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

SIMPLE SUMMARY: Pancreatic cancer has a less than 9% 5-year survival rate among patients because it is very difficult to detect and diagnose early. Combinatorial chemotherapy with surgery or radiotherapy is a potential remedy to treat pancreatic cancer. However, these strategies still have side effects such as hair loss, skin soreness and fatigue. To overcome these side effects, angiogenesis inhibitors such as sunitinib are used to deliver targeted blood vessels around tumor tissues, including pancreatic cancer tumors. It is still controversial whether antiangiogenesis therapy is sufficient to treat pancreatic cancer. So far, many scientists have not been focused on the tumor types of pancreatic cancer when they have developed antipancreatic cancer medication. Here, we used heparin–taurocholate (LHT) as an anticancer drug to treat pancreatic cancer through inhibition of angiogenic growth factors. In this study, we examined the anticancer efficacy of LHT on various types of pancreatic cancer in an orthotopic model. 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.