Rofecoxib has different effects on chemokine production in colorectal cancer cells and tumor immune splenocytes.
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.
School of Clinical Sciences, University of Liverpool, Crown St, Liverpool, UK.
Alice J
AJ
Walmesley
Jehad
J
Zweiri
Stephen E
SE
Christmas
Alastair J M
AJ
Watson
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*
D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; D015232:Dinoprostone