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J Immunother. 2007 Sep;30(6):614-23.

Rofecoxib has different effects on chemokine production in colorectal cancer cells and tumor immune splenocytes.

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  • 1School of Clinical Sciences, University of Liverpool, Crown St, Liverpool, UK.

Abstract

Cyclooxygenase-2 (COX-2) is overexpressed in colon tumors. Its main product is the immunosuppressive prostaglandin PGE2 that aids tumor immune escape. In this study, we analyzed mechanisms of action of the COX-2 inhibitor rofecoxib on the immune response to colorectal cancer in an animal model. The murine colorectal cancer cell line MC26, and splenocytes from BALB/c mice immune to irradiated MC26 cells, were incubated with rofecoxib or PGE2. In MC26 cells, 100 nM rofecoxib caused a complete abrogation of PGE2 production and inhibited cell proliferation. Splenocytes from tumor immune mice showed a 300% (P<0.01) increase in proliferation in response to irradiated MC26 cells, amplified to 450% (P<0.01) by 1 microM rofecoxib (n=3). MC26 cells incubated with 1 microM rofecoxib showed increased gene expression of CCL3, CCL5, and CCL20 (P<0.01). enzyme-linked immunosorbent assay tests also showed increased production of CCL5 and CCL20 (P<0.01). PGE2 reversed this effect causing a 40% reduction in chemokine gene expression (n=3). In contrast, splenocytes from naive BALB/c mice stimulated with irradiated MC26 cells had only a marginal chemokine response to rofecoxib. PGE2 caused a 50% down-regulation of CCL5 and CCL20 at the gene level (n=2) and 30% and 40% reduction of CCL3, CCL4, CCL5, and CCL20 at the protein level (n=2). Hence rofecoxib has a 2-fold effect upon the immune response to MC26 cells, by enhancing production of chemokines chemotactic for dendritic cells and also reducing PGE2-mediated inhibition of lymphoproliferation. Together, these may be sufficient for an effective TH1-mediated antitumor response. Rofecoxib may have potential as an addition to existing immunotherapy strategies.

PMID:
17667525
DOI:
10.1097/CJI.0b013e31805ca039
[PubMed - indexed for MEDLINE]
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