Diet and Cancer. Series Editor Adriana Albini. For further volumes:

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2 Diet and Cancer Series Editor Adriana Albini For further volumes:

3 Gabriella Calviello Simona Serini Editors Dietary Omega-3 Polyunsaturated Fatty Acids and Cancer 123

4 Editors Prof. Gabriella Calviello Università Cattolica Sacro Cuore - Roma Istituto di Patologia Generale Largo F. Vito, Roma Italy g.calviello@rm.unicatt.it Dr. Simona Serini Università Cattolica Sacro Cuore - Roma Istituto di Patologia Generale Largo F. Vito, Roma Italy serini_s@yahoo.it ISBN e-isbn DOI / Springer Dordrecht Heidelberg London New York Library of Congress Control Number: Springer Science+Business Media B.V No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Contents Part I Possible Mechanisms 1 Possible Mechanisms of ω-3 PUFA Anti-tumour Action... 3 Michael B. Sawyer and Catherine J. Field Part II ω-3 PUFAs and Colon Cancer 2 ω-3 PUFAs and Colon Cancer: Epidemiological Studies Yasumi Kimura 3 ω-3 PUFAs and Colon Cancer: Experimental Studies and Human Interventional Trials Simona Serini, Elisabetta Piccioni, and Gabriella Calviello Part III ω-3 PUFAs and Hormone-Related Cancers (Breast and Prostate) 4 ω-3 PUFAs and Breast Cancer: Epidemiological Studies Paul D. Terry and Pamela J. Mink 5 ω-3 PUFAs and Prostate Cancer: Epidemiological Studies Pierre Astorg 6 ω-3 PUFAs: Interventional Trials for the Prevention and Treatment of Breast and Prostate Cancer Isabelle M. Berquin, Iris J. Edwards, Joseph T. O Flaherty, and Yong Q. Chen 7 ω-3 PUFAs, Breast and Prostate Cancer: Experimental Studies Iris J. Edwards, Isabelle M. Berquin, Yong Q. Chen, and Joseph T. O Flaherty Part IV ω-3 PUFAs and Other Cancers 8 ω-3 PUFAs and Other Cancers Kyu Lim and Tong Wu v

6 vi Contents 9 The Influence of ω-3 PUFAs on Chemo- or Radiation Therapy for Cancer W. Elaine Hardman 10 ω-3 PUFAs and Cachexia Michael J. Tisdale Index

7 Contributors Pierre Astorg Unité Nutrition et Régulation Lipidique des Fonctions Cérébrales (NuReLiCe), INRA, Jouy-en-Josas, France, Isabelle M. Berquin Departments of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA, Gabriella Calviello Institute of General Pathology, Catholic University, L.go F. Vito 1, Rome, Italy, Yong Q. Chen Departments of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA, Iris J. Edwards Department of Pathology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA, Catherine J. Field Alberta Institute for Human Nutrition, 4-126A HRIF East, University of Alberta, Edmonton, AB, Canada, W. Elaine Hardman Department of Biochemistry and Microbiology, Byrd Biotechnology Science Center, Marshall University School of Medicine, Huntington, WV 25755, USA, Yasumi Kimura Department of Nutrition and Life Science, Fukuyama University, Fukuyama, Hiroshima, , Japan, Kyu Lim Department of Biochemisty, Cancer Research Institute and Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, Korea, Pamela J. Mink Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA, Joseph T. O Flaherty Departments of Internal Medicine and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA, joflaher@wfubmc.edu vii

8 viii Contributors Elisabetta Piccioni Institute of General Pathology, Catholic University, L.go F. Vito 1, Rome, Italy, Michael B. Sawyer Departments of Oncology, University of Alberta, Edmonton, AB, Canada, Simona Serini Institute of General Pathology, Catholic University, L.go F. Vito 1, Rome, Italy, Paul D. Terry Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA, Michael J. Tisdale Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK, Tong Wu Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,

