Increased consumption of omega 3 fats is widely promoted globally because of a common belief that it will protect against, or even reverse, diseases such as cancer, heart attacks and stroke.
But two systematic reviews published today find that omega 3 supplements may slightly reduce coronary heart disease mortality and events, but slightly increase risk of prostate cancer. Both beneficial and harmful effects are small.
If 1,000 people took omega 3 supplements for around four years, three people would avoid dying from heart disease, six people would avoid a coronary event (such as a heart attack) and three extra people would develop prostate cancer.
The sister systematic reviews are published today in the British Journal of Cancer and the Cochrane Database of Systematic Reviews.
Omega 3 is a type of fat. Small amounts are essential for good health and can be found in the food that we eat including nuts and seeds and fatty fish, such as salmon.
Omega 3 fats are also readily available as over-the-counter supplements and they are widely bought and used.
The research team looked at 47 trials involving adults who didn’t have cancer, who were at increased risk of cancer, or had a previous cancer diagnosis, and 86 trials with evidence on cardiovascular events or deaths.
More than 100,000 participants were randomised to consume more long-chain omega-3 fats (fish oils), or maintain their usual intake, for at least a year for each of the reviews.
They studied the number of people who died, received a new diagnosis of cancer, heart attack or stroke and/or died of any of the diseases.
Lead author Dr Lee Hooper, from UEA’s Norwich Medical School, said: “Our previous research has shown that long-chain omega 3 supplements, including fish oils, do not protect against conditions such as anxiety, depression, stroke, diabetes or death.
“Our previous research has shown that long-chain omega 3 supplements, including fish oils, do not protect against conditions such as anxiety, depression, stroke, diabetes or death.”
“These large systematic reviews included information from many thousands of people over long periods. This large amount of information has clarified that if we take omega 3 supplements for several years we may very slightly reduce our risk of heart disease, but balance this with very slightly increasing our risk of some cancers. The overall effects on our health are minimal.
“The evidence on omega 3 mostly comes from trials of fish oil supplements, so health effects of oily fish, a rich source of long-chain omega 3, are unclear.
Oily fish is a very nutritious food as part of a balanced diet, rich in protein and energy as well as important micronutrients such as selenium, iodine, vitamin D and calcium – it is much more than an omega 3 source.
“But we found that there is no demonstrable value in people taking omega 3 oil supplements for the prevention or treatment of cancer. In fact, we found that they may very slightly increase cancer risk, particularly for prostate cancer.
“However this risk is offset by a small protective effect on cardiovascular disease.
“Considering the environmental concerns about industrial fishing and the impact it is having on fish stocks and plastic pollution in the oceans, it seems unhelpful to continue to take fish oil tablets that give little or no benefit.”
Funding: The research was funded by the World Health Organisation (WHO).
Omega-3 PUFAs and the Possible Mechanisms of Action in Cancer Complications
Omega-3 PUFAs are essential fatty acids, containing between 18 and 22 carbons, with the first double bond on the third carbon, counting from the omega end. Omega-3 PUFAs comprise three different active molecules:
(i) α-linolenic acid (ALA; 18:3n-3),
(ii) eicosapentaenoic acid (EPA; 20:5n-3), and
(iii) docosahexaenoic acid (DHA; 22:6n-3). ALA is synthesized in plants and can be found in seeds, nuts, and plant oils. EPA and DHA are not synthesized by the organism and can only be found in the flesh of cold-water fish [30].
Interestingly, ALA can be converted to EPA and DHA by several reactions of elongation and desaturation, but these conversions produce small amounts of EPA and DHA in the organism [31].
The omega-6 arachidonic acid (AA; 20:4n-6) and linoleic acid (LA; 18:2n-6) are also essential fatty acids. Notably, both became major components of the cell membrane due to the increase of Western diets, rich in cereals and vegetable oils, containing excessive omega-6 PUFAs and leading to an undesired omega-6/omega-3 ratio of 20:1 [32].
The metabolic pathways of AA and LA share the same enzymes that convert ALA to EPA and DHA, indicating that there is competition between the pathways. In inflammatory processes, membrane phospholipids are cleaved by phospholipase A2 (PLA2) to release AA to the cytoplasm and initiate the production of highly inflammatory eicosanoids (such as prostaglandin E2 and leukotriene B4) by the action of cyclooxygenases and lipoxygenases.
