Omega-3s in cancer prevention and treatment

Nina Bailey BSc MSc, PhD RNutr

1

In 1992, the BNF Task Force on Unsaturated Fatty Acids suggested a desirable population intake for EPA and DHA of 0.5% of energy, which equates to about 8g/week (1.14g/day) for women and 10g/week (1.42g/day) for men, equivalent to 2-3 medium servings of oil-rich fish per week

For a 77kg individual to raise their omega-3 index from 4.2% to 8% they would need a daily dose of 16mg/kg omega-3 (equivalent to 1.25g) (Flock et al. 2013)

Current UK omega-3 recommendations

450mg EPA and DHA daily (2 portions fish weekly, of which one should be oily)

Mean consumption of oily fish (all age groups) was below the recommended one portion (140g) per week (rolling programme for 2012 and 2013 to 2013 and 2014) and equivalent to 13–29 grams per week in children and 54–87 grams per week in adults

Figure source: Stark KD et al., 2016

Is omega-3 ‘deficiency’ a global burden?

2

Anti-inflammatory eicosanoid production

DGLA

GLA

LA

EPA

ETA

SDA

ALA

Delta -6 desaturase

Delta -5 desaturase

Cyclooxygenase (COX)/lipoxygenase (LOX)

Elongase

Series-2 prostaglandins Series-2 thromboxanes Series-4 leukotrienes Hydroxy fatty acids

AA

COX/LOX

Omega-6 Omega-3 A western diet which is characterised by high intake of omega-6 polyunsaturated fatty acids (PUFAs), and lower intake of omega-3 PUFAs, has been suggested to play a role in both carcinogenesis and cancer outcomes Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids derived from AA and EPA that have been implicated in various pathological processes, such as inflammation and cancer (Simopoulos 2002)

Key structural role & anti-inflammatory

docosanoid production Resolvins Protectins

DHA Elongase & desaturase

Pro-inflammatory eicosanoid production

Series-3 prostaglandins Series-3 thromboxanes Series-5 leukotrienes Hydroxy fatty acids

Resolvins

3

A history of ‘evidence’ for a role of omega-3 in cancer

Diet and cancer

• Doll & Peto (1981) suggested that dietary factors might account for as much as 70% of cancer but the specific aspects of diet that were most important were unclear at that time

• The large differences in cancer rates among countries, striking changes in these rates among migrating populations, and rapid changes over time within countries indicate that some aspects of lifestyle or environment are largely responsible for the common cancers in Western countries (Willet, 2001)

Fish consumption and cancer

• The consumption of even relatively small amounts of oily fish may have a protective effect against the risk of several cancers, especially those of the digestive tract (Fernandez et al. 1999)

Omega-3 and cancer

• Inflammation dictates tumour initiation, progression and growth (Azrad et al. 2013)

• Large amount of experimental evidence demonstrates that omega-3s have anti-inflammatory and anti-cancer activity, with recent studies investigating their role in cancer prevention & treatment, in cancer cachexia treatment and in the enhancement of anti-tumour therapies (Laviano et al. 2013)

4

Pro-inflammatory

COX-1/COX2 COX-1/COX2

5-LOX 5-LOX

AA EPA

PGE3

LTB5

PGE2

LTB4

Proliferation Hypermethylation of tumour suppressor genes, increases

expression of aromatase

Migration & invasion Activation of E4 receptor and

PI3k/Akt/mTOR pathway

Anti-proliferation

Down-regulates COX-2 and ERK 1 / 2 pathway

Anti-angiogenic

Inhibits Ang2 and MMP-9

Proliferation Activation of BLT1 & BLT2 receptors,

MEK/ERKPI3K/Akt pathway

Angiogenesis TF-kB & VEGF

Invasion and metastasis

STAT-3 & MMPs

Anti-proliferation Counteract LTB4.

down stream molecular targets are currently unclear

Cancer risk Cancer progression

Cancer risk Cancer progression

Better outcomes

Poorer outcomes

AA and EPA metabolism contribute to cancer risk and progression through pro-and anti-

inflammatory lipid metabolites that stimulate cell proliferation, angiogenesis and migration

Souce: Azrad et al. 2013

Inflammation creates the ideal ‘tumour microenvironment’ and is now widely recognised as an enabling characteristic of cancer in regard to

enhanced cell proliferation, cell survival, cell migration and angiogenesis

5

Arachidonic acid

COX-1

Constitutive ‘gate-keeping

functions’

Homeostatic function Gastrointestinal tract

Renal tract Platelet function

Macrophage differentiation

Induced

Inflammation

Phospholipid

PLA2

COX-2

Both phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2) are over-expressed in certain disease states and targets for intervention (Kumar et al. 2013)

The importance of compounds derived from arachidonic acid (AA) in inflammatory-driven disease is evident from the range of pharmaceutical products that target the actions of AA such as:

• Non-steroidal anti-inflammatory drugs (NSAIDs such as aspirin & ibuprofen)

• Leukotriene antagonists (e.g. montelukast,

zafirlukast) • COX-2 inhibitors (e.g. rofecoxib, celecoxib)

The inhibitory effects of eicosapentaenoic acid (EPA) on PLA2 and COX-2 results in decreased AA availability and decreased AA metabolism, respectively

Omega‐3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?

