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.
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.
Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Michiel
M
de Bruin
Godefridus J
GJ
Peters
Ruud
R
Oerlemans
Yehuda G
YG
Assaraf
Allan J
AJ
Masterson
Auke D
AD
Adema
Ben A C
BA
Dijkmans
Herbert M
HM
Pinedo
Gerrit
G
Jansen
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism; D020298:U937 Cells; D000096743:Interferon gamma Receptor
D043925:Angiogenesis Inducing Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016209:Interleukin-8; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D017471:Receptors, Interferon; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012460:Sulfasalazine; D013939:Thymidine Phosphorylase; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; C489548:NFKB1 protein, human