Resistance to
5-fluorouracil (5-FU) is a serious problem in
cancer therapy and overcoming it is required in order to improve the efficacy of
cancer chemotherapy.
Histone deacetylase (
HDAC) inhibitors are used in
cancer treatments and, recently, it has been reported that
HDAC inhibitors can overcome resistance to various anti-
cancer drugs in vitro. In the present study, a 5-FU-resistant
breast cancer cell line was established, and the effects of
HDAC inhibitors in these cells were examined. The 5-FU-resistant cell line MDA-MB-468 (MDA468/FU) was established by continuous exposure of the parental cells to
5-FU. This subline was characterized by high resistance to
5-FU, higher
mRNA expression levels of
thymidylate synthetase and
dihydropyrimidine dehydrogenase (DPD), and lower
mRNA expression levels of
uridine monophosphate synthetase (UMPS) than the parental cells.
Gimeracil, a DPD inhibitor, did not affect the sensitivity of MDA468/FU cells to
5-FU.
Oteracil, a UMPS inhibitor, decreased the cytotoxicity of
5-FU in MDA468 cells, but not in MDA468/FU cells. The
HDAC inhibitors,
valproic acid and
suberanilohydroxamic acid sensitized the two cell lines to
5-FU in a concentration-dependent manner. In conclusion, the results of the present study revealed that
HDAC inhibitors increase the sensitivity to
5-FU in 5-FU-sensitive and -resistant cells.