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Interleukin (IL)-8, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF) appear to be critically involved in immune responses associated with inflammation, infection and tumor growth. Regulation of these mediators was studied in the human colon carcinoma cell line DLD-1. Here we report that pyrrolidine dithiocarbamate (PDTC) not only augmented tumor necrosis factor-alpha-induced release of IL-8, but also mediated IL-8 expression as a single stimulus. Mutational analysis of the IL-8 promotor and electrophoretic mobility shift analysis revealed that activation of the transcription factor activator protein-1 (AP-1) and a constitutive nuclear factor-kappaB (NF-kappaB) binding activity in DLD-1 cells were mandatory for PDTC-induced IL-8 expression. Besides IL-8, PDTC also upregulated the expression of HO-1 and VEGF in these cells. Induction of IL-8 by PDTC was not restricted to DLD-1 cells, but was observed in Caco-2 colon carcinoma cells and in peripheral blood mononuclear cells. PDTC is currently advocated for use as a chemotherapeutic drug in the treatment of certain malignancies, among them colorectal cancer. Induction of IL-8, HO-1 and VEGF may affect therapeutic applications of this agent.

carcinogenesis

Expression of interleukin-8, heme oxygenase-1 and vascular endothelial growth factor in DLD-1 colon carcinoma cells exposed to pyrrolidine dithiocarbamate