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

Authors:
  • GPGodefridus J. Peters
    Godefridus J. Peters
  • RORuud Oerlemans
    Ruud Oerlemans
  • YAYehuda G. Assaraf
    Yehuda G. Assaraf
  • AMAllan J. Masterson
    Allan J. Masterson
  • AAAuke D. Adema
    Auke D. Adema
  • BDBen A. C. Dijkmans
    Ben A. C. Dijkmans
  • HPHerbert M. Pinedo
    Herbert M. Pinedo
  • GJGerrit Jansen
    Gerrit Jansen
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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-κB (NF-κB), 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-α and interferon-γ. 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-κB-dependent signaling pathways can provoke a marked and sustained down-regulation of macrophage-related angiogenic factors. However, this may also negatively affect capecitabine efficacy.

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