Simvastatin enhances the chemotherapeutic efficacy of S-1 against bile duct cancer: E2F-1/TS downregulation might be the mechanism

Anticancer Drugs. 2013 Nov;24(10):1020-9. doi: 10.1097/CAD.0b013e328364f935.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects
  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Drug Combinations
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • E2F1 Transcription Factor / biosynthesis*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Oxonic Acid / administration & dosage
  • Oxonic Acid / adverse effects
  • Oxonic Acid / pharmacology*
  • Oxonic Acid / therapeutic use
  • Simvastatin / administration & dosage
  • Simvastatin / pharmacology*
  • Simvastatin / therapeutic use
  • Tegafur / administration & dosage
  • Tegafur / adverse effects
  • Tegafur / pharmacology*
  • Tegafur / therapeutic use
  • Thymidylate Synthase / biosynthesis*
  • Xenograft Model Antitumor Assays

Substances

  • Drug Combinations
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Simvastatin
  • Thymidylate Synthase