Abstract 2831: Studies on the mechanistic basis of the anticancer activity of 2,4-disulfonyl-PBN (OKN-007)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Sulfatase 2 (Sulf2) is a protein which resides in the extracellular matrix of cancer cells and enzymatically removes sulfate from the 6-O-sulfate esters of heparin. Several tumors have been shown to be enriched in Sulf2 in comparison to normal tissues where it is either absent or present at very low levels. The action of Sulf2 alters growth factor binding to the extracellular matrix of cells and has been shown to be important in the development of many cancers including breast, lung, liver, colon, and pancreas. Sulf2 mobilizes fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF) and stromal derived growth factor-1 (SDF-1) bound to heparin. We found that OKN-007 acts to weakly inhibit the aryl sulfatase activity of Sulf2 acting on the substrate 4-methylumbelliferyl-sulfate (4-MUS) and to more effectively inhibit the enzymatic activity of Sulf2 when it acts upon its natural substrate the 6-O-sulfate ester of heparin. The Sulf2 enzymatic activity was potently inhibited by suramin, a compound that has 6 phenyl-sulfonyl groups as part of its chemical structure and has been shown to have anti-cancer activity. Utilizing the natural substrate we have shown that other sulfonyl-phenyl compounds act to suppress the activity of Sulf2. We have conducted preliminary studies to see if OKN-007 has anti-cancer activity in a breast cancer mouse xenograph model. Balb/c female ovariectomized Estradiol pellet-implanted nude mice were implanted with MCF-7 breast cancer cells and OKN-007 was administered at 250mg/kg/day in the drinking water. The experiment was terminated at week 5 at which time the data showed that OKN-007 decreased the average tumor volume by 33%. OKN-007 has been shown to have anti-cancer activity in the rat C6 model of glioma. The anti-cancer mechanism of action of OKN-007 is still unknown. Recently we have explored the potential of OKN-007 to alter cancer cell migration in a gradient involving the chemokine SDF-1 and its cellular receptor CXCR4. The CXCL4/SDF-1 gradient is considered to be important in the metastasis of primary cancers. Results with rat C6 glioma cells, U87MG human glioma cells as well as MCF-7 breast cancer cells indicate that OKN-007 at low concentrations inhibits cancer migration in a CXCR4/SDF-1 gradient. These observations need to be explored in more depth utilizing animal models of cancer metastasis. Research supported in part by US Army Concept Grant W81XWH-09-1-0352. Dr. Floyd holds the Merrick Foundation Chair in Aging Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2831. doi:1538-7445.AM2012-2831