9 Introduction: Omega-3 PUFAs, Why Do We Speak About Them? Gabriella Calviello and Simona Serini Abstract In spite of the fact that few dietary components are so widely recognized as able to improve human health such as ω-3 polyunsaturated fatty acids (PUFAs), so that their sector in the nutritional market has been increasingly growing worldwide, many unresolved questions still remain about them. In particular, there is urgent need for better understanding their possible role as anti-neoplastic agents. First of all, the chemical structure, the intracellular metabolism, and the dietary sources and bioavailability of these dietary fatty acids will be described in this introductive chapter to make easier the comprehension of the remaining parts of the book. Afterward, a brief outline of ω-3 PUFA reported benefits in different fields of human health will be provided. In this introductive part we will tackle also the problem of the discrepancies occurring between the results of most experimental studies on animals and cultured cells, which, almost univocally, suggest the beneficial anti-neoplastic effects of these fatty acids, and the outcome of several of the epidemiological observational studies, which, conversely, shows a scarce or null positive association between high intake of fish or fish oil at high content in ω-3 PUFAs and prevention of different kinds of cancer. Finally, a brief outline of the organization of the present book will be provided. Keywords ω-3 PUFA Metabolism Dietary sources Bioavailability Anti-neoplastic effects Introduction There are few dietary components that are so widely recognized as able to improve human health like ω-3 polyunsaturated fatty acids (PUFAs), and whose sector in the nutritional market has been increasingly growing worldwide. However, despite G. Calviello (B) Institute of General Pathology, School of Medicine, Catholic University, L.go F. Vito Rome, Italy g.calviello@rm.unicatt.it ix

10 x Introduction: Omega-3 PUFAs, Why Do We Speak About Them? their large fame and easy commercial availability, many unresolved questions still remain about them. For instance, may their intake represent an actual preventive strategy against cancer? Is their ingestion safe for healthy people? Do they have the potential to act as chemotherapic agents in combination or not with other conventional anti-cancer therapies? Which kind of cancer patients could actually benefit from treatments with ω-3 PUFAs? At what stages of cancer growth and progression their intake could be considered really fruitful? The present book has been thought in order to collect the findings and opinions of several influential scientists in the fields and thus to help answering these and other questions. The beneficial effect of ω-3 PUFAs on hormone-related cancers (breast and prostate cancer) and colon cancer has received most of the attention, and for this reason they will be treated in separate chapters. ω-3 PUFAs, however, appear to exert their positive influence also toward a number of other kinds of cancers, including leukemias/lymphomas, melanoma, neuroblastoma, liver, and lung cancer. However, before treating these specific topics, a general introduction will be furnished in this chapter with the aim to clarify some basic aspects regarding ω-3 PUFAs, such as their chemical structure and metabolism, their sources and bioavailability, and the other diseases whose incidence or progression can be favorably affected by these fatty acids. Chemistry and Metabolism of ω-3 PUFAs Fatty acids (FA) are constituted by carbon chains of various lengths in which carbons are bound by single or double bonds. A methyl group is present at one end (the n or ω end) and a carboxyl group at the other end. The lack or presence of double bonds between the carbons defines the two classes of saturated and unsaturated fatty acids (UFA). Depending on the presence of one or more double bonds in the carbon chain, UFAs are divided into monounsaturated fatty acids (MUFAs) and PUFAs. The prevalent PUFAs found in nature belong to the ω-3 and ω-6 classes of PUFAs, whose first double bond is, respectively, placed either three carbons (in the ω-3 or n 3 position) or six carbons (in the ω-6 or n 6 position) from the methyl end of the carbon chain. The three main dietary ω-3 PUFAs are α-linolenic acid (C18:3 n 3, all-cis-9,12,15-octadecatrienoic acid, ALA), eicosapentaenoic acid (C20:5 n 3, all-cis-eicosa-5,8,11,14,17-pentaenoic acid, EPA), and docosahexaenoic acid (C22:6 n 3, all-cis-docosa-4,7,10,13,16,19-hexaenoic acid, DHA) (Fig. 1). ALA, together with linoleic acid (LA, 18:2 n:6), is considered the essential fatty acid (EFA), namely the diet must necessarily provide them, since the desaturase needed to place the double bond in position ω-3 or ω-6 in the PUFAs is lacking in mammals. On the other hand, this desaturase is present in vegetables, which, therefore, represent the main dietary source of ALA and LA for mammals. Many commonly used vegetables oils are enriched in LA (corn, safflower, and soybean oils), whereas canola oil, ground flaxseed, and walnuts contain high levels of ALA. PUFAs belonging to one of the two different classes (ω-3 or ω-6) are not interconvertible into PUFAs of the other class. In our tissues, ALA and LA can be metabolized by the sequential action of several desaturases and elongases to produce EPA and arachidonic acid (AA, 20:4 n 6), respectively. Further

