Heparin and Liver Heparan Sulfate Can Rescue Hepatoma Cells from Topotecan Action

Abstract

Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer.

Fabrication and Characterization of Heparin/Collagen Sponge for in Vitro Differentiation of Wharton’s Jelly-Derived Mesenchymal Stem Cells into Hepatocytes

“…Heparin is one of the contents of Disse space and heparinized biomaterials imitate in vivo hepatocytes niche (34). Heparinized biomaterials have been shown to conduct primary hepatocyte phenotype and functional preservation (35).…”

Prognostic value and prospective molecular mechanism of miR‑100‑5p in hepatocellular carcinoma: A comprehensive study based on 1,258 samples

“…Ling et al (53) suggested that blocking heparan sulfate function in the heparin-binding domains of fibroblast growth factor receptor 1 inhibited growth of cancer cells. Dudás et al (54) showed that heparin and heparan sulfate may interfere with the function of topotecan in liver and liver cancer. Given these previous findings, it was hypothesized that miR-100-5p may exert a regulatory function on the biosynthesis of heparan sulfate, which may provide potential candidate targets for drug development in HCC.…”

Heparin/Collagen 3D Scaffold Accelerates Hepatocyte Differentiation of Wharton’s Jelly-Derived Mesenchymal Stem Cells

“…Designating a simulated scaffold is a necessary issue for creating liver surrogate and functional engineered construct to be used in regenerative approaches or toxicology tests. Heparinized collagen scaffold can mimic the natural environment of the hepatocytes that is an essential element in maintaining the hepatocyte functions [12,13]. An improvement in hepatocyte viability and angiogenesis was reported by culturing the primary hepatocytes in heparinized collagen gel within polyurethane foam [18].…”

“…Disse space also contains glycosaminoglaycans such as heparan sulfate that influence hepatocyte functions [3]. Heparin and heparan sulfate reduced cell death in the hepatocyte cell line [12]. Increase in liverspecific marker expression in the primary hepatocytes cultured on heparin hydrogel [13] suggested heparin containing hydrogels as an appropriate niche for stem cell development toward hepatogenic linage.…”