Role of type O-glycosylation in the cytotoxic activity of various chemotherapeutic agents as a function of their physicochemical properties: evaluation of mucinous cancer cell lines.

• Online Access: http://hdl.handle.net/2047/d10017112

Mucins are cell surface glycoproteins with protective functions. They are over-expressed in a variety of cancerous conditions. In addition to protection, lubrication and signal transduction functions they have long been implicated in the invasion, metastasis, poor prognosis and extremely poor survival of cancer patients. This exaggerated expression of mucin isoforms in tumor cells is accompanied by their aberrant O-glycosylation. Although O-glycosylation inhibitors have previously been predominantly used to study mucin structure, function and biosynthesis, it has recently been shown that pre-exposing human pancreatic cancer cells with O-glycosylation inhibitors significantly enhances the cytotoxic effects of 5-FU in pancreatic cancer cells. This has spurred speculation on whether the deviant O-glycosylation in tandem with the overexpression of mucins could play a role in tumor refractoriness to chemotherapy. In this study we explore the atypical mucin O-glycan in tumor cells as an emerging barrier to various chemotherapeutic agents varying as a function of their physicochemical properties. Chemotherapeutic agents belonging to several different classes of anti-neoplastics and possessing different physicochemical properties, such as molecular weight and hydrophilic and lipophilic character, have been employed. Cytotoxicity studies were carried out with these agents in the presence and absence of benzyl-alpha-GalNAc, an O-glycosylation inhibitor. A significant benefit in cytotoxic drug effect was observed when each one of these chemotherapeutic agents was used in conjunction with a non-toxic concentration of benzyl-alpha-GalNAc. Neither the physicochemical properties of the agents employed nor the differences in concentrations of agents used influence the extent to which chemotherapeutic agents benefited from inhibition of mucin O-glycosylation. It now appears that mucinous carcinomas may develop resistance to chemotherapy on account of the rigid aberrantly O-glycosylated mucin barrier which limits drug uptake into the target cell. This project looks also to determine whether the benefits in cytotoxicity following inhibition of mucin O-glycosylation in pancreatic cancer cells extends to include mucin expressing cell lines derived from other organs and tissues.