11 G. Calviello and S. Serini xi Fig. 1 Chemical structures of the major dietary ω-3 PUFAs. ALA: α-linolenic acid; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid ALA 1 ω 2 3 COOH EPA 1 ω 2 3 COOH DHA 1 ω 2 3 COOH desaturase, elongase, and partial peroxisomal beta-oxidation steps are needed [1, 2] to generate ω-3 PUFAs longer than EPA, such as DHA (for a detailed description of all the reactions, see Fig. 7.1). It has been shown that the ALA affinity for 6- desaturase is higher than that of LA. However, if the Western diet is adopted, in which LA is present in higher amounts than ALA, LA becomes the EFA preferentially desaturated [3]. As a result, the endogenous production of EPA and DHA by the precursor ALA is not very efficient in humans, and the efficiency of the conversion of ALA to EPA or DHA becomes particularly low in preterm infants and may also decline with old age [4]. Consequently, the main sources of EPA and DHA are animal tissues deriving from poultry, fat fish, and seafood, which contain high levels of these fatty acids. However, the current dietary supplies of the majority of Western countries are able to furnish very low amounts of ω-3 PUFAs. It has been calculated that the dietary ratio of ω-6 to ω-3 PUFAs ranges from 15/1 to 16.7/1 in Western diets and, therefore, is much lower than the ratio of 1/1 present in wild animal s and probably also in our ancestor s diets [5]. In the short periods of time over the past years an absolute and relative change of ω-3/ω-6 PUFA ratio in Western diets has occurred which could help to explain the increasing incidence of some kinds of human diseases [5]. Both ω-3 PUFAs and ω-6 PUFAs have the potential to influence gene expression and the unchanged dietary ratio between ω-6 PUFAs and ω-3 PUFAs of 1/1 over millions of years could have substantially influenced genetic modifications and human evolution. Now, a substantial decrease in EPA and DHA incorporated in cellular membranes and the concomitant increase in AA may have produced dangerous consequences for human health. Intracellular Metabolism of ω-3 PUFAs and Competition with Arachidonic Acid At this point, the description of the oxidative metabolism of AA and EPA, and, in particular, of the influence of ω-3 PUFAs on the oxidative metabolism of AA, seems particularly useful to understand the possible benefits deriving from the substitution

12 xii Introduction: Omega-3 PUFAs, Why Do We Speak About Them? of AA for these fatty acids in membranes. Following a series of cellular stimulations, AA is released from membranes by the action of phospholipase A 2 (PLA 2 ) and metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes into the oxygenated metabolites prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and hydro fatty acids, collectively known as eicosanoids [6] (Fig. 2). The AA-derived eicosanoids are biologically highly efficient, acting at very small concentrations. They have the potential to influence key events of physiological and pathological processes, including proliferation, survival, and inflammation [7]. The formation of the AA products is normally controlled, but in some pathological conditions such as cancer excessive amounts are produced [8]. After ingestion of fish or fish oil, dietary EPA and DHA may induce a decreased eicosanoid production by AA and reduce all the molecular responses related to the oxidative metabolism of AA in different ways including (a) the partial replacement of AA in cell membranes, since they compete with it for acylation in position sn-2 of membrane phospholipids; (b) the direct competition of EPA and AA for PLA2 2 AA 2-series PGs 2-series TXs COX-1 COX-2 EPA 3-series PGs 3-series TXs 5 LOX 12-LOX 15- LOX 4-series LTs 5-series LTs Fig. 2 Competition between arachidonic acid (AA) and eicosapentaenoic acid (EPA) for cyclooxygenases (COX) and lipoxygenases (LOX). Phospholipase A 2 (PLA 2 ) catalyzes the hydrolysis of membrane phospholipids to release free AA and EPA. Afterward, free AA and EPA are converted by the same enzyme COX and LOX to their oxygenated metabolites prostaglandins (PGs), tromboxanes (TXs), and leukotrienes (LTs), collectively named eicosanoids. AA- and EPA-derived eicosanoids possess different biological activities. Plenty of works have shown proinflammatory and pro-carcinogenic activities for AA-derived eicosanoids (see the text for further details)

