Sulfasalazine down-regulates the expression of the angiogenic factors platelet-derived endothelial cell growth factor/thymidine phosphorylase and interleukin-8 in human monocytic-macrophage THP1 and U937 cells

Michiel de Bruin, Godefridus J Peters, Ruud Oerlemans, Yehuda G Assaraf, Allan J Masterson, Auke D Adema, Ben A C Dijkmans, Herbert M Pinedo, Gerrit Jansen

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

Abstract

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) and interleukin-8 (IL-8) are angiogenic factors produced by tumor infiltrating macrophages. Here, we show that prolonged exposure of human monocytic/macrophage THP1 and U937 cells to sulfasalazine, an anti-inflammatory drug and inhibitor of nuclear factor-kappaB (NF-kappaB), resulted in down-regulation of PD-ECGF/TP and IL-8 (mRNA, protein and activity) along with elimination of their induction by tumor necrosis factor-alpha and interferon-gamma. Concomitantly, sulfasalazine-exposed cells were markedly resistant to 5'-deoxyfluorouridine, the last intermediate of capecitabine requiring activation by PD-ECGF/TP. This is the first report suggesting that disruption of NF-kappaB-dependent signaling pathways can provoke a marked and sustained down-regulation of macrophage-related angiogenic factors. However, this may also negatively affect capecitabine efficacy.

Original languageEnglish
Pages (from-to)1054-60
Number of pages7
JournalMolecular pharmacology
Volume66
Issue number4
DOIs
Publication statusPublished - Oct 2004

Keywords

  • Angiogenesis Inducing Agents/metabolism
  • Anti-Inflammatory Agents, Non-Steroidal/pharmacology
  • Blotting, Western
  • Gene Expression/drug effects
  • Humans
  • Interleukin-8/genetics
  • Macrophages/drug effects
  • Monocytes/cytology
  • NF-kappa B p50 Subunit
  • NF-kappa B/metabolism
  • RNA, Messenger/metabolism
  • Receptors, Interferon/metabolism
  • Receptors, Tumor Necrosis Factor, Type I/metabolism
  • Receptors, Tumor Necrosis Factor, Type II/metabolism
  • Sulfasalazine/pharmacology
  • Thymidine Phosphorylase/genetics
  • Transcription Factor RelA
  • Transcription Factors/metabolism
  • U937 Cells

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