Specific Inhibition of Heparanase by Glycopolymers for Cancer and Diabetic Therapeutics

ABSTRACT

Specific Inhibition of Heparanase by Glycopolymers for Cancer and Diabetic Therapeutics

Heparanase has been illustrated to regulate aggressive tumor behavior and to play important roles in autoimmune diabetes. Heparanase cleaves polymeric heparan sulfate (HS) molecules into smaller chain length oligosaccharides, allowing for release of angiogenic growth factors promoting tumor development and autoreactive immune cells to reach the insulin-producing b cells. Interaction of heparanase with HS chains is regulated by substrate sulfation sequences, and only HS chains with specific sulfation patterns are cleaved by heparanase. Therefore, heparanase has become a potential target for anticancer and antidiabetic drug development. Several molecules have been developed to target heparanase activity, but only carbohydrate molecules have advanced to clinical trials. However, the carbohydrate-based heparanase inhibitors are heterogeneous in size and sulfation pattern leading to nonspecific binding and unforeseen adverse effects, thus halting their translation into clinical use.

Our group has recently discovered that the sulfation pattern of pendant disaccharide moiety on synthetic glycopolymers could be synthetically manipulated to achieve optimal heparanase inhibition. We have determined that glycopolymer with 12 repeating units was the most potent inhibitor of heparanase (IC50 = 0.10 ± 0.36 nM). This glycopolymer was further examined for cross-bioactivity, using a solution based competitive biolayer interferometry assay, with other HS-binding proteins (growth factors, P-selectin, and platelet factor 4) which are responsible for mediating angiogenic activity, cell metastasis, and antibody-inducedthrombocytopenia. The synthetic glycopolymer has low affinity for these HS-binding proteins in comparison to natural heparin. In addition, the glycopolymer possessed no proliferative properties towards human umbilical endothelial cells (HUVEC) and a potent antimetastatic effect against 4T1 mammary carcinoma cells. Furthermore, our recent results illustrated that treatment of cultured mouse pancreatic b cells with heparanase significantly reduced their survival. In stark contrast, the b cells treated with heparanase plus the synthetic glycopolymer exhibited a survival rate comparable to the b cells treated with the vehicle PBS. In addition, we treated insulin-secreting human pancreas islets with heparanase in the presence or absence of the glycopolymer inhibitor. Alcian blue staining of HS contents indicated that the the glycopolymer inhibitor protected the human islets from destruction of extracellular HS contents caused by elevation of heparanse. The extracellular HS contents play important roles in preserving pancreas β cell function and protecting β cells from destruction by heparanase.

Time and Location: 
3:30pm | Mechanical Engineering Building (MEC) Rm 205
Academic Year: 
2020
Event Date: 
Friday, February 14, 2020
Semester: 
Speaker: 
Dr. Hien Nguyen
Speaker Title: 
Wayne State University
Host: 
Professor Clifford Stains