Inhibition of reverse transcriptase activity of HIV by polysaccharides of brown algae

Brown algae have two kinds of acid polysaccharides present in the extracellular matrix: sulfated fucan and alginic acid. We have previously isolated and characterized fucans from several species of brown seaweed. The characterized fucans from Dictyotaceae are heterofucans containing mainly fucose, galactose, glucose, xylose, and/or uronic acid. The fucan from Fucus vesiculosus is a homofucan containing only sulfated fucose. We assessed the activity of these fucans as inhibitors of HIV from reverse transcriptase (RT). Using activated DNA and template primers poly(rA)-oligo(dT), we found that fucans at a concentration of 0.5-1.0 mu g/mL had a pronounced inhibitory effect in vitro on the avian reverse transcriptase, with the exception of xylogalactofucan isolated from Spatoglossum schroederi, which had no inhibitory activity. The alginic acid (1.0 mu g/mL) inhibited the reverse transcriptase activity by 51.1% using activated DNA. The inhibitory effect of fucans was eliminated by their desulfation. Furthermore, only xylofucoglucuronan from S. schroederi lost its activity after carboxyreduction. We suggest that fucan activity is not only dependent on the ionic changes but also on the sugar rings that act to spatially orientate the charges in a configuration that recognizes the enzyme, thus determining the specificity of the binding. (C) 2008 Elsevier Masson SAS. All rights reserved.62530330

Hedgehog signaling maintains chemoresistance in myeloid leukemic cells

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The development of resistance against chemotherapy remains one of the major challenges in the clinical management of leukemia. There is still limited insight into the molecular mechanisms that maintain the chemotherapy-resistant phenotype, despite the obvious clinical relevance that such knowledge would have. In this study, we show that the chemotherapy-resistant phenotype of myeloid leukemia cells correlates with activation of the Hedgehog (Hh) pathway, whereas in chemosensitive cells, such activation is less pronounced. Importantly, the overexpression of Hh pathway components induces chemoprotection and inhibition of the pathway reverts chemoresistance of Lucena-1 cells, apparently by interfering with P-glycoprotein-dependent drug resistance. Our data thus identify the Hh pathway as an essential component of multidrug resistance (MDR) myeloid leukemia and suggest that targeting the Hh pathway might be an interesting therapeutic avenue for overcoming MDR resistance in myeloid leukemia. Oncogene (2010) 29, 6314-6322; doi:10.1038/onc.2010.375; published online 30 August 2010294863146322Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Top-Institute pharmaMaag-, Lever-, DarmstichtingConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq