The Effects of Conjugated Linoleic Acids on Cancer
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processes Review The Effects of Conjugated Linoleic Acids on Cancer Marko Dachev 1,*, Jana Bryndová 1, Milan Jakubek 2 , ZdenˇekMouˇcka 1 and Marian Urban 1 1 Food Research Institute Prague, 102 00 Prague, Czech Republic; [email protected] (J.B.); [email protected] (Z.M.); [email protected] (M.U.) 2 Department of BIOCEV, First Faculty of Medicine, Charles University Prague, 252 50 Vestec, Czech Republic; [email protected] * Correspondence: [email protected] Abstract: Conjugated linoleic acids (CLA) are distinctive polyunsaturated fatty acids. They are present in food produced by ruminant animals and they are accumulated in seeds of certain plants. These naturally occurring substances have demonstrated to have anti-carcinogenic activity. Their po- tential effect to inhibit cancer has been shown in vivo and in vitro studies. In this review, we present the multiple effects of CLA isomers on cancer development such as anti-tumor efficiency, anti- mutagenic and anti-oxidant activity. Although the majority of the studies in vivo and in vitro summarized in this review have demonstrated beneficial effects of CLA on the proliferation and apoptosis of tumor cells, further experimental work is needed to estimate the true value of CLA as a real anti-cancer agent. Keywords: conjugated linoleic acids (CLA); anti-cancer; anti-tumor; anti-mutagenic; anti-oxidant; proliferation; apoptosis Citation: Dachev, M.; Bryndová, J.; 1. Introduction Jakubek, M.; Mouˇcka,Z.; Urban, M. The Effects of Conjugated Linoleic Fatty acids are important elements of the human body, having biological, structural Acids on Cancer. Processes 2021, 9, and maintenance roles. There is a great research of interest towards the fatty acids and its 454. https://doi.org/10.3390/ potential health benefits [1]. Depending on the presence or absence of the double bonds, pr9030454 fatty acids are classified into two major classes: saturated and unsaturated. Saturated fatty acids contain only single bonds, whereas unsaturated fatty acids contain double or triple Academic Editor: Carla Vitorino bonds. Unsaturated fatty acids that contain two or more double bonds are referred to as polyunsaturated fatty acids (PUFA). There are various types of PUFA, classified by their Received: 15 January 2021 chemical structure. The first type includes fatty acids which double bonds are separated by Accepted: 25 February 2021 methylene group (-CH2-), all found with cis configuration. This type of naturally occurring Published: 3 March 2021 fatty acids are known as essential fatty acids. Common non-conjugated PUFA are linoleic or !−6 (9 cis, 12 cis-C18:2), found in nuts, seed and vegetable oils and α-linolenic or !−3 Publisher’s Note: MDPI stays neutral (9 cis, 12 cis, 15 cis-C18:3), found in seed, oil of plants, fish and seafood. In the second type with regard to jurisdictional claims in the double bonds have conjugated bonds and includes fatty acids in multiple positional published maps and institutional affil- (9 cis, 11 trans-C18:2 and 10 trans, 12 cis-C18:2) isomers known as conjugated fatty acids iations. (CFA). A group of CFA, containing 18 carbons and 2 conjugated bonds are known as conjugated linoleic acids (CLA), those having 18 carbons and 3 double bonds are referred to as conjugated linolenic acids (CLNA) and those having 20 carbons and 5 double bonds are conjugated eicosapentaenoic acids (CEPA). A well-studied example of conjugated fatty Copyright: © 2021 by the authors. acids is CLA. Licensee MDPI, Basel, Switzerland. CLA are naturally occurring isomers of fatty acids found in ruminant animal food This article is an open access article products [2]. There are 28 known CLA isomers identified with different position (ranging distributed under the terms and from D7, D9 to D12, D14) of cis or trans geometry. The most common biological isomers conditions of the Creative Commons are the cis-9, trans-11(c9, t11), which accounts for more than 80% of CLA isomers in dairy Attribution (CC BY) license (https:// products and cis-12, trans-10 (t10, c12), present in some ruminant fats [3]. The natural creativecommons.org/licenses/by/ product of CLA is a mixture of two isomers: c9, t11 and t10, c12 available by partial 4.0/). Processes 2021, 9, 454. https://doi.org/10.3390/pr9030454 https://www.mdpi.com/journal/processes Processes 2021, 9, x FOR PEER REVIEW 2 of 18 Processes 2021, 9, 454 2 of 17 uct of CLA is a mixture of two isomers: c9, t11 and t10, c12 available by partial hydrogena- hydrogenationtion of linoleic acid of linoleic and/or acid isomerization and/or isomerization of cis unsaturate of cisdunsaturated fatty acids, using fatty acids,bacterial using en- bacterialzymes as enzymes catalysts as(Figure catalysts 1) [4] (Figure. Many1)[ bacteria4]. Many have bacteria been reported have been to reportedconvert free to convert LA into freeCLA: LA Butyrivibrio into CLA: Butyrivibrio fibrisolvens fibrisolvens[5], Megasphaera[5], Megasphaera elsdenii [6] elsdenii, Lactobacillus[6], Lactobacillus reuteri [7] reuteri, L. acidi-[7], L.dophilus acididophilus [8], L plantarum[8], L