13 G. Calviello and S. Serini xiii COX and 5-LOX, and production of EPA-derived eicosanoids (3-series TX, 3- series PG, and 5-series LT), which show lower biological activity than AA-derived eicosanoids [9] (Fig. 2); (c) the EPA- and DHA-induced reduction of COX-2, the inducible form of COX, which is expressed mainly during inflammation and tumor growth [10, 11]. Moreover, recently it was found that both EPA and DHA may be metabolized to previously unknown potent bioactive (in the nm range) eicosanoid and docosanoid products with anti-inflammatory and protective properties [12]. They have been comprised in the classes of resolvins, docosatriens, and protectins. Resolvins derived from EPA and DHA are named resolvins E and D [13]. DHA is the parent compound for docosatrienes, containing conjugated triene structures [14]. Neuroprotectins indicate docosatrienes and D-series resolvins that have been shown to exert neuroprotective and anti-inflammatory actions [14]. Aspirin can trigger in vivo the synthesis of a further highly active series of these compounds (17 R D-series resolvins and docosatrienes) [14] (Fig. 3). PLA2 2 EPA DHA Microbial P450 LOX Aspirin COX-2 LOX 17R-Resolvins D-series (AT RvD1-D4) LOX Resolvins E-series (E1 and E2) 17S-Resolvins D-series (RvD1-D4) Protectin D1/ Neuroprotectin D1 Fig. 3 Formation of novel discovered potent bioactive eicosanoids and docosanoids from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The figure reports the recent acquisitions according to which EPA and DHA may be metabolized to previously unknown novel compounds (named resolvins and protectins) with high potency as anti-inflammatory and proresolving agents [see the text and Ref. [13] for further details]. PLA 2 : phospholipase A 2 ;COX: cyclooxygenase; LOX: lipoxygenase

14 xiv Introduction: Omega-3 PUFAs, Why Do We Speak About Them? Dietary Sources and Bioavailability of ω-3 PUFAs Fatty fish is a good natural source for the long-chain ω-3 PUFAs EPA and DHA. Fish oil supplements are other sources artificially added to the diet and include fish oil capsules containing high levels of EPA and/or DHA and food enriched with fish oils. Recently, given the possible contamination of marine fish, effort has been made to obtain purified ω-3 PUFAs from a source different from fish, and algal oils have been obtained from cultured microalgae, which could represent a quite safe and convenient source of non-fish-derived ω-3 PUFAs. Recently also walnuts have been considered a good source of ω-3 fatty acids [15], being rich in ALA. Even though the conversion of ALA into longer ω-3 PUFAs (see above) is generally considered low, it has been shown that a moderate consumption of walnuts (4 walnuts/day for 3 weeks) markedly increases the blood levels of ALA and of its metabolic derivative, EPA. Probably, as suggested by the authors, plant ALA, at the high levels found in appropriate food items, such as walnuts, may favorably affect the ω-3 long-chain PUFA status. Bioavailability of ω-3 PUFAs is generally evaluated measuring their amount or concentrations in total lipids or lipid fractions (free fatty acids, triglycerides, phospholipids, cholesterol esters) in plasma, serum, lymph, platelets, and red blood cells as well as in the tissues under study. For instance, if we consider plasma total lipids, high amount of ω-3 PUFAs may be incorporated into them. For instance, starting from a basal serum total lipid level of about 20 μm EPA and 80 μm DHA in humans [16], a dietary fish oil supplementation (3.0 g/day EPA + DHA) or daily servings of salmon (1.2 g/day EPA + DHA) [17, 18] may allow an enrichment of total serum lipids ranging from 100 to 130% for EPA and from 25 to 45% for DHA. Even higher increases have been reported for total phospolipids after dietary supplementation with EPA + DHA ethyl esters (1.9 and 0.9 g/day, respectively) (250% for EPA and 40% for DHA) [17, 18]. However, a not completely clarified aspect of PUFA metabolism is what is the best ω-3 PUFA source to obtain an optimal absorption. It was recently shown that, irrespective of the source of ω-3 PUFAs present in formula supplements for infants (either egg PL or low EPA fish oil and fungal TG), the concentrations of EPA and DHA achieved in the different infant lipid plasma fractions (total PL, TG, and CE) were very similar [19]. Accordingly, the intake of equivalent doses of EPA and DHA given either as a mixture of EPA and DHA ethyl esters or as a natural fish oil (containing mainly ω-3 PUFAs esterified to TG) led to similar serum levels of EPA and DHA in adults [20]. However, recently, it was found that high concentrations of ω-3 PUFAs in plasma were achieved better if the dietary source of these fatty acids was fish (containing mainly ω-3 PUFAs esterified in glycerol lipids), rather than capsules containing ω-3 PUFA ethyl esters [18 22]. Recently it was also reported that algal-oil DHA capsules and cooked salmon were bioequivalent in providing DHA to plasma and red blood cells [23]. Even though levels of EPA and DHA in serum or plasma lipids may give important information regarding the bioavailability of these fatty acids, recently the enrichment of erythrocyte membranes (the so called ω-3 index) has been considered a better biomarker for ω-3 PUFAs [24], at least to establish the risk of coronary heart disease

