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Investigations in a variety of cancer types with a range of chemotherapy agents have reported greater efficacy of chemotherapy when marine n-3 long-chain polyunsaturated fatty acids (LCPUFAs) are added to the diet (Murphy et al, 2011). The mechanisms of action of these antineoplastic agents vary, suggesting that n-3 LCPUFAs modulate responses via diverse range of mechanisms. The n-3 LCPUFAs are also suggested to have antitumour effects including inhibition of angiogenesis and metastasis (Baracos et al, 2004); however, the specific mechanisms behind these effects have not been elucidated. Furthermore, n-3 LCPUFAs have been implicated in decreasing the severity of secondary cancer complications including cancer cachexia. Regardless of the exact mechanisms, previous studies suggest that n-3 LCPUFAs may have potential as an effective adjuvant to chemotherapy treatment, may have direct anticancer effects, and may help to ameliorate some of the secondary complications associated with cancer. In this review we briefly describe the chemical structure of n-3 LCPUFAs, the anticancer effects associated with their use in cancer patients, and some of the potential benefits they may have in patients who develop cancer cachexia.

Marine PUFAs

Marine PUFAs are divided into two classes: omega-3 (n-3) and omega-6 (n-6); the n-3 and n-6 indicate the position of the first double bond with regard to the terminal methyl end of the molecule (Gurr et al, 2008). The n-3 and n-6 PUFAs are stored in membrane phospholipids (Schmitz and Ecker, 2008), and are responsible for numerous cellular functions including cell membrane structure, fluidity, signalling, and cell-to-cell interaction (Colomer et al, 2007). They also regulate other bodily functions including blood pressure, blood clotting, and nervous system function and development (Wall et al, 2010). The n-3 and n-6 fatty acids are considered to be essential nutrients and are required in the diet. Although the synthesis of longer, more saturated n-3 fatty acids within human tissues is possible when provided with the precursor linolenic acid, the rate of synthesis to longer more unsaturated fatty acids in humans is limited (Schmitz and Ecker, 2008). Eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) are long-chain n-3 fatty acids (Gurr et al, 2008) found in all fish species, with oily fish from cold climates containing the highest levels of EPA and DHA, although levels differ depending on a number of factors such as environment and fat content (Wall et al, 2010).

Arachidonic acid (AA) is a major intermediate derived from n-6 fatty acids that competes for the same metabolic pathway as EPA, as they are both catalysed by the same enzymes (Schmitz and Ecker, 2008), and therefore when high levels of EPA are consumed in the diet, AA levels are reduced and in part substituted by EPA (Wall et al, 2010). The reverse also occurs when high levels of AA or low levels of EPA are consumed in the diet (Wall et al, 2010). In addition to playing important roles in cellular and bodily functions, n-3 and n-6 are precursors to eicosanoids that have a vital function in regulating inflammatory processes (Wall et al, 2010). Polyunsaturated fatty acids are stored in cellular membranes, and are released via hydrolysis and esterification by phospholipase A2 (PLA2) before metabolism into eicosanoids (Schmitz and Ecker, 2008). Eicosanoids can be divided into four categories: prostaglandins, thromboxanes, leukotrienes, and hydroxyeicosatetraenoic acids (Wall et al, 2010), which differ in action depending on if they are a derivative of AA or EPA. Eicosanoids from AA are responsible for inducing pro-inflammatory, pro-arrhythmic, and vasoconstrictive responses, whereas eicosanoids from EPA have the contrasting effects of anti-inflammatory, anti-arrhythmia, and vasodilative responses (Schmitz and Ecker, 2008).

Anticancer actions of marine PUFAs

Both EPA and DHA have received much attention recently because of the emergence of studies reporting their effects as broad-spectrum health-promoting agents, including their use in the prevention and treatment of cancer. Table 1 summaries key clinical studies that have investigated the use of n-3 LCPUFAs in the treatment of cancer and treatment or prevention of cachexia.

Table 1 Use of marine-derived n-3 LCPUFAs in cancer prevention, cancer therapy, and the prevention and treatment of cancer cachexia
Full size table

