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

doi:10.1124/mol.104.000315

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

Mol Pharmacol. 2004 Oct;66(4):1054-60. doi: 10.1124/mol.104.000315. Epub 2004 Jul 21.

Authors

Michiel de Bruin¹, Godefridus J Peters, Ruud Oerlemans, Yehuda G Assaraf, Allan J Masterson, Auke D Adema, Ben A C Dijkmans, Herbert M Pinedo, Gerrit Jansen

Affiliation

¹ Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

PMID: 15269287
DOI: 10.1124/mol.104.000315

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inducing Agents / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Blotting, Western
Gene Expression / drug effects*
Humans
Interferon gamma Receptor
Interleukin-8 / genetics
Interleukin-8 / metabolism*
Macrophages / drug effects*
Macrophages / metabolism
Monocytes / cytology
Monocytes / drug effects
NF-kappa B / metabolism
NF-kappa B p50 Subunit
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
Thymidine Phosphorylase / metabolism*
Transcription Factor RelA
Transcription Factors / metabolism
U937 Cells

Substances

Angiogenesis Inducing Agents
Anti-Inflammatory Agents, Non-Steroidal
Interleukin-8
NF-kappa B
NF-kappa B p50 Subunit
NFKB1 protein, human
RNA, Messenger
Receptors, Interferon
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II
Transcription Factor RelA
Transcription Factors
Sulfasalazine
Thymidine Phosphorylase