15 G. Calviello and S. Serini xv mortality, especially sudden cardiac death. Also in other pathologic fields this index may be useful, mirroring the incorporation of these FA in cell membranes of other body districts, where ω-3 PUFAs may actually produce their beneficial effects. The use of this index appears interesting, since it is just the membrane enrichment with ω-3 PUFAs which is often considered crucial to explain their beneficial effects. Moreover, according to many authors, the membrane ω-3/ω-6 PUFA ratio has been considered even a better index to explain their beneficial effects [25]. Beneficial Effects of ω-3 PUFAs on Human Health Currently, the beneficial action of ω-3 polyunsaturated fatty acids (PUFAs) in cancer prevention, therapy, and cachexia is supported by plenty of evidence that will be examined in the following chapters with detail [26 30]. However, the first observation of a possible beneficial healthy effect of ω-3 PUFAs, dating back to about four decades ago, was the relationship existing between the low mortality from cardiovascular diseases of Greenland Inuit populations and their high consumption of fish [31]. Nowadays, the role of ω-3 PUFAs as nutritional factors with the potential to prevent the incidence as well as to lower the progression of different chronic pathologic conditions has been well established. Most of the results have been obtained in the cardiovascular field, and now it is well recognized that ω-3 PUFAs beneficially improve dyslipidemias, especially lowering plasma levels of triglycerides [32]. Moreover, it has been proven that they slightly decrease blood pressure [33], inhibit the formation of atherosclerotic plaque [34], and reduce the risk of sudden death [35], cardiac arrhythmias [36], and stroke [37] in individuals with established cardiac pathologies. Furthermore, they can be useful in preventing the pathological vascular complications of diabetes [38]. On this basis, many nutritionist and cardiologist agencies worldwide agree in recommending at least two or three fish portions/week for the primary and secondary prevention of cardiovascular diseases and supplementations of ω-3 PUFAs as fish oil extracts [39 41]. Consequently, the prescription of fish oil capsules has currently become common in clinical cardiology practice. The increased sales of drinks and food products fortified with ω-3 PUFAs worldwide also demonstrate the extreme popularity of the notion that ω-3 PUFAs exert various health effects. Recently, their dietary intake has been also recommended during pregnancy and lactation [4, 42] since it has been established that ω-3 PUFAs exert crucial effects on growth and neurological development of fetuses and newborn infants [43, 44]. Plenty of data have been published on the subject, and it has been shown that maternal plasma phospolipid (PL) concentration of PUFAs increases during pregnancy, probably mobilized from maternal stores [45]. Especially DHA increases in plasma PL, and this is related to the fact that fetus needs PUFAs, especially DHA, for the normal development of its brain and retina [46, 47]. It has been shown that during pregnancy women may become increasingly deficient in DHA [45], and probably the maternal capacity to meet the high fetal requirement for DHA [48] may work at its limits or

: Overview of EFA metabolism

: Overview of EFA metabolism Figure 1 gives an overview of the metabolic fate of the EFAs when consumed in the diet. The n-6 and n-3 PUFAs when consumed in the form of dietary triglyceride from various food sources undergoes digestion