Many epidemiological studies have suggested that a diet high in n-3 LCPUFA, such as the Japanese and Mediterranean diets, has lower incidences of cancer (Baracos et al, 2004; Gerber, 2012). Although it is difficult to draw solid conclusions regarding their benefit from epidemiological studies, prospective studies assessing n-3 LCPUFA intake for extended periods have shown inverse associations between intake and cancer risk. A study of over 90 000 subjects in Japan showed a significant, dose-dependent decrease in risk of development of hepatocellular carcinoma in people with a higher fish and n-3 PUFA intake, even in a high-risk group after adjustment for additional risk factors (Sawada et al, 2012). Hepatocellular carcinoma is an inflammatory-linked cancer, triggered by hepatitis virus infection and toxin exposure, and therefore the anti-inflammatory action of n-3s may be responsible for the decrease shown. A prospective study over 22 years studying fish intake and colorectal cancer risk in American physicians showed similar results, with lower risk of cancer development associated with higher n-3 PUFA intake (Hall et al, 2008). These associations persisted after controlling for known risk factors and possible confounding issues, indicating that there is a strong probability that the effect was indeed caused by the consumption of n-3-rich foods and supplements. Both these studies and others have proposed the anti-inflammatory properties of n-3 fatty acids as the likely mechanism for cancer prevention (Baracos et al, 2004; Hall et al, 2008; Sawada et al, 2012). The World Cancer Research Fund/American Institute for Cancer Research (2007) Expert Report provides a comprehensive review of further studies relating to the prevention of cancer through food, nutrition, and physical activity, including marine-derived n-3 LCPUFAs such as EPA and DHA (AICR and WCRF, 2007). Numerous in vitro and in vivo studies have demonstrated that n-3 LCPUFA supplementation, in particular EPA and DHA, can inhibit tumour growth through a variety of other proposed mechanisms, including apoptosis, inhibition of angiogenesis, and alterations to cell signalling, all of which have been implicated in the reduced risk of cancer development seen in study populations with high n-3 LCPUFA intake (Baracos et al, 2004).

Several experimental studies utilising a variety of chemotherapeutic agents and tumour types have reported a greater efficacy of chemotherapy with the addition of n-3 LCPUFA. In particular, EPA and DHA modulate this response via diverse mechanisms (Baracos et al, 2004). Eicosapentaenoic acid and DHA have previously been shown to increase tumour sensitivity to irinotecan therapy and protect nontarget tissues, including a reduction of gastrointestinal toxicity (Baracos et al, 2004). More recently, Murphy et al 2011 have shown that the administration of 2.5 g day−1 of an EPA+DHA supplement to non-small cell lung cancer (NSCLC) patients undergoing platinum-based chemotherapy caused a two-fold increase in therapy response rate and clinical benefit when compared with patients undergoing the same treatment without additional supplementation (Murphy et al, 2011). Patients in the supplement group were also able to undertake on average an additional 3 weeks of chemotherapy, and showed a trend toward increased survival (Murphy et al, 2011). Improved chemotherapy outcomes have been observed in breast cancer patients undergoing anthracycline-based chemotherapy when a daily DHA supplement was highly incorporated into circulating phospholipids (Bougnoux et al, 2009). The potential for DHA supplementation to sensitise tumours to treatment was suggested because of high antitumour activity observed with high incorporation of DHA in plasma phospholipids. This may be due to membrane enrichment with the highly peroxidisable DHA, leading to increased peroxidation of membranes caused by oxidative stress induced by the cancer therapy (Bougnoux et al, 2009; Das, 2011). The addition of n-3 LCPUFA has been demonstrated to improve tumour toxicity, reduce off-target toxicity, and act to protect off-target tissues. Because of reduced symptom burden and toxicity, longer treatment times are achievable, leading to extended survival duration, and providing a strong rationale for the inclusion of marine PUFA as a concurrent treatment during chemotherapy.

Supplementation with marine-sourced n-3 PUFAs has been shown to exert some benefit on the general health and quality of life (QoL) in cancer patients. A recent study in NSCLC patients showed that daily supplementation with EPA/DHA, in conjunction with standard treatment, improved QoL, physical function, cognitive function, and global health status compared with control patients (van der Meij et al, 2012). The study also demonstrated that patients undergoing the treatment tended to have higher physical activity than the control group. The EPA supplementation in lung cancer patients has also shown improved general well-being after a 60-day period, with patients in one study showing significant improvements in body weight, energy intake, appetite, and QoL (Elia et al, 2006). Patients had improved nutritional status, and a reduction in circulating acute-phase proteins, indicating reduced inflammation, as shown in previously mentioned studies. However, results from a recent study of enteral EPA and DHA supplementation post surgery in oesophagogastric cancer demonstrated that although circulating levels of n-3 fatty acids were increased, there was no improvement in morbidity, mortality, or length of hospital stay (Sultan et al, 2012), indicating that the benefit of n-3 LCPUFA supplementation is not universal, and may be dependent upon when supplementation is provided during the progression of cancer or treatment course.