The membrane lipid composition modification from an omega-6 PUFA to omega-3 PUFA profile is very important because it increases the production of omega-3-derived mediators, such as thromboxane A3 and prostacyclin I3, which are weaker inducers of inflammation [33].
Supporting this mechanism, a systematic review and meta-analysis demonstrated that omega-3 PUFAs were able to reduce thromboxane B2 blood levels in subjects with a high risk of cardiovascular diseases, along with a decrease of leukotriene B4 in the neutrophils of unhealthy patients [34].
Regarding lymphocyte membranes, an in vitro and pilot clinical study evaluated the fatty acid composition of CD4+T cell membranes after EPA and DHA supplementation. The in vitro analysis showed that EPA or DHA incubation increased the membrane contents of omega-3 PUFAs. Additionally, the pilot clinical study from the same article evaluated the membrane composition of lymphocytes in elderly individuals after six weeks of omega-3 PUFA supplementation and observed a similar omega-3 PUFA-rich membrane [35].
Additionally, a review article demonstrated that EPA and DHA supplementation are often employed in the nutritional therapy of cancer patients and promotes beneficial effects during cancer treatment due to a membrane modulation [36].
On the other hand, an analysis of the fatty acid composition of the red blood cells of cancer patients showed that there was no difference between the omega-3 PUFAs contents in the membrane of cancer patients and healthy subjects, irrespective of their diet.
Interestingly, the same cancer patients showed higher omega-6 PUFA contents and an increased desaturation activity, demonstrating a higher inflammatory profile [37].
The notion that an omega-3 PUFA-enriched membrane could be favorable for disease management was corroborated by the discovery of pro-resolution mediators of inflammation, derived from omega-3 PUFAs.
Over the past decade, the identification of resolvins, protectins/neuroprotectins, and maresins was a milestone—currently, it is well-recognized that solving, rather than inhibiting, inflammation is quite an interesting approach for the treatment of a series of chronic illnesses such as cancer.
In acute inflammation, the production of prostaglandins by the action of cyclooxygenases-1 and -2 is essential for blood flow regulation and an increase of endothelial permeability. Additionally, the production of leukotrienes is required for leukocyte migration [38].
Notably, it was believed that all products of the inflammatory process, such as eicosanoids, prostanoids, cytokines, and chemokines, are diluted over time and that the inflammation process would be resolved [39].
Nevertheless, studies demonstrated that a group of lipid pro-resolution mediators, derived from arachidonic acid (AA), namely lipoxins, were crucial to stopping the pro-inflammatory signals, indicating that the resolution of inflammation is an active process [40].
Lipoxins can inhibit the entrance of new neutrophils and stimulate macrophages to clear apoptotic neutrophils [41]. Remarkably, omega-3 PUFAs are crucial for the generation of potent pro-resolution mediators, with similar actions to lipoxins, such as resolvins, protectins, neuroprotectins, and maresins.
Resolvins are divided into the series E (RvE) and D (RvD), originating from EPA and DHA, respectively. As for protectins, neuroprotectins and maresins originate from DHA, but maresins are produced only by macrophages [42,43,44].
These mediators of resolution can decrease the leukocyte infiltration and reduce cellular debris, leading to the cessation of the inflammatory process [44]. Notably, they have been widely investigated, showing beneficial effects in a series of preclinical inflammation models.
Regarding the effects of these pro-resolution mediators in cancer, RvD1, RvD2, and RvE1 were capable of reducing the debris-stimulated cancer progression by inducing macrophage phagocytosis and diminishing pro-inflammatory cytokines [45].
Likewise, DHA-derived pro-resolution mediators, such as neuroprotectin D1, maresin 1, and RvD1 and RvD5, displayed important analgesic effects in a mouse model of postoperative pain after bone fracture when administered after surgery. Nevertheless, the same study demonstrated that DHA administration before surgery partially reduced postoperative pain due to the conversion of DHA to pro-resolution mediators [46].
Concerning the effects of resolution mediators on depression, RvE1 and RvE2 intracerebroventricular (i.c.v.) administration significantly decreased lipopolysaccharide (LPS)-associated depressive behavior via the activation of the resolvin receptor ChemR23 according to the assessment of LPS-induced depression in a mouse model [47].
Similarly, a study of our group revealed the beneficial effects of RvD2 treatment in the depression-like behavior in a mouse model of fibromyalgia [48]. A critical review speculated that the resolution of inflammation is flawed in cancer-cachexia, suggesting that the induction of the resolution process would be beneficial for cancer-cachectic patients [49]. Surprisingly, there are no experimental or clinical studies investigating the effects of pro-resolution mediators in cancer cachexia.
