$, makes it worthwhile to explore beneficial dietary interventions, such as EPA. In patients with inflammatory bowel disease$^{34}$ (IBD) and either rheumatoid arthritis (RA) or osteoarthritis$^{35}$, krill oil supplementation (high in EPA) led to significant clinical reductions in intestinal inflammation and arthritic symptoms, respectively. In fact, EPA and DHA are both used as adjuvant immunosuppressants in the clinic to treat RA or IBD, as they are primarily inflammatory diseases$^{36}$. Cell studies have consistently demonstrated that omega-3 fatty acids like EPA act as precursors to other anti-inflammatory molecules like resolvins$^{2}$ and block the production of pro-inflammatory molecules called cytokines by binding to the enzymes that catalyze their production$^{37}$. Overall, EPA contributes to an ameliorated inflammatory profile, which could be beneficial for a multitude of health conditions, including cancer risk. Promoting Neurological Development and Alleviating Neurological Disorders

Intake of omega-3 fatty acids like EPA has been associated with improved symptoms of depression and overall cognitive health. In patients with Parkinson’s Disease, treatment with 800 mg DHA and 290 mg EPA daily for 6 months vastly improved their depression symptoms compared to the placebo group$^{38}$, and EPA and DHA seem to work synergistically to alleviate depression$^{9}$. Whether EPA or DHA is more effective than the other is unclear, but the combination of both has been demonstrated to be beneficial for mental health outcomes. Studies have also established a link between low intake of omega-3 fatty acids and a higher risk of cognitive decline, supporting EPA’s role in protecting cognitive health$^{39}$. A 2-year study on cognitively healthy elders found that daily consumption of 200 mg EPA and 500 mg DHA led to no progressive decline in cognitive function$^{40}$, and higher plasma levels of EPA has been associated with less atrophy of brain gray matter$^{2}$, a notable risk factor for cognitive decline.

What Are Its Main Drawbacks?

N.B: the drawbacks associated with EPA are similar to those associated with DHA, so this section can also be found in the review about DHA as an anticancer nutrient.

Dietary intake from animal sources is incredibly important, since de novo synthesis (i.e. from your body producing it) is inefficient$^{2}$, and plant-based foods do not contain EPA$^{9}$. Further, the studies on its health benefits have some inconsistent data due to the influence of genetics, the baseline plasma ratio of omega-6 fatty acids to omega-3 fatty acids, and the particular source of EPA$^{3}$. Lastly, absolute intake of omega-3 fatty acids seems not to be as important as the omega-6 to omega-3 ratio in the diet; thus, intake of EPA must be done alongside a diet low in omega-6 fatty acids (typically found in refined vegetable oils and foods cooked in vegetable oils$^{10}$).

EPA and fish oil supplements may also have harmful interactions with several common medications used to treat cardiovascular disease (such as blood thinners, anti-coagulants, and blood pressure medications), and should be avoided in some individuals taking these medications$^{53}$.

How Does It Work?

The anticancer properties of EPA have generally been elucidated via cell line and animal model studies and fall under three general categories: increased cancer cell apoptosis (programmed cell death), blocking certain enzymes involved in inflammation, and modulating certain gene expression pathways.

What Are Its Mechanisms of Action?