As previously discussed, inflammation can be a key factor in cancer, and poses a critical target for cancer therapy. The importance of the circulating n-3 to n-6 fatty acid ratio in blood has been highlighted by a study in breast cancer survivors investigating the effect of PUFA on multidimensional fatigue and inflammation (Alfano et al, 2012). Physical fatigue symptoms and impact were significantly associated with increased inflammation, with higher C-reactive protein (CRP) levels associated with greater risk of fatigue even after adjustment for multiple co-risk factors. Increased n-3 relative to n-6 in the diet was associated with a clinically significant reduction in inflammation, whereas high n-3 intake also correlated with reduced behavioural, sensory and cognitive aspects of fatigue. The reduced risk of fatigue with increased n-3 consumption implies an inflammation-mediated association between PUFA consumption and fatigue in this population. As increased inflammation is associated with decreased survival intervals for breast cancer patients (Alfano et al, 2012), this provides an important target for future research. The n-3 LCPUFAs, in particular EPA and DHA, have been implicated to have an inhibitory effect on pro-inflammatory cytokines, subsequently reducing inflammation. Supplementation with EPA/DHA increases acetylcholine levels, in turn blocking the release of cytokines such as tumour necrosis factor-α (TNF-α), interlukin-1, and interlukin-6, with the replacement of AA by EPA and DHA causing altered production of eicosanoids towards less inflammatory products (Calder, 2002; Arab et al, 2006). Inflammation caused by redox imbalance has also been shown to be reduced by EPA/DHA supplementation via decreased production of ROS by COX-2 and upregulation of antioxidant systems (Arab et al, 2006; Kim and Chung, 2007). This anti-inflammatory approach is further supported by the use of EPA and DHA in conjunction with Cox-2 inhibitors in supportive cancer care in order to reduce symptom clusters (Cerchietti et al, 2007). Lung cancer patients given either fish oil (1 g, 18% EPA and 12% DHA) and celecoxib or fish oil with placebo over a 6-week period showed significantly improved appetite, less fatigue, and lower CRP levels than at baseline. The group receiving the combined treatment group also showed increased body weight and muscle strength compared with baseline, and lower CRP levels with increased body weight and muscle strength compared with fish oil alone. The addition of celecoxib to fish oil modulates eicosanoid metabolism, reducing symptoms of secondary syndromes in cancer (Cerchietti et al, 2007), in particular those associated with inflammation, and provides a strong argument for the use of fish oil as part of a multimodal therapy for the treatment of these conditions.

There is a high prevalence of depression in cancer patients (10–30%) compared with the general population (5–10%), with depression leading to reductions in drug compliance and effectiveness (Chochinov, 2001). There is some difficulty in distinguishing between reactive demoralisation and clinical depression, or the overlapping symptoms of illness and depression, which may contribute to clinical depression being underrecognised and undertreated in patients with cancer (Raison and Miller, 2003). However, the increased expression of shared inflammatory cytokine pathways may lead to increased prevalence of clinical depression in a cancer patient population (Raison and Miller, 2003). As such, treatments that address pro-inflammatory cytokine activity in cancer, such as supplementation with EPA or DHA, may also contribute towards the alleviation of clinical depression in susceptible patients.

Marine PUFAs and secondary cancer complications

Complications associated with cancer vary between patients, tumour type, and disease stage, and can take a number of forms including infection, pain, nausea, fatigue, anxiety, and cachexia (Cerchietti et al, 2007).

Cancer cachexia is a complication of cancer that occurs in patients with advanced solid tumour cancers (Tisdale, 2009). Cachexia is a multidimensional condition, characterised by involuntary weight loss of >5%, that involves a number of tumour and host factors in its progression. These include tumour-induced pro-cachectic and pro-inflammatory responses, systemic inflammation, and altered metabolism, leading to a loss of skeletal muscle and adipose tissue (Donohoe et al, 2011; Fearon et al, 2011), and can severely affect QoL through fatigue, weakness, and reduced physical activity (Tisdale, 2009), with patients facing a poor prognosis (Guarcello et al, 2007).

The ubiquitin–proteasome pathway is one pathway responsible for the breakdown of proteins, and may be initiated by tumour-derived factors such as TNF-α (Sullivan-Gunn et al, 2011). Downstream factors such as AA and reactive oxygen species have also been implicated in its induction (Sullivan-Gunn et al, 2011). The weight loss occurring in cachexia is also attributed to the loss of adipose tissue via lipolysis. This is initiated by lipid-mobilising factor (LMF), and the tumour and host factor zinc-α2-glycoprotein (ZAG) that are overexpressed in cachectic patients (Russell and Tisdale, 2005).

