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


RESULTS
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.


CONCLUSIONS
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.
Hamaguchi
Jun
J
Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. hama@med.hokudai.ac.jp
Nakagawa
Hiroaki
H
Takahashi
Masato
M
Kudo
Takeaki
T
Kamiyama
Naoya
N
Sun
Bailong
B
Oshima
Takahiro
T
Sato
Yuji
Y
Deguchi
Kisaburo
K
Todo
Satoru
S
Nishimura
Shin-Ichiro
S
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004361:Drug Tolerance; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D051379:Mice; D011134:Polysaccharides / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017026:Swainsonine / Q000494:pharmacology*
D011134:Polysaccharides; D012333:RNA, Messenger; D017026:Swainsonine; D005472:Fluorouracil