RT Journal Article
SR Electronic
T1 Sulindac Sulfone Inhibits K-ras-dependent Cyclooxygenase-2 Expression in Human Colon Cancer Cells
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 6607
OP 6610
VO 60
IS 23
A1 Taylor, Michele T.
A1 Lawson, Kathryn R.
A1 Ignatenko, Natalia A.
A1 Marek, Sarah E.
A1 Stringer, David E.
A1 Skovan, Beth A.
A1 Gerner, Eugene W.
YR 2000
UL http://cancerres.aacrjournals.org/content/60/23/6607.abstract
AB 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. ©2000 American Association for Cancer Research.