Both the major isomers of CLA: cis-9, trans-11 C18:2 and trans-10, cis-12 C18:2 were considered as potential inhibitors of the tumorigenesis. In experiments conducted on animals, CLA inhibited the development of chemically induced can-cer [17, 18] – e.g. altered the latency and metastasis of the highly metastatic transplantable line in mouse mammary tumor [19]. In 2002, it was announced that CLA isomers might protect against the development of breast cancer in post-menopausal women [20]. These results were confirmed by studies conducted with the use of 2 cell lines in cultures of the human breast cancer cells MDA – MB-231 and MCF-7. In these studies it was reported that CLA might inhibit the development of breast cancer through regulation of the expression of the key enzymes e.g. stearoyl-CoA desaturase (SCD) [21]. In this year, it was shown that CLA may inhibit human breast cancer through activation of the apoptosis via the estrogen receptor alpha – ER α (about 75% of breast cancers are estrogen ER α positive) [22].
Considerable evidence demonstrates that anticancer activity of CLA may be also associated with inhibition of the angiogenesis (by depression of growth factors secretion).
Dietary CLA decreased serum levels of vascular endothelial growth factor (vEGF) and whole mammary gland levels of vEGF and its receptor (Flk-1) in the cells. Additionally, CLA inhibited angiogenesis in vitro in the dose-dependent manner [23, 24].
cells. Apoptosis involves the activation of a highly regulated series of intracellular events in which the cell actively par-ticipates in its own death. Genes such as bcl-2 and proteolytic enzymes such as the caspases, play an important role in apoptotic cell death in other cell types [32].
As has been shown CLA (especially the trans-10, cis-12 isomer) markedly limited the divisions of cancer through induction of apoptosis and inhibition of DNA synthesis (by the lowering polyamine synthesis and enzyme polymer-ase activity) [25, 33, 34, 35]. Isomer trans-10, cis-12 C18:2 may also induce apoptosis by inducing apoptosis of pre-neoplastic and pre-neoplastic mammary epithelial cells through ER stress [31]. Ou et al. show that isomer trans-10, cis-12 C18:2 induced a time- and concentration-dependent cleav-age of caspases-3 and -9, and release of cytochrome c from mitochondria to cytosol [31]. Also levels of antiapoptotic protein – Bcl-2 were down-regulated after trans-10, cis-12-CLA treatment, whereas proapoptotic protein – Bax were up-regulated by CLA [31].
It was noticed that tumor cells do not possess sufficient antioxidant defense systems compared to healthy cells, and they are more susceptible to oxidative and peroxidative damage. Polyunsaturated fatty acids are the main intracel-lular substrates for lipid peroxidation, thus PUFA derived reactive lipid compounds could damage cell membranes, change the cellular composition or cytoskeletal assembly, modify membrane transport systems or enzymes or inhibit polymerase reactions and polyamine synthesis. Supplemen-tation of cells with CLA also increased the susceptibility of tumor cells to lipid peroxidation [25]. Cultivation of cells with CLA leads to an increased ROS synthesis, partly by PPAR-alpha mechanism. An increase in ROS concentration in the cell may stimulate apoptosis [36].
Conjugated linoleic acid also up-regulate anticancer de-fenses through modification of an immune and inflam-matory responses and modulation of immune function
Recent publications demonstrated that CLA isomers modulated immune function in humans and animals [35].
In animals CLA reduced immune – induced wasting and enhanced ex vivo lymphocyte proliferation and decreased tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production. In mice, increased lymphocyte pro-liferation and IL-2 production. Furthermore, evidence suggests that the mixture of CLA isomers exert distinct effects on immune function. Specifically, these isomers have differential effects on specific T cell populations and immunoglobulin subclasses in animal and human studies [37]. CLA improved natural killer cell cytotox-icty and humoral and T cells responses [25] to mitogens [38, 39]. Both isomers increased IL-2 production, pro-liferation and release of granzyme [37, 40]. Mixtures of CLA also up-regulated the humoral function: increased IgG and IgM, IgA production of spleen lymphocytes in a dose – dependent manner production [41, 42] and re-duced macrophage function e.g. rere-duced the synthesis of
inflammatory mediators [43, 44, 45, 46] and/or inflam-matory enzymes [47, 48].
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R O C Z N I K I P O M O R S K I E J A K A D E M I I M E D Y C Z N E J W S Z C Z E C I N I E 2008, 54, 3, 126–129
MAŁGORZATA KAZIMIERCZAK, STANISŁAWA BIELECKA-GRZELA, ADAM KLIMOWICZ1