6

EPA as a chemopreventative agent in colorectal cancer

Changes in the mucosal omega-3 and omega-6 fatty acid status occur early in the colorectal adenoma-carcinoma sequence, with a stepwise reduction in EPA observed from benign adenoma to more advanced carcinoma (Dukes’ B to Dukes’ C-D) with a corresponding increase in the AA to EPA ratio (Fernandez-Banares et al. 1996) Increasing numbers of studies are focusing on pure EPA as a safe and potentially viable chemopreventative agent for the treatment of CRC

• Phase I trial

• EPA has been shown to reduce intestinal adenoma multiplicity by 79% in animal models of familial adenomatous polyposis (FAP) (Fini et al. 2010)

• Phase II trial • In humans, the effects of EPA (2g daily for 6 months) on rectal polyp growth in patients with

familial adenomatous polyposis (FAP) produced a 22.4% decrease in adenoma numbers and a 29.8% reduction in adenoma size (West et al. 2010)

• Phase III trial (ongoing) • The primary aim of the seAFOod study is to determine if a 12-month intervention with 2g EPA daily

prevents the development of colorectal adenomas, either alone or in combination with aspirin (Hull et al. 2013)

7

The seAFOod Polyp Prevention Trial

The standard treatment to identify and remove bowel polyps is via colonoscopy which reduces future bowel cancer risk but it is not 100% effective at preventing bowel cancer Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP) The primary end-point is the number of participants with one or more adenomas detected at routine one-year colonoscopy

Secondary end-points include the number of adenomas (total and ‘advanced’) per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as ‘intermediate risk’ for future surveillance Exploratory end-points include levels of bioactive lipid mediators such as omega-3 resolvin E1 and PGE in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination Monitor changes in omega-3 index and AA to EPA ratio indicative of ‘responders’ using biomarkers to identify a ‘change in risk’ Hull et al. 2013

8

Why fish oils sometimes ‘fail’ • Study participants are often recruited irrespective of their baseline levels in EPA+DHA, and treated with fixed doses, ignoring the large inter-individual variability in omega-3 status or variability in uptake

• It is often the case that individuals with the lowest omega-3 levels are the best ‘responders’ to fish oil

supplementation

• Omega-3 digested, absorbed and subsequently incorporated into cells and tissues – taking an omega-3 is not the same as increasing omega-3 levels

• Such factors may contribute to the tendency towards neutral results in many intervention trials. The omega-3 index has many features that qualify it as not only a biomarker of intake, but also as risk marker and most importantly, a risk factor and target for intervention

• The potential impact of an intervention may well be determined by successful cellular uptake of omega-3 and the failure to reach an optimal omega-3 index may go towards explaining inconsistencies reported in many clinical trials

• Establishing base line ‘biomarker’ levels may make it possible to identify ‘responders’ within the clinical trial setting by monitoring the changes in biomarker levels

von Schacky 2015

. 9

The beneficial effects of EPA & DHA on cancer survival

Omega-3 levels in cancer patients are up to 50 % lower than in healthy individuals; low omega-3 fatty acids are related to loss of adipose tissue and skeletal muscle, an indication of poor treatment response and reduced survival of cancer patients, thus suggesting that supplementation with omega-3 PUFA will be beneficial:

Several clinical studies have clearly demonstrated that the immune status is a major prognostic factor for the survival time in cancer patients

• Surgery, radiotherapy and chemotherapy can induce a significant decline in the ratio of T-helper cells to T-suppressor cells (Lissoni et al. 2009)

• Omega-3s have demonstrated immuno-modulatory effects, i,e. EPA & DHA restore the decreased ratio of T-helper cells to T-suppressor cells, resulting in prolonged survival of patients with cancer (Gogos et al. 1998)

• As tumour cells can be made more sensitive to chemotherapy than non-tumour cells when membrane lipids are enriched with omega-3, the addition of omega-3 fatty acids can improve the outcome of chemotherapy and overall survival rates (Barrera 2012)

The impact of omega-3 on survival time is dependent on successful incorporation highlighting the importance of biomarker analysis

10

Source: Tsoli & Robertson.2012

Cancer cachexia is a debilitating inflammatory-driven weight loss syndrome characterised by disease-induced starvation and wasting that occurs in up to 80% of patients with advanced cancer, and is responsible for death in up to 20% of cases (Utech et al. 2012) •Pure EPA has been shown to be effective in managing cachexia in experimental models via inhibition of NFkB, inhibition of cachectic factors [Proteolysis inducing factor (PIF) and lipid mobilising factor (LMF)] and via the reduction of pro-inflammatory cytokines •EPA decreases inflammation and increases lean body mass in pilot studies, but results from RCT are mixed and the current evidence remains inconsistent

