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Sulindac Sulfone Inhibits K-ras-dependent Cyclooxygenase-2 Expression in Human Colon Cancer Cells¹

Cancer Biology Interdisciplinary Graduate Program [M. T. T., E. W. G.] and Departments of Radiation Oncology [N. A. I. , E. W. G.] and Biochemistry [K. R. L., E. W. G. ], University of Arizona, and Arizona Cancer Center [S. E. M., D. E. S. , B. A. S., E. W. G.], Tucson, Arizona 85724

Both the sulfide and sulfone metabolites of sulindac, a nonsteroidal anti-inflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has been reported to suppress ras-dependent signaling. However, the mechanisms by which sulindac sulfone suppresses cancer growth are not as defined. We studied the effects of these sulindac metabolites in human colon cancer-derived Caco-2 cells that have been transfected with an activated K-ras oncogene. Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more quickly when injected into severe combined immunodeficiency disease mice than parental cells, and this tumorigenesis was suppressed by treatment with sulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulted in a decrease in prostaglandin synthase E₂ production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin synthase E₂ production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of sulindac exert COX-dependent effects by distinct mechanisms.

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