Research

Swainsonine reduces 5-fluorouracil tolerance in the multistage resistance of colorectal cancer cell lines

Jun Hamaguchi¹ , Hiroaki Nakagawa² , Masato Takahashi¹ , Takeaki Kudo¹ , Naoya Kamiyama³ , Bailong Sun¹ , Takahiro Oshima¹ , Yuji Sato¹ , Kisaburo Deguchi² , Satoru Todo¹ and Shin-Ichiro Nishimura²

¹  Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan

²  Graduate School of Advanced Life Science, Hokkaido University, Sapporo 001-0021, 001-0021, Japan

³  Department of Sensory Physiology, Asahikawa Medical College, Asahikawa 078-8510, Japan

author email corresponding author email

Molecular Cancer 2007, 6:58doi:10.1186/1476-4598-6-58

Published:	21 September 2007

Abstract

Background

Drug resistance is a major problem in cancer chemotherapy. Acquisition of chemo-resistance not only reduces the effectiveness of drugs, but also promotes side effects and markedly reduces the patient's quality of life. However, a number of resistance mechanisms have been reported and are thought to be the reason for the difficulties in solving drug-resistance problems.

Result

To investigate the mechanisms of drug resistance, a set of cell lines with different levels of sensitivity and possessing different mechanisms of resistance to 5-fluorouracil (5-FU) was established from a colorectal cancer cell line. The expression of thymidylate synthase, orotic acid phosphoribosyltransferase and dihydropyrimidine dehydrogenase, which are well known to be related to drug resistance, differed among these cell lines, indicating that these cell lines acquired different resistance mechanisms. However, swainsonine, an inhibitor of N-glycan biosynthesis, reduced 5-FU-tolerance in all resistant cells, whereas the sensitivity of the parental cells was unchanged. Further analysis of the N-glycan profiles of all cell lines showed partial inhibition of biosynthesis and no cytotoxicity at the swainsonine dosage tested.

Conclusion

These observations suggest that N-linked oligosaccharides affect 5-FU resistance more widely than do drug-resistance related enzymes in colorectal cancer cells, and that the N-glycan could be a universal target for chemotherapy. Further, swainsonine may enhance the performance of chemotherapy by reducing tolerance.