In addition to being used as an adjuvant to cancer therapy, n-3 LCPUFAs have been tested to alleviate the symptoms of cancer cachexia (Table 1). Weed et al (2011) demonstrated that EPA supplementation was significantly associated with an increase in lean body mass in cachectic patients, a gain that may be attributed to the downregulation of the ubiquitin–proteasome pathway (Tisdale, 2009). The EPA supplementation of 2.2 g day−1 over treatment duration has also been shown to assist in the maintenance of weight and muscle mass in NSCLC patients undergoing chemotherapy compared with patients undergoing chemotherapy without EPA supplementation (Murphy et al, 2011). The anti-inflammatory properties of EPA have also been implicated in reducing acute-phase proteins, such as CRP, that may contribute to muscle wasting in cachexia (Murphy et al, 2011). A study by Guarcello et al (2007) showed a significant decrease in CRP levels in cachectic patients supplemented with EPA, whereas the levels in control group increased.

In studies of varying cancer types, EPA has shown significant (Guarcello et al, 2007) and nonsignificant (Fearon et al, 2006; Weed et al, 2011) increases in body weight, indicating that the type of cancer may also play a role in EPA responsiveness, with gastrointestinal cancer patients gaining a significant amount of weight compared with the lung cancer patients (Fearon et al, 2006). The weight gain may be attributed to a number of different mechanisms, including increases in lean body mass and the downregulation of ZAG (Russell and Tisdale, 2005) via the interference with glucocorticoid signalling (Tisdale, 2009), reducing the degradation of adipose tissue.

Despite several clinical studies showing no statistically significant gain in weight and lean body mass, it is important to note that many studies do report improved QoL (Fearon et al, 2006; van der Meij et al, 2012). In a study of EPA and DHA, patients reported high level of improvements in pain and overall health and a significant increase in body weight (Taylor et al, 2010). Increased total energy expenditure and physical activity levels have been observed in patients taking EPA supplements in trials, indicating improved physical capacity (Moses et al, 2004; van der Meij et al, 2012). Any improvement the physical activity, ability to perform daily tasks, fatigue, weakness, and overall health of patient greatly enhances their QoL, and leads to improved prognosis (Moses et al, 2004; Donohoe et al, 2011; van der Meij et al, 2012). Thus, n-3 LCPUFAs may be a consideration as part of a multimodal approach to treat cancer and associated complications such as cachexia (Colomer et al, 2007).

Limitations of marine PUFA use

Although marine PUFAs have been shown to have considerable potential to prevent and augment the treatment of cancer and complications such as cachexia, there are still a number of limitations associated with their use in cancer patients. Because of a significant number of cancer patients experiencing nausea, the consumption of therapeutic doses of fish oil (>3 g per day) or more purified EPA/DHA (>2 g EPA, >1.4 g DHA per day) may be impractical, because of the commonly experienced side effect of ‘fishy’ reflux experienced by many patients consuming fish oil or EPA/DHA supplements. In addition, investigations by Roodhart et al (2011) raised the question as to whether all PUFAs provide benefit, particularly in patients receiving chemotherapy (Roodhart et al, 2011). They suggest that the PUFAs 12-oxo-5,8,10-heptadecatrienoic acid (KHT (n-6)) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)) may be involved in the induction of resistance to chemotherapy. Although these compounds may have a profound pharmacological effect, others have described their abundance to be low, with analyses of various fish oil preparations placing them between 0% and 1.56% of total lipid content (Osman et al, 2001; Wolyniak et al, 2005). Murphy et al 2012) have previously highlighted the inconsistencies presented by these claims when compared with the published literature, and the concern that recommending the reduction of essential fatty acids may have a detrimental effect in this patient population. The discovery that KHT and 16:4(n-3) may play a role in chemotherapy resistance highlights that there is a need for supplementation of marine PUFA supplements to be carefully assessed, with a focus on promoting purified n-3 LCPUFA supplements over less refined whole fish oil, rather than the broad discouragement of this often beneficial augmentation to treatment in patients undergoing chemotherapy.

Conclusions

Polyunsaturated fatty acids derived from marine sources, including EPA and DHA, are widely consumed as supplements within the community, including cancer patients. The prescription of n-3 LCPUFAs in a therapeutic context is also increasing in patients receiving treatment for a range of cancer types. There is also now sufficient literature to suggest that the use of supplements containing EPA and DHA may have potential as an effective adjuvant to chemotherapy treatment and may help ameliorate some of the secondary complications associated with cancer. Although this review was not exhaustive, our investigations indicate that supplementation with fish oil (>3 g per day) or EPA/DHA (>1 g EPA and >0.8 g DHA per day) is associated with positive clinical outcomes. However, other components of fish oil may be detrimental to cancer treatment, and further research is still required to determine the mechanisms by which both marine-derived n-3 PUFAs and other fish-oil derived compounds are mediating their effects.