EPA must be digested, absorbed and subsequently incorporated into cells and tissues to exert physiological functions therefore unless low incorporation is controlled for, differential incorporation of EPA may dilute the effect of EPA on improvements in lean body mass EPA supplementation may be more effective if provided earlier rather than later, when muscle loss is accelerated (Murphy et al. 2011)

11

Summary Western dietary and lifestyle factors, particularly those that create an

inflammatory environment, contribute significantly to cancer risk

Low omega-3 coupled with a high AA to EPA ratio may play a role in driving carcinogenesis

Modifying diet to reduce systemic inflammation by increasing the omega-3 index and manipulating the AA to EPA ratio has the potential to modify cancer risk and cancer outcomes

Integration of omega-3 fatty acid supplementation into the therapeutic approach to cancer patients is a novel and promising concept, which goes beyond their potential role in reversing cancer cachexia, promoting weight maintenance and improving muscle mass, chemotherapy and overall survival rates and quality of life

Using biomarkers is essential for identifying ‘responders’ More trials needed to clarify the unique and individual roles of EPA

and DHA in cancer prevention and treatment

12

References

Slide 2

• British Nutrition Foundation. Unsaturated fatty acids nutritional and physiological significance: the report of the British Nutrition Foundation's task force. New York: Chapman & Hall, 1992.

• https://www.gov.uk/government/statistics/ndns-results-from-years-5-and-6-combined

• Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM.

• Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. J Am Heart Assoc. 2013 Nov 19;2(6):e000513.

• Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the bloodstream of healthy adults. Prog Lipid Res. 2016 Jul;63:132-52.

Slide 3

• Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002 Oct;56(8):365-79.

Slide 4

• Azrad M, Turgeon C, Demark-Wahnefried W. Current evidence linking polyunsaturated Fatty acids with cancer risk and progression. Front Oncol. 2013 Sep 4;3:224.

• Doll R, Peto R. Avoidable risks of cancer in the United States. J Natl Cancer Inst 1981;66:1196-1265.

13

References

Slide 4

• Fernandez E, Chatenoud L, La Vecchia C, Negri E, Franceschi S. Fish consumption and cancer risk. Am J Clin Nutr. 1999 Jul;70(1):85-90.

• Laviano A, Rianda S, Molfino A, Rossi Fanelli F. Omega-3 fatty acids in cancer. Curr Opin Clin Nutr Metab Care. 2013 Mar;16(2):156-61.

• Willett WC. Diet and cancer: one view at the start of the millennium. Cancer Epidemiol Biomarkers Prev. 2001 Jan;10(1):3-8.

Slide 5

• Azrad M, Turgeon C, Demark-Wahnefried W. Current evidence linking polyunsaturated Fatty acids with cancer risk and progression. Front Oncol. 2013 Sep 4;3:224.

Slide 6

• Kumar N, Drabu s, Mondal SC. NSAID’s and selectively COX-2 inhibitors as potential chemoprotective agents against cancer: 1st Cancer Update. Arabian Journal of Chemistry. 2013 6: 1–23

Slide 7

• Fernandez-Bafiares F, Esteve M, Navarro E, Cabre E, Boix J , Abad-Lacruz A, Klaassen J, Planas R, Humbert P, Pastor C, Gassull MA. Changes of the mucosal n3 and n6 fatty acid status occur early in the colorectal adenoma-carcinoma sequence. Gut 1996 38: 254-259

• Fini L, Piazzi G, Ceccarelli C, Daoud Y, Belluzzi A, Munarini A, Graziani G, Fogliano V, Selgrad M, Garcia M et al: Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice. Clin Cancer Res 2010, 16(23):5703-5711.

14

References

Slide 7

• 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(7):918-925.

(Slides 7 & 8)

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 Jul 29;14:237

Slide 9

• Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol. 2012;2012:137289

• Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos F. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial. Cancer. 1998 Jan 15;82(2):395-402.

• Lissoni P, Brivio F, Fumagalli L, Messina G, Meregalli S, Porro G, Rovelli F, Vigorè L, Tisi E, D'Amico G. Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res. 2009 May;29(5):1847-52.

15

References

Slide 10

• Murphy RA, Yeung E, Mazurak VC, Mourtzakis M. Influence of eicosapentaenoic acid supplementation on lean body mass in cancer cachexia. Br J Cancer. 2011 Nov 8;105(10):1469-73.

• Tsoli M, Robertson G. Cancer cachexia: malignant inflammation, tumorkines, and metabolic mayhem. Trends Endocrinol Metab. 2013 Apr;24(4):174-83.

• Utech AE, Tadros EM, Hayes TG, Garcia JM. Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markers. J Cachexia Sarcopenia Muscle. 2012 Dec;3(4):245-51.

Slide 11

• von Schacky C. Omega-3 fatty acids in cardiovascular disease--an uphill battle. Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:41-7.

16