Dr. Paola Persico
In recent years several studies in Human Medicine and, more recently, in Veterinary Medicine have highlighted the role of the conjugated linoleic acid (CLA) in the modulation of lipid and protein metabolism in the modulation of the immune system and in the anticancer activity.
The conjugated linoleic acid (CLA) is a long-chain fatty acid consisting of several isomers, they have been identified two forms (cis-9, trans-11 and trans-10, cis-12) particularly biologically active.
The conjugated linoleic acid is a natural origin product, which can be found primarily in bovine-derived products, the most studied in recent years: more than 1,200 studies have been published since 2000.
The mechanisms by which CLA inhibits carcinogenesis appear to include the reduction of cell proliferation, cell cycle and apoptosis alteration.
In addition, CLA seems to modulate markers of immune response and the formation of eicosanoids.
MODULATION OF THE IMMUNE SYSTEM
CLA influence the modulation of the immune response by interfering with the production of eicosanoids.
This mechanism is implemented through the inhibition of the constitutive cyclooxygenase (COX) enzyme interfering with the RNA messenger.
CLA regulates the production of lymphocytes, monocytes and macrophages because it binds with PPAR receptors in the core level.
These receptors are expressed in the immune system and are involved in the regulation of several genes implicated in the proliferation of lymphocytes, monocytes and macrophages.
Studies have shown that the mechanism by which CLA regulates the immune system is its ability to reduce, in the tissues, the level of arachidonic acid which is a major substrate for the synthesis of prostaglandin PGE2.
PGE2 is a regulator of TNF-a, a fundamental factor in several disease states (carcinogenesis, inflammation, etc.).
In animal studies it has been shown that the administration of CLA leads to an increase of suppressor T lymphocytes (CD8 +) and an increase of the activities they mediated.
In cultures of lymph cells and in rat serum it was shown that CLA increases the production of IgA, IgG and IgM while reducing the production of IgE (these latter cytokines are present when developing an allergic reaction of type 1 mediated by Th2 lymphocytes).
From these observations it can be assumed that the administration of CLA in the diet stimulates the synthesis of cytokines by Th1 lymphocytes and inhibits that of Th2 lymphocytes.
ANTICANCER ACTIVITY
From numerous studies it appears that the mechanism by which CLA is able to modulate the proliferation of neoplastic cells in both the blocking of DNA synthesis and responsible proteins.
Some studies show that CLA can inhibit tumor growth by promoting those signals that determine the apoptosis of neoplastic cells in many tissues (breast, liver, adipose).
Modulation of carcinogenesis is based in complex cellular mechanisms that seems lead to change the metabolism of fatty acids in the phospholipids favoring the inhibition of eicosanoid derived from arachidonic acid, such as PGE2 and PGE2 a.
Eicosanoids seem to modulate carcinogenesis in many tissues such as the mammary gland, skin, prostate and colon.
Some stages of the process of carcinogenesis, such as cell proliferation, local and systemic inflammation, the platelet aggregation and the cell differentiation, are particularly sensitive to eicosanoids.
The CLA seems to act on the incorporation in the phospholipids of the arachidonic acid thus reducing the presence of inflammatory eicosanoids.
Another mechanism that induces reduction of eicosanoids through CLA is the inhibition of the expression or the activity of the constitutive cyclooxygenase (COX-1) enzyme and the inducible form (COX-2).
COX-2 is produced as a response to inflammatory stimuli and leads to the formation of PGE2 (inflammation mediators).
Some studies have shown that high levels of COX-2 are associated with tumor progression and to apoptosis inhibition of cancer cells.
The occurrence or the overexposure of COX-2 found in many types of cancer are believed responsible for the production of factors that promote the formation of new blood vessels (angiogenesis), tumor proliferation, tumor cell of numerous alterations and the apoptosis block (mechanism indispensable leading to programmed cell death).
In the genesis of cancer it is also implicated the nitric oxide in response to the action of some classes of cytokines.
Excessive nitric oxide reacts with superoxide radicals to form a compound that leads to subsequent dependent oxidative damage of cell membranes, proteins and DNA.
The inhibition of the enzyme (iNOS), which leads to the formation of nitric oxide in response to the action of some classes of cytokines, determines a reduction of angiogenesis.
The CLA appears to suppress both the production of PGE2 and the nitric oxide in activated macrophages reducing the levels of messenger RNA for COX-2 and iNOS.
Bibliography:
– M.A. Belury “Inhibition of Cancerogenesis by Conjugated Linoleic Acid: Potential Mechanism of Action” Journal of Nutrition, October 25.2006, pp. 2995-2998
– K. Subbaramaiah, A.J. Dannenberg “Cyclooxygenase 2: a molecular target for cancer prevention and treatment” Trends in Pharmacological Sciences. 2004, 24, 96-102
– K.N.M. Khann, D.W. Knapp, D. B. Denicola et al. “Expression of cycloxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs” American Journal of Veterinary Research, 2000, 61: 471-481