Omega-3 PUFAs can activate G protein-coupled receptors, generating intracellular effects. Firstly, Briscoe et al. (2003) identified the FFA1 receptor, formerly known as the G-protein coupled receptor 40 (GPR40), as a free fatty acid receptor.
It was observed that long-chain fatty acids could cause a concentration-dependent increase in intracellular calcium in human embryonic kidney (HEK293) cells expressing FFA1 [7]. The expression of the FFA1 receptor indicates that this receptor is an important molecular target for metabolism control, as observed in the gastrointestinal tract, pancreatic β-cells, and brain [50,51,52].
Regarding the effects of FFA1 in the metabolism, the activation of this receptor is associated with glucagon-like peptide-1 (GLP-1) and cholecystokinin release [53,54]. More recently, it was observed that the FFA1 receptor is expressed in the melanocortin system, specifically in the neuropeptide Y/Agouti-related peptide (NPY/AgRP) and proopiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons [55]. Interestingly, the FFA1 expression is upregulated in other tissues under pathological situations, such as periodontitis, which is associated with metabolic syndrome [56].
Regarding the antidiabetic effect, FFA1 has been widely investigated as a molecular target for diabetes, mainly due to the glucose-stimulated insulin secretion via protein kinase C/inositol triphosphate (PKC/IP3) activation and, consequently, intracellular calcium increase, inducing insulin release [57,58].
In virtue of this effect, TAK-975, a synthetic selective FFA1 agonist, was tested until phase II of clinical trials for diabetes management. Unfortunately, the clinical investigation had been interrupted because patients developed hepatoxicity and liver failure [59,60].
More recently, the role of the FFA1 receptor in the central nervous system has attracted interest. The activation of this receptor by DHA demonstrated analgesic effects in different experimental pain models [11,12,61,62]. As for FFA1 ligands, long-chain fatty acids are considered endogenous agonists, mainly DHA, but the studies demonstrated that oleic acid is also a potent FFA1 agonist [10,61,62,63].
Omega-3 PUFAs as Part of Pharmaconutrition in Cancer Patients
The areas of immunonutrition and pharmaconutrition have emerged due to the impact of nutrients in the organism being greater than the nutrition itself. Nevertheless, pharmaconutrition, which is characterized by nutrient supplementation at pharmacological doses, seems to be more promising than immunonutrition, defined as a nutrient-enriched diet [73].
Malnourished cancer patients can display a diminished response to cancer therapy, increase in infections, an extension of the length of hospital stay, an augmentation of the risk of postoperative complications, and death [74,75].
Patients may experience mechanical and functional alterations, especially when the tumor is located in the gastrointestinal tract. Additionally, they can display adverse effects related to cancer treatment, such as nausea, vomiting, mucositis, xerostomia, and/or dysphagia [76].
Also, a high inflammatory state in cancer patients might be related to cancer complications, such as depression, cachexia, pain, and paraneoplastic syndromes [77,78]. Immunonutrition with omega-3 PUFAs, glutamine, arginine, and ribonucleotides is often prescribed to cancer patients and is believed to maintain immunocompetence during the treatment [79,80].
Conversely, other clinical randomized trials observed that immune-enhancing diets, when offered to cancer patients, failed to improve the immune response and were no different from standard diets [81,82,83].
Alternatively, pharmaconutrition is employed as a nutrient supplementation during cancer treatment in order to diminish treatment-related complications. Currently, omega-3 PUFAs can be considered as pharmaconutrients, acting as receptor agonists, modulating molecular pathways, reducing the inflammatory response, increasing the chemotherapy efficacy, and consequently improving the overall survival of cancer patients [84,85,86].
Curiously, low contents of omega-3 PUFAs in the mammary region seem to contribute to breast cancer multifocality, indicating that omega-3 PUFA supplementation is important for cancer management and prevention [87]. Therefore, omega-3 PUFA-based pharmaconutrition is likely useful for handling cancer-related outcomes.
Cancer-Related Pain
Most cancer patients experience different types of pain associated with the disease. Cancer patients often report intense pain, leading to a lower performance status [88]. Pain might be related to tumor localization, but it can also arise due to chemotherapy treatment and/or surgery [89].
Notably, cancer pain comprises inflammatory and neuropathic mechanisms in virtue of tumor mass development [90]. Signaling molecules that are released by the environment are responsible for tissue remodeling and for tumor invasion and metastasis.
