Modifications on glycosidic enzymes as a strategy to alter tumour cell adhesion

Abstract

Alterations in the expression of carbohydrates and the enzymes involved in their synthesis (glycosidases and glycosyltransferases) can be considered as universal feature of malignant transformation. Iminosugars, monosaccharide analogues compounds, have emerged as a new class of glycosidase inhibitors and have been suggested as therapeutic tools to inhibit tumour metastasis. The addition of an N-alkyl chain to iminosugars seems to increase their efficiency. We have test the cytotoxicity of D-fagomina and (2R,3S,4R,5S)-2-(hydroxymethyl)-5-methylpyrrolidine-3,4-diol and their N-alkyl derivatives. The N-alkyl derivative have shown an inhibition of ¿-L-fucosidases i ¿-D-glucosidases. Lewis antigens are fucosylated oligosaccharides carried by glycoproteins and glycolipids, synthesized by the sequential action of fucosyltransferases (FucT) and sialyltransferases (ST). Their aberrant expression such as the over expression of sialylated antigens (sLea and sLex) has been viewed as one of the underlying mechanisms for metastasis in different carcinomas, due to the interaction of those antigens with the E-selectin present on endothelial cells that mediate the extravasation of cancer cells. Clinical studies have described that the presence of chronic inflammation in the digestive tract increase the risk of carcinogenesis. Therefore we have described the regulation by pro-inflammatory cytokines (IL-1ß and IL-6) of fucosyltransferases involved in Lewis antigen synthesis. In the other hand, we have studied FucT III and FucT V implications in the synthesis of Lewis antigens and how changes on Lewis antigens expression pattern alter the adhesion capacities of MKN45 cells.