Anticancer Effect of Heparin–Taurocholate Conjugate on Orthotopically Induced Exocrine and Endocrine Pancreatic Cancer

Abstract

Pancreatic cancers are classified based on where they occur, and are grouped into those derived from exocrine and those derived from neuroendocrine tumors, thereby experiencing different anticancer effects under medication. Therefore, it is necessary to develop anticancer drugs that can inhibit both types. To this end, we developed a heparin–taurocholate conjugate, i.e., LHT, to suppress tumor growth via its antiangiogenic activity. Here, we conducted a study to determine the anticancer efficacy of LHT on pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET), in an orthotopic animal model. LHT reduced not only proliferation of cancer cells, but also attenuated the production of VEGF through ERK dephosphorylation. LHT effectively reduced the migration, invasion and tube formation of endothelial cells via dephosphorylation of VEGFR, ERK1/2, and FAK protein. Especially, these effects of LHT were much stronger on PNET (RINm cells) than PDAC (PANC1 and MIA PaCa-2 cells). Eventually, LHT reduced ~50% of the tumor weights and tumor volumes of all three cancer cells in the orthotopic model, via antiproliferation of cancer cells and antiangiogenesis of endothelial cells. Interestingly, LHT had a more dominant effect in the PNET-induced tumor model than in PDAC in vivo. Collectively, these findings demonstrated that LHT could be a potential antipancreatic cancer medication, regardless of pancreatic cancer types.

Bile Acids: Physiological Activity and Perspectives of Using in Clinical and Laboratory Diagnostics

“…The reduced activity of the FXR gene in human colorectal tumors correlated to the dysplasia grade [47,53,124] and was associated with metalloproteinase-7, which is one of the tumor's aggression factors [139]. At the same time, the activation of FXR and administration of its agonists (e.g., TCA) leads to suppression of intestinal adenomas [140]. All these findings show a consequent mechanism of tumor progression via BAs and their link to dietary and microbial factors.…”

Non-Anticoagulant Activities of Low Molecular Weight Heparins—A Review

“…In addition, these conjugates may inhibit tumor growth through multiple mechanisms. The heparin–taurocholate conjugate not only reduces the proliferation of cancer cells but also reduces the production of vascular endothelial growth factor through ERK dephosphorylation [ 102 ]. By dephosphorylating VEGFR, ERK, and FAK proteins, heparin-bovine cholate conjugate effectively reduced endothelial cell migration, invasion, and tube formation.…”