plantarum [9], and[9 ],Bifidobacterium and Bifidobacterium breve [10] breve. [10]. FigureFigure 1.1. StructureStructure ofof linoleiclinoleic acidacid (LA),(LA),c c9,9,t t1111 andandt 10,t10,c c12-CLA.12-CLA. CLACLA isis an an essential, essential, but but minor minor component component of of fats fats that that enters enters the the human human body body primarily primar- fromily from the sourcesthe sources of dairy of dairy products products and meat and meat from ruminantfrom ruminant animals animals [11]. The [11 physiological]. The physio- propertieslogical properties of CLA of have CLA received have received considerable considerable attention attention over the over past the few past decades few decades due to theirdue to documented their documented health-promoting health-promoting benefits benefits and biological and biological functions. functions. The main The health main propertieshealth properties described described of CLA of include CLA include the reduction the reduction of carcinogenesis, of carcinogen diabetes,esis, diabetes obesity, andobe- atherosclerosissity and atherosclerosis in different in different animal and animal cell and line cell studies line [studies12]. Although [12]. Although CLA was CLA firstly was reportedfirstly reported by Booth by in Booth 1935 inin butter 1935 in fat, butter one of fat the, one first of health the first beneficial health propertiesbeneficial attributedproperties toattributed CLA was to its CLA anti-carcinogenic was its anti-carcinogeni effects discoveredc effects discovered in the late 70in sthe by late Pariza 70 s et by al. Pariza [13,14 et]. Theal. [ CLA13,14 was]. The described CLA was as described an anti-carcinogen as an anti isolated-carcinogen from friedisolated ground from beef fried [14 ground–16]. Since beef then,[14–16 various]. Since studies then, various (in vivo studiesand in vitro(in vivo) demonstrated and in vitro) thatdemonstrated CLA could that act byCLA promoting could act theby promoting inhibitory the effects inhibitory on tumor effect cells on growth tumor [cell17]. growth However, [17]. the However, mechanisms the mechanisms of action throughof action which through CLA which acts againstCLA acts cancer against are cancer not fully are clear not atfully present. clear Anotherat present. important Another questionimportant is question the dose is and the which dose and isomer which is necessary isomer is tonecessary bring the to desired bring the beneficial desired effects.benefi- Incial most effects. of the In studies,most of CLAthe studies mixture, CLA was mixture demonstrated was demonstrated as a potential as anti-cancer a potential agent anti- tocancer regulate agent the to tumorregulate growth the tumor through growth different through metabolic different pathways metabolic and pathways to alter and lipid to peroxidation,alter lipid peroxidation, cell proliferation cell proliferation and apoptosis and[ apoptosis18]. Some [ of18]. the Some studies of the demonstrated studies demon- the effectivestrated the dose effectiv of a singlee dose isomer of a singlec9, t11-CLA, isomer but c9, not t11t-10,CLA,c12-CLA but not [17 t–10,19 ].c12 Contrary-CLA [17 to– the19]. initialContrary studies, to the there initial have studies been, few there reports have ofbeen CLA few that reports did not of showCLA that any did inhibitory not show effects any againstinhibitory cancer effects and against even showed cancer promotionand even showed on tumor promotion progression on tumor [20]. progression [20]. TheThe objectiveobjective ofof thisthis reviewreview isis toto summarizesummarize variousvarious reportsreports onon animals,animals, cellcell models,models, asas wellwell asas clinicalclinical studies,studies, toto provideprovide anan ideaidea onon thethe aspectsaspects ofof CLACLA anti-canceranti-cancer benefitsbenefits and its mechanisms of actions. and its mechanisms of actions. 2. Animal Models 2. Animal Models Pioneering research, done by Michal Pariza and colleagues, showed that the extracts of grilledPioneering ground beef research, exerted done anti-mutagenic by Michal Pari activity,za and and colleagues, that the responsible showed that anti-mutagen the extracts wasof grilled CLA [ground21]. Feeding beef exerted the mice anti with-mutagenic CLA developed activity, and only that half the the responsible number of anti tumor-mu- formationstagen was CLA andlowered [21]. Feeding the incidence the mice ofwith carcinogenesis CLA developed [13– 16only,21 ].half Various the number animal of studies tumor Processes 2021, 9, 454 3 of 17 reported the effects of CLA (synthetic or natural source) in vivo, demonstrating the CLA inhibition on initiation, promotion and progression of cancer [22]. Different animal models have been used to prove the inhibitory effects of CLA in different cancer developments (Table1). Table 1. Effects of conjugated linoleic acids (CLA) in carcinogenesis (animal models). Cancer Inducer Animal CLA Source Effects Reference Type Incresed apoptotic index, Colon DMD 1 SD rats CLA mixture Park et al. [23] lower number of tumors. Incresed apoptosis, and Colon AOM 2 SD rats CLA mixture Shiraishi et al. [24] activity of Caspase-3.