Tumor Selective Antiproliferative Naphthoxylosides

Sammanfattning: Proteoglycans (PG) are highly anionic macromolecules consisting of a core protein covalently substituted with long unbranched polysaccharide chains called glycosaminoglycans (GAGs). PGs are central components in multicellular organisms, and they may occur in the extracellular matrix (ECM), at the cell surface, or in the secretory pathway. At the tumor cell surface, PGs and GAGs are involved in the pathophysiological steps of tumor progression by regulation of tumor proliferation, invasion, metastasis, angiogenesis, and stem cell differentiation. Xylose is an unusual structural component of mammalian cells and it serves as the linker between the protein and the GAG chain in PG. β-D-xylosides attached to various hydrophobic aglycons can penetrate plasma membranes and act as artificial primers for GAG formation, independently of core protein synthesis. The overall purpose of this project was to investigate the antiproliferative activity of xyloside primed GAG chains and to study different aspects on how xylosides or xyloside primed GAG chains inhibit growth of cancer cells. This thesis demonstrates that the xyloside primed GAG chains produced by tumor cells inhibit growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside pro-drug, while surrounding normal cells do not produce any antiproliferative GAG chains. We have also shown effects on histone acetylation, indicating epigenetic effects.