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

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.
AuthorsJian-Peng Cai, Wei Chen, Xun Hou, Li-Jian Liang, Xiao-Yi Hao, Xiao-Yu Yin
JournalAnti-cancer drugs (Anticancer Drugs) Vol. 24 Issue 10 Pg. 1020-9 (Nov 2013) ISSN: 1473-5741 [Electronic] England
PMID23941814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drug Combinations
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Simvastatin
  • Thymidylate Synthase
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis (drug effects)
  • Bile Duct Neoplasms (drug therapy, metabolism, 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, adverse effects, pharmacology, therapeutic use)
  • Simvastatin (administration & dosage, pharmacology, therapeutic use)
  • Tegafur (administration & dosage, adverse effects, pharmacology, therapeutic use)
  • Thymidylate Synthase (biosynthesis)
  • Xenograft Model Antitumor Assays

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