1. Inducing Cancer Cell Apoptosis: EPA has been shown, in cell lines, to trigger the activation of multiple processes involved in the programmed cell death, or apoptosis, of cancer cells. In mouse tumor cells, EPA was found to upregulate the expression of a protein called Bax and downregulate the expression of a protein called Bcl-2, which are pro-apoptotic and anti-apoptotic, respectively$^{41}$. This was accompanied by the induced release of a molecule called cytochrome c from mitochondria, leading to the activation of caspases-3 and -9, which are key mediators of apoptosis and important players in halting cancer progression$^{41}$. Further, EPA contributes to non-enzymatic lipid peroxidation in cancer cells, which triggers cancer cell apoptosis$^{11}$. Overall, by enhancing intracellular reactive oxygen species, activating caspase proteins, disrupting the membrane potential of mitochondria$^{7}$, and upregulating the Hippo pathway involved in apoptosis and restraining cell proliferation$^{42}$, EPA encourages cancer cell apoptosis$^{43}$, leading to reduced cancer growth and reduced overall progression.
2. Inhibiting Cancer Cell Cycle Progression and Viability: EPA has been shown to inhibit the cell viability of various cancer cells in vitro and in mouse models. When added to SW480 human colon cancer cells, 0-20 µg/mL of EPA for 48-120 hours (in conjunction with DHA) led to markedly reduced cell viability, with the effect most pronounced at 72 hours$^{44}$. Furthermore, EPA downregulates a particular signaling pathway known as the Wnt/β-catenin signaling pathway, which normally upregulates the expression of proteins involved in cell cycle progression, called cyclins. EPA inhibits this pathway and subsequently inhibits cancer cell proliferation and tumorigenesis$^{45}$. Similarly, EPA regulates the Hippo pathway, which is important in inhibiting cell growth and proliferation, and is often dysregulated in cancer. Through this pathway, EPA functions to inhibit cell proliferation and activate apoptosis$^{42}$. Lastly, it has been suggested that by regulating calcium channels to activate a particular protein called eIF2α kinase, EPA contributes to reduced expression of oncogenes (cancer-driving genes) and G1 cyclins, which signal the promotion of the cell cycle for cell division$^{9}$.
3. Blocking Cancer-Promoting Inflammatory Pathways: Perhaps the most prominent feature of EPA is its ability to compete with arachidonic acid (an omega-6-derived pro-inflammatory molecule) for two enzymes, COX-2 and 5-LOX. When EPA acts as an alternative substrate (binding molecule) for COX-2, it causes the enzyme to produce the anti-inflammatory PGE-3 molecule (which encourages apoptosis and reduces inflammation), instead of producing the pro-inflammatory and pro-tumorigenic PGE-2 molecule$^{46}$. In human colorectal cancer cells, the production of PGE-3 from EPA treatment was associated with reduced adenoma number and size$^{46}$, and in a mouse model of leukemia, apoptosis was triggered in leukemia stem cells upon EPA treatment$^{47}$. Furthermore, resolvin E is a compound derived from EPA metabolism in the body and is known to be important in treating inflammation-driven diseases, such as cancer$^{2}$. With regards to the receptors involved, EPA can bind to peroxisome proliferator-activated receptors-alpha and -gamma (PPAR), which bind to and form a heterodimer with the retinoid X receptor (RXR). This heterodimer translocates to the nucleus, where it binds to particular DNA regions called peroxisome-proliferator responsive elements (PPRE) and inhibits the expression of NF-kB and therefore pro-inflammatory genes, contributing to reduced inflammation and reduced potential cancer progression$^{48}$.

What Are Typical Doses and Durations?

Generally, the Food and Agricultural Organization (FAO) and World Health Organization (WHO) recommend a combined daily intake of EPA and DHA of at least 250 mg, which should be raised to 1-1.5 g for individuals with cardiovascular disease risk factors or high blood triglyceride levels$^{2}$. Consuming 2-3 oily fish servings a week, accounting for 500 mg/day$^{9}$, meets the minimum recommended intake of EPA and DHA$^{2}$. To minimize the burden of chronic disease, 1000-2000 mg (1-2g) of EPA and DHA daily is recommended$^{9}$. With regards to cancer prevention, no minimum has been established to our knowledge, but clinical trials that found efficacy in cancer prevention have used 5 g of EPA for 12 weeks (showing skin cancer risk reduction$^{49}$) and 2 g/day for 3 months (showing colorectal cancer risk reduction$^{50}$), among other ranges of doses and durations. Details for each study can be found in the section below. Lastly, it has been suggested that 600 mg to 3.6 g of omega-3 supplementation alongside conventional cancer therapies like radiotherapy or chemotherapy may help reduce the risk of toxicity and enhance patient survival rates$^{51}$. Daily intake of EPA and DHA (1.5 g/ day) for long periods of time could also alleviate the risk of cancer cachexia, one systematic analysis found$^{52}$.

Summary of Data

Cancer Prevention A total of 20 randomized clinical trials that investigated EPA as a cancer-preventative nutrient were identified on PubMed. The data from the trials is summarized below.

📄 Detailed EPA (cancer prevention) human clinical trial study notes analyzed by Anticancer.ca

Cancer Treatment A total of 11 randomized clinical trials that investigated EPA as a cancer-treating nutrient were identified on PubMed. The data from the trials is summarized below.

📄 Detailed EPA (cancer treatment) human clinical trial study notes analyzed by Anticancer.ca

Other Cancer Treatments

A total of 42 randomized clinical trials that investigated EPA as a nutrient alleviating other outcomes like nutritional status, bone resorption, and general inflammation during cancer or cancer treatment were identified on PubMed. The data from the trials is summarized below.

📄 Detailed EPA (other cancer treatments) human clinical trial study notes analyzed by Anticancer.ca

References

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• Eicosapentaenoic Acid
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• How Does It Work?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• References
• About This Article
• Disclaimer