It is well established that there is a strong link between inflammation and carcinogenesis; as a result, the development and use of anti-inflammatory products to inhibit or slow the progress of cancer offers considerable therapeutic potential.
Current pharmaceutical approaches that have been demonstrated to reduce cancer risk are often associated with a variety of detrimental side effects. There are, however, several naturally occurring fatty acid substances with anti-inflammatory properties which, when used in their highly purified forms, have demonstrated excellent safety profiles and highly promising anti-cancer activities.
NSAID use and cancer risk
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are pharmaceuticals used to reduce pain and inflammation. They work by inhibiting the actions of the enzyme cyclooxygenase (COX) from which all inflammatory mediating prostaglandins are produced. There are two COX enzymes that are regulated independently; COX-1 is constitutively expressed, carrying out important ‘housekeeping’ functions, such as maintaining gastrointestinal tract lining and platelet aggregation, and the inducible COX-2 form, expressed in response to certain stimuli and which results in the production of inflammatory regulating end products. The inappropriate over-expression of COX-2 seen in the majority of cancers is, however, known to play a key role in tumourigenesis, making it a viable target for intervention. For example, data from 91 epidemiological studies examining the dose response of relative risk and level of NSAID intake for ten human malignancies found a significant exponential decline in the risk with increasing intake of NSAIDs (mainly aspirin and ibuprofen). Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63% for colon, 39% for breast, 36% for lung and 39% for prostate cancer. NSAID effects became apparent after five or more years of use and were stronger with longer duration.
Whilst the protective effects on cancer risk seem encouraging, the long term use of NSAIDs can lead to a myriad of potential side effects, including gastrointestinal, renal and cardiovascular complications. The gastric ulcer formation and bleeding experienced by some users are due to the inhibition of COX-1. Recognising the important homeostatic function of COX-1 and in an attempt to reduce undesirable side effects, this led to the development of selective COX-2 inhibitors, which were expected to have higher safety profiles than standard NSAIDs. Several selective COX-2 inhibitors, however, have been shown to produce detrimental side effects similar to NSAIDS, resulting in their withdrawal from the market. For example, Merck & Co were forced to withdraw a selective COX-2 inhibitor in September 2004 because of evidence of an increased risk of confirmed serious thrombotic events (including myocardial infarction and stroke) compared to placebo, following long-term use. The following year, Pfizer withdrew another product from the EU market because a serious and potentially fatal skin reaction associated with its use outweighed the benefits of the drug. Thus, whilst NSAIDs and COX-2 inhibitors may offer anti-inflammatory and analgesic effects, their long-term use as potential anti-cancer agents may not be feasible.
Non-pharmaceutical COX-2 inhibition
There is increasing evidence that polyunsaturated fatty acids play a role in cancer risk and progression. The omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid eicosapentaenoic acid (EPA) are the precursors to the family of eicosanoids that regulate immune and inflammatory processes. When AA is released from cell membranes by the action of phospholipase enzymes, COX-2 converts it to prostaglandin H2 (PGH2). PGH2 is the common precursor for all other prostaglandins, all of which have pro-inflammatory effects and the pathway is itself a key target for cancer therapies. EPA, in contrast, is the precursor to anti-inflammatory lipid mediators and competes with AA for COX-2 activity. Dietary intake of EPA can reduce the amount of AA available for conversion to prostaglandins by COX-2 and, in addition to blocking the production of pro-inflammatory mediators, also produces a more favourable anti-inflammatory prostaglandin profile. Unsurprisingly, the ratio of AA to EPA both in the diet and in cell membranes will provide valuable information on inflammatory status and has even been postulated as a cancer biomarker. Given that the tumour microenvironment is associated with high AA, high COX-2 expression and overproduction of inflammatory tumour-driving end products, supplementation with EPA in its highly purified form has major therapeutic potential as an anti-cancer nutraceutical via its anti-inflammatory modulating effects. Indeed, such benefits have been demonstrated in both in vitro and animal models and, because of its excellent safety and tolerability profile, is giving rise to numerous human intervention studies, with increasingly promising outcomes.
AA, EPA and tumourigenesis
A high cell proliferation rate and a low rate of apoptosis are the hallmark of abnormal cell growth. AA and EPA have opposing effects on the proliferation, differentiation and apoptosis of genetically altered cells and therefore on the disposal/accumulation of DNA damaged tissue. EPA’s anti-proliferative effects, combined with its ability to induce programmed cell death of genetically altered cells, switch off a number of cancer ‘driving’ genes and reduce angiogenesis (a critical process that affects tumour growth and dissemination) suggests that purified EPA supplementation, in addition to its anti-inflammatory benefits, may have a significant impact on halting disease progression. For example, there is accumulating evidence for the role of EPA as a protective nutraceutical in colorectal cancer initiation and progression and it is thought that the increasing numbers of clinical trials of EPA in bowel cancer patients may eventually lead to the development of a new treatment for bowel cancer. Aberrant crypt foci (ACF) are clusters of abnormal tissue within the colon and rectum that have the potential to develop into polyps, the precursor lesions that can progress to cancer. Several clinical trials have shown supplemental EPA to reduce inflammation, protect against colorectal ACF formation and reduce the size and number of established polyps.[6-8]
According to the World Health Organisation, cancer is a leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in 2008, with figures estimated to reach 13.1 million deaths by 2030.(9) Almost all cancers (80–90%) are believed to be caused by environmental factors and, of these, 30–40% of cancers are directly linked to diet. Dietary fat has been one of the most studied macronutrients thought to be related to cancer risk, based on epidemiological evidence relating total fat consumption and cancer risk. The understanding that it is the influence of individual fatty acid types rather than fat as a whole has helped clarify key aspects of how these nutrients relate to cancer risk, initiation, progression and prognosis. The marine derived omega-3 fatty acid EPA not only offers protection against cancer risk, but human intervention studies are consistently showing its potential as a chemo-active nutrient in its nutraceutical form.
1. Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM: Cyclooxygenases in cancer: progress and perspective. Cancer letters 2004, 215:1-20.
2. Harris RE, Beebe-Donk J, Doss H, Burr Doss D: Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncology reports 2005, 13:559-583.
3. Garassino, MC, Montorfano, G, Fallini, M, Adorni M, Berra B, Rizzo AM: A new biomarker in cancer patients: The arachidonic acid/eicosapentaenoic acid (AA/EPA) ratio AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Sep 12-15, 2006
4. Azrad M, Turgeon C, Demark-Wahnefried W: Current Evidence Linking Polyunsaturated Fatty Acids with Cancer Risk and Progression. Frontiers in oncology 2013, 3:224.
5. Hull MA, Sandell AC, Montgomery AA, Logan RF, Clifford GM, Rees CJ, Loadman PM, Whitham D: A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial. Trials 2013, 14:237.
6. Higurashi T, Hosono K, Endo H, Takahashi H, Iida H, Uchiyama T, Ezuka A, Uchiyama S, Yamada E, Ohkubo H, et al: Eicosapentaenoic acid (EPA) efficacy for colorectal aberrant crypt foci (ACF): a double-blind randomized controlled trial. BMC cancer 2012, 12:413.
7. Courtney ED, Matthews S, Finlayson C, Di Pierro D, Belluzzi A, Roda E, Kang JY, Leicester RJ: Eicosapentaenoic acid (EPA) reduces crypt cell proliferation and increases apoptosis in normal colonic mucosa in subjects with a history of colorectal adenomas. International journal of colorectal disease 2007, 22:765-776.
8. West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA: Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut 2010, 59:918-925.