Proyectos de Ley radicados en el Congreso de la República en materia de Derecho

Azoxymethane (AOM) has been used extensively by investigators to induce colon tumors in chemoprevention studies. AOM is a potent carcinogen causing a high incidence of colon tumors in rodents that have similar biological properties to human colon tumors.

The AOM-induced model is cost efficient and reliably to causes epithelial cells to undergo pathogenesis from pre-neoplastic lesions, aberrant crypt foci (ACF), to adenomas and malignant adenocarcinomas. Although genetically engineered mouse models of CRC are available, AOM induces gene and protein expression changes that also occur in human CRC and enhances expression of COX-2 and iNOS, as well as adenomatous polyposis (APC) mutations [65]. In rats, AOM is metabolized by

cytochrome P450, specifically isoform CYP2E1. The first step is the hydroxylation of the methyl group of AOM to form methylazoxymethanol (MAM). MAM is then broken down by alcohol dehydrogenase in the liver, colon, kidney, and lung, into formaldehyde and a highly reactive alkylating methyldiazonium ion. This reaction forms DNA adducts resulting in GC to AT transitions and mutagenesis in colonic enterocytes [65].

Aberrant crypt foci (ACF) as colonic pre-neoplastic lesions in colons of

carcinogen treated mice were first described by Bird in 1987 [66]. ACF are hypothesized to be early, pre-neoplastic changes and accepted as morphologic markers of

carcinogenesis. In methylene or alcian blue stained colonic mucosa, ACF can be

distinguished from adjacent, normal crypts by their strong uptake of the blue stain. There

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are also elevation of the foci above the mucosal surface, large luminal diameters, elliptical luminal openings, and thicker epithelial linings surrounding the foci [67].

The AOM-induced colon cancer model activates several pathways including K-ras, β-catenin and TGFβ. K-ras is a small G-protein that regulates both mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/Akt intracellular

pathways which regulate cell growth, proliferation and glucose metabolism. Activation of PI3K/Akt can increase cell survival pathways via phosphorylation of downstream targets, including NFκB, and Bcl-xl [68]. PI3K/Akt also blocks p53 and the Forkhead family of transcription factors/Fas-ligand to decrease apoptosis [69]. In the cell cycle pathway, PI3K/Akt deactivates glycogen synthase kinase 3 (GSK-3) and promotes cyclin D1 and myc to increase cell proliferation. Downstream of PI3K/Akt, COX-2 has also been shown to be involved in the carcinogenesis of AOM [69].

β-Catenin is a multifunctional protein that regulates proliferation, differentiation and apoptosis in intestinal epithelial cells and is commonly dysregulated in colon ACF and tumors [70, 71]. β-Catenin is a downstream effector and functions as a transcription factor of the canonical Wnt/β-catenin/T-cell factor (Tcf) signaling pathway (Figure 2.5).

Several studies have reported that over expression and nuclear accumulation of β-catenin is an early event in colon carcinogenesis [71, 72]. AOM causes β-catenin mutations at codon 33 and 41, which are the serine and threonine residues that are targets for GSK-3β phosphorylation. In normal cells, cytoplasmic β-catenin levels are kept low through continuous degradation by the ubiquitin-proteasome pathway, which is controlled by a complex containing GSK-3β, adenomatous polyposis coli (APC), and axin [73].

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Figure 2.5 The canonical Wnt/β-catenin/T-cell factor (Tcf) signaling pathway

In malignant cells, the binding of Wnt proteins inhibits GSK-3β phosphorylation activity, which prevents β-catenin ubiquitination and degradation, so that β-catenin accumulates in the cytoplasm and translocates to the nucleus. This β-catenin is then free to bind to transcription factors from the LEF/Tcf family, and activates the transcription of a variety of target genes, such as cyclin D1 and c-Myc, which are growth-promoting genes. β-Catenin that lacks GSK-3β phosphorylation sites is associated with cancer.

Studies link mutations in β-catenin, APC, or axin as an early critical event in the

development of colon carcinogenesis, suggesting that activated GSK-3β complexes may function as tumor suppressors in normal cells by promoting β-catenin degradation.

Dysregulation levels of GSK-3β have been found both in human colon cancer cell lines and in primary colon tumors. Thus, the inactive expression of GSK-3β may promote

β-catenin

β-catenin

β-catenin Tcf/LEF

Cyclin D1, c-Myc

β-catenin β-catenin

P P

Proteosome

β-catenin degradation GSK-3β

axin APC

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neoplastic transformation by promoting cytosolic β-catenin accumulation and subsequent translocation into the nucleus to regulate transcription of genes.

In summary, there is a potential role for yerba mate tea in preventing colon carcinogenesis through inhibition of chronic inflammation; however, this pathway needs to be studied. Therefore, the overall objective of this research was to evaluate the anti-inflammatory and anti-colon cancer potential of yerba mate tea and its constituents using in vitro and in vivo models. We expect that the results of this research will provide a better understanding of the mechanisms by which yerba mate can be used to prevent inflammation and therefore colon carcinogenesis.

2.7 References

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