Cytotoxic and partial hepatoprotective activity of sodium ascorbate against hepatocellular carcinoma through inhibition of sulfatase-2 in vivo and in vitro.

Hepatocellular carcinoma (HCC) is characterized by elevation in the activity of sulfatase-2, an extracellular enzyme that catalyzes removal of 6-O-sulfate groups from heparan sulfate. Therefore, we conducted this study to investigate the cytotoxic activity of the strong water-soluble antioxidant, sodium ascorbate, against HCC both in vivo and in vitro. Sodium ascorbate enhanced animal survival in vivo and reduced HepG2 cells survival. The protein levels of heparan sulfate proteoglycans (HSPGs), insulin like growth factor (IGF)-2, sulfatase-2 and glypican-3 were assessed. Inflammation was evaluated by measuring the gene and protein expression of NFκB, TNF-α, IL-1β, IL-4, IL-6 and IL-10. We found that sodium ascorbate blocked HCC-induced activation of sulfatase-2 leading to restoration of HSPGs receptors associated with reduction in IGF-2 and glypican-3. Sodium ascorbate exerts anti-inflammatory activity by reducing the expression of NFκB, CRP, TNF-α, IL-1β and IL-6 associated with enhanced expression of the anti-inflammatory cytokines, IL-4 and IL-10. In conclusion, cytotoxic effects of sodium ascorbate against HCC can be partially explained by inhibition of sulfatase-2, restoration of HSPGs receptors and deactivation of the inflammatory pathway.