Abstract 556: Extracellular sulfatase 2; enzymatic inhibition by OKN-007 a disulfonylphenyl nitrone with anticancer activity and other sulfamate and sulfone compounds

Abstract

Abstract Sulfatase 2 (Sulf2) is an extracellular enzyme which catalyzes the removal of 6-O-sulfate groups on glucosamine from subregions of the glycosaminoglycan heparin sulfate. Sulf2 action alters the binding of protein ligand growth factors such as VEGF, FGF-2, TGF and SDF-1 to heparin and cellular receptors. Sulf2 is enriched in several tumors including breast cancer, pancreatic cancer, lung cancer and liver cancer and studies in experimental models have shown its action is important in cancer development. We have shown that PBN (α-phenyl-tert-butylnitrone) nitrones have anti-cancer activity in experimental cancer models including the rat choline deficiency liver cancer model, the mouse APCmin model of colon cancer and the rat C6 glioma model. Studies of the PBN derivative 2,4-disulfonylphenyl-tert-butylnitrone in the C6 glioma model showed that it has more potent anti-cancer activity in this model than PBN. We considered that the sulfonyl groups on OKN-007 acting to inhibit the activity of Sulf2 could account for its anti-cancer activity and therefore set up experiments to test this concept. We have shown that OKN-007 does inhibit Sulf2 at biological meaningful concentrations. In addition we have partially completed an MCF-7 xenograph study that indicates OKN-007 administered orally does suppress cancer growth in this model. We have also shown that another compound suramin that has 6 sulfonyl groups and has been shown to have anti-cancer activity also suppressed the enzymatic activity of Sulf2. In addition we have also tested some compounds that have sulfamate and sulfone functional groups and have found that they also show some activity in suppressing the enzymatic action of Sulf2. Studies are continuing to elucidate the significance of the action of OKN-007 on Sulf2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 556. doi:10.1158/1538-7445.AM2011-556