Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours.
Current treatments for pancreatic cancer have failed to effectively manage the disease, and hence, more effective treatment approaches are urgently needed. Studies suggest that mucin O-glycosylation limits the cytotoxic effect of fluorouracil (5-FU) against the growth of human pancreatic cancer cells in vitro. In the present study, we investigated the relationship between the levels of mucin O-glycosylation expressed in pancreatic tumours and the antitumour effect of 5-FU. The inhibition of O-glycosylation was achieved by intratumoural (IT) injections of benzyl-alpha-GalNAc. Immunohistochemical staining of human pancreatic tumours revealed relatively high (Capan-1) and moderate (HPAF-II) expression levels of MUC1 mucin compared to MUC1 negative control (U-87 MG human glioblastoma) tumours. The antitumour effects of 5-FU (given systemically) against Capan-1 tumours improved significantly following IT injections of benzyl-alpha-GalNAc. Histochemical staining of tumour sections revealed a reduced number of neoplastic cells in tumours exposed to benzyl-alpha-GalNAc prior to 5-FU treatment compared to 5-FU alone. Furthermore, intracellular uptake of 5-FU by Capan-1 cells was significantly greater following injections of benzyl-alpha-GalNAc; however, no such effect was observed with U-87 MG cells. Mucin overexpression reduces intracellular drug uptake, antineoplastic and antitumour drug effects, which may have important clinical implications in treatment.
Kalra
Ashish V
AV
Northeastern University, Bouvé College of Health Sciences, Department of Pharmaceutical Sciences, Boston, MA 02115, USA.
Campbell
Robert B
RB
D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001593:Benzyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D005472:Fluorouracil / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006031:Glycosylation / Q000187:drug effects; D051379:Mice; D018396:Mucin-1 / Q000032:analysis / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D017211:Treatment Failure; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D018396:Mucin-1; C080739:benzyl-alpha-N-acetylgalactosamine; D000116:Acetylgalactosamine; D005472:Fluorouracil