Simvastatin has inhibitory effects on
cancers. The present study aimed to investigate the interactive effects between
simvastatin and S-1 against
bile duct cancer and its mechanisms. The effects of
simvastatin and
5-fluorouracil (5-FU) alone or in combination on the growth and apoptosis of the human
cholangiocarcinoma cell line EGI-1 and the gallbladder
carcinoma cell line Mz-ChA-1 cells were evaluated in vitro. Real-time PCR and western blot were used to determine E2F-1 and
thymidylate synthase (TS) expressions in the treated cells. Tumoricidal efficacy of
simvastatin and S-1 was further investigated in a subcutaneous
bile duct cancer model in NOD/SCID mice.
Simvastatin enhanced the cytotoxicity of
5-FU on
bile duct cancer cells in vitro. IC50 of
5-FU alone was 4.34 μmol/l for EGI-1 and 13.9 μmol/l for MZ-ChA-1, whereas it decreased markedly to 0.90 and 2.95 μmol/l, respectively, when combined with
simvastatin. The Chou and Talalay combination index of
5-FU and
simvastatin was 0.41 and 0.40 at IC50 for EGI-1 and MZ-ChA-1, respectively.
Simvastatin alone or plus
5-FU significantly suppressed E2F-1 and TS expressions in EGI-1 and MZ-ChA-1.
Simvastatin plus
5-FU induced greater proportion of apoptotic cells on both EGI-1 and MZ-ChA-1, with an increase in cleaved
caspase-3 levels, compared with
simvastatin or
5-FU alone (all P < 0.05).
Simvastatin plus S-1 induced greater
tumor inhibition than
simvastatin or S-1 alone with E2F-1/TS downregulation in vivo (all P < 0.05).
Simvastatin and S-1 exerted synergistic effects against
bile duct cancer, which might be mediated by E2F-1/TS downregulation. The combination could be a reasonable regimen in the management of
bile duct cancer.