These molecules can be pro-inflammatory cytokines, chemokines, and growth factors, which are released by cells in order to modulate tumor growth [91]. Additionally, chemo- and radiotherapy induce toxicity and inflammation, evoking painful symptoms, decreasing patients’ quality of life and, consequently, diminishing the treatment adherence [92].
Peculiarly, we were not able to find any clinical or experimental studies on omega-3 supplementation for alleviating tumor-related pain. Similarly, clinical evidence of the effects of omega-3 supplementation in therapy-related pain is still scarce.
Preclinical and clinical evidence on the neuroprotective effects of omega-3 PUFAs on chemotherapy-associated pain is provided in Table 1. Supporting the favorable analgesic actions of omega-3 PUFAs, a systematic review demonstrated that a nutritional supplement enriched with fish oil decreased the symptoms of fatigue and pain in patients during chemo- and/or radiotherapy, probably due to weight maintenance and reduced inflammatory status [93,94].
Table 1
A summary of the articles discussed above regarding the effects of omega-3 PUFAs in cancer and cancer-treatment complications.
| Authors | Cancer-Related Complication | Species | Cancer Type | Treatment Scheme | Major Outcome |
|---|---|---|---|---|---|
| Hershmann et al., 2015 [96] | Aromatase-inhibitor associated arthralgia | Human | Breast cancer | 3.3 g 1 FO (560 mg EPA + DHA; 40:20) | Decreased pain, evaluated by the 2 BPI between the baseline and week 24 (p < 0.01) |
| Shen et al., 2018 [97] | Aromatase-inhibitor associated arthralgia | Human | Breast cancer (obese) | 3.3 g FO (560 mg EPA + DHA; 40:20) | Pain reduction in 3 BMI > 30 kg/m² patients (p = 0.02) |
| Martínez et al., 2018 [98] | Aromatase-inhibitor musculoskeletal symptoms (AIMSS) | Human | Breast cancer | 460 mg EPA + DHA 12.5 mg hydroxytyrosol 50 g curcumin | Decrease of the BPI total score after 30 days (p = 0.011) |
| Ghroreishi et al., 2012 [99] | Paclitaxel-induced neuropathy | Human | Breast cancer | 640 mg FO (54% DHA + 10% EPA) | 70% did not develop neuropathy no pain score assessed |
| Maschio et al., 2018 [100] | Bortezomib-related neuropathy | Human | Multiple myeloma | Neuronorm® (400 mg DHA + 600 mg ALA) | Pain failed to increase significantly (p = 0.33) |
| Freitas et al., 2016 [11] | Cyclophosphamide-induced hemorrhagic cystitis | Mice | – | 20% FO-enriched diet or 1 µmol/kg i.p. | Decrease in spontaneous pain behavior and abdominal allodynia (p < 0.01) |
| Ye et al., 2018 [95] | Oral and paw cancer pain | Mice | Oral squamous cell carcinoma | RvD1 (100 ng or 200 ng) or RvD2 (100 ng or 200 ng) i.p. | RvD2 inhibited thermal and mechanical pain; RvD1 inhibited thermal pain |
1 FO: Fish oil; 2 BPI: Brief pain inventory; 3 BMI: body mass index.
One might dispute the mechanisms underlying the analgesic effects of omega-3 PUFAs in cancer patients. A study, conducted by our research group, demonstrated that an omega-3 PUFA-enriched diet evoked analgesic effects in a mouse model of cyclophosphamide-induced visceral pain due to the overexpression of the FFA1 receptor in the spinal cord [11].
According to studies on other pain models, the activation of the FFA1 receptor induces the release of β-endorphin, noradrenaline, and serotonin, accounting for the analgesic actions of DHA [12,62].
Recently, it was observed that RvD2 decreased cancer pain in an experimental model of oral squamous cell carcinoma, probably via the downregulation of RvD2 receptors in this cancer cell, indicating that the resolution pathways could be suppressed. Another possible mechanism is the inhibition of several members of the transient receptor (TRP) family, such as TRPV1, TRPA1, TRPV3, and TRPV4 by RvD2 [95].
In virtue of the conversion of omega-3 PUFAs in specialized pro-resolution mediations, such as resolvins, protectins, and maresins, it is tempting to suppose that omega-3 PUFA supplementation prior to or during cancer treatment could inhibit or delay the appearance of treatment complications, such as pain and neuropathy.
Source:
University of East Anglia
