A 4-deoxy analogue of N-acetyl-D-glucosamine inhibits heparan sulphate expression and growth factor binding in vitro

作者：van Wijk Xander M R; Oosterhof Arie; van den Broek Sebastiaan A M W; Griffioen Arjan W; ten Dam Gerdy B; Rutjes Floris P J T; van Delft Floris L; van Kuppevelt Toin H^*

来源：Experimental Cell Research, 2010, 316(15): 2504-2512.

DOI：10.1016/j.yexcr.2010.04.025

• Glycosaminoglycan
• Heparan sulfate
• Deoxysugar
• N-acetyl-D-glucosamine
• Growth Factor Binding
• Angiogenesis

Heparan sulphate (HS) is a long, linear polysaccharide, which has a basic backbone of -beta 1-4GlcA-alpha 1-4GlcNAc- units. The involvement of HS in many steps of tumourigenesis, including growth and angiogenesis, makes it an appealing target for cancer therapy. To target the biosynthesis of HS by interfering with its chain elongation, a 4-deoxy analogue of N-acetyl-D-glucosamine (4-deoxy-GlcNAc) was synthesized. Using immunocytochemistry and agarose gel electrophoresis it was shown that incubation with the 4-deoxysugar resulted in a dose dependent reduction of HS expression of MV3 melanoma cells, 1 mM resulting in an almost nullified HS expression. The parent sugar GlcNAc had no effect. 4-deoxysugar treated cells were viable and proliferated at the same rate as control cells. Other glycan structures appeared to be only mildly affected, as staining by various lectins was generally not or only modestly inhibited. At 1 mM of the 4-deoxysugar, the capacity of cells to bind the HS-dependent pro-angiogenic growth factors FGF-2 and VEGF was greatly compromised. Using an in vitro angiogenesis assay, 4-deoxysugar treated endothelial cells showed a sharp reduction of FGF-2-induced sprout formation. Combined, these data indicate that an inexpensive, easily synthesized, water-soluble monosaccharide analogue can interfere with HS expression and pro-angiogenic growth factor binding.

• 出版日期2010-9-10