Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells

William Fazzone, Peter M Wilson, Melissa J Labonte, Heinz-Josef Lenz, Robert D Ladner, Melissa LaBonte Wilson

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

Despite recent therapeutic advances, the response rates to chemotherapy for patients with metastatic colon cancer remain at approximately 50% with the fluoropyrimidine, 5-fluorouracil (5-FU), continuing to serve as the foundation chemotherapeutic agent for the treatment of this disease. Previous studies have demonstrated that overexpression of thymidylate synthase (TS) is a key determinant of resistance to 5-FU-based chemotherapy. Therefore, there is a significant need to develop alternative therapeutic strategies to overcome TS-mediated resistance. In this study, we demonstrate that the histone deacetylase inhibitors (HDACi) vorinostat and LBH589 significantly downregulate TS gene expression in a panel of colon cancer cell lines. Downregulation of TS was independent of p53, p21 and HDAC2 expression and was achievable in vivo as demonstrated by mouse xenograft models. We provide evidence that HDACi treatment leads to a potent transcriptional repression of the TS gene. Combination of the fluoropyrimidines 5-FU or FUdR with both vorinostat and LBH589 enhanced cell cycle arrest and growth inhibition. Importantly, the downstream effects of TS inhibition were significantly enhanced by this combination including the inhibition of acute TS induction and the enhanced accumulation of the cytotoxic nucleotide intermediate dUTP. These data demonstrate that HDACi repress TS expression at the level of transcription and provides the first evidence suggesting a direct mechanistic link between TS downregulation and the synergistic interaction observed between HDACi and 5-FU. This study provides rationale for the continued clinical evaluation of HDACi in combination with 5-FU-based therapies as a strategy to overcome TS-mediated resistance.

Original languageEnglish
Pages (from-to)463-73
Number of pages11
JournalInternational journal of cancer. Journal international du cancer
Volume125
Issue number2
DOIs
Publication statusPublished - 15 Jul 2009

Bibliographical note

Copyright 2009 UICC.

Keywords

  • Base Sequence
  • Cell Division
  • Cell Line, Tumor
  • Colonic Neoplasms
  • DNA Primers
  • Drug Synergism
  • Enzyme Inhibitors
  • Flow Cytometry
  • Gene Expression Regulation, Enzymologic
  • Histone Deacetylase Inhibitors
  • Humans
  • Polymerase Chain Reaction
  • Pyrimidines
  • Thymidylate Synthase

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