Schematic representation of possible mechanism of action of OKN-007 in IC3752 pGBM tumor bearing mice.

Heparan sulfate proteoglycans (HSPG) consist of a protein core and heparan sulfate (HS) chains consisting of linear carbohydrate chains of repeating disaccharide units. Dependent on the HSPG core protein, HSPGs are found at the cell surface (1), in the extracellular matrix (2), or in secretory vesicles [98]. Essential for their function in cell signaling, the HS chains undergo extensive post-translational modifications, including sulfation on the 6-O- position of glucosamine [19]. By removing 6-O-sulfates on HS chains and mobilizing protein ligands from HSPG sequestration in the extracellular environment (3), the SULF-2 can increase the solubility of a variety of growth factors (e.g. PDGF) (4) thus increasing the activation of PDGFR-α and downstream signaling pathways in tumor cells (5) [98]. Similarly to SULF2, decorin is also associated to the PDGFRα pathway. Interestingly, decorin does not co-localize with PDGFRα, but binds directly to its natural ligand PDGF, directly blocking the activity of PDGFRα (6) [104]. Our current data showed that OKN-007 was able to decrease the immunoexpression of SULF2 (7) and PDGFRα (8), and increase the expression of decorin (9) in IC3752 pGBM tumor bearing mice, which may be also associated to the inhibition of tumor angiogenesis and cell proliferation (10) also observed in OKN-007 treated animals. SO3-: sulfate, PDGF: Platelet-derived growth factor. The schematic is a modification of combined schemes obtained from Oncotarget, 3(5): 568–575, Phillips JJ (2012) [98] (With permission from Impact Journals), and from FEBS Journal, 280(10):2150–2164, Baghy K et al., (2013) [104] (With permission from John Wiley and Sons).