Inhibition of N-linked glycosylation by tunicamycin enhances sensitivity to cisplatin in human head-and-neck carcinoma cells

Tunicamycin (TM), a naturally occurring antibiotic, blocks the first step i n the biosynthesis of N-linked oligosaccharides in cells. In this study, we investigated whether changes in N-linked glycosylation affect the sensitiv ity of head-and-neck carcinoma cell lines to cis-diaminedichloroplatinum(II ) (cisplatin) in vitro and in vivo. In vitro treatment of the IMC-3 and KB cell lines with TM significantly decreased the 50% inhibitory concentration (IC50) of cisplatin, as determined by the MIT assay (24.15 to 10.97 mu g/m l, p < 0.05). In addition, TM significantly decreased the IC50 of cisplatin against established cisplatin-resistant IMC-3/CR cells (> 100 to 14.4 mu g /ml, p < 0.05) to levels similar to those against parental IMC-3 cells. TM treatment decreased the number of Con A- and L-PHA-binding sites on the sur face of tumor cells but had no effect on the intracellular platinum concent ration. Induction of apoptosis in vitro by TM plus cisplatin in combination was increased compared with that by cisplatin alone. Furthermore, in vivo administration of TM plus cisplatin in combination significantly inhibited local tumor growth in the cisplatin-resistant in vivo C3H/He mouse model as compared with the control group (p < 0.05) and increased in vivo apoptosis of tumor cells. Our results suggest that the manipulation of glycosylation by TM in tumor cells might be a useful therapeutic strategy for successful chemotherapy using cisplatin against head-and-neck cancer. (C) 1999 Wiley- Liss, Inc.