Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells.
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.
Taylor
M T
MT
Cancer Biology Interdisciplinary Graduate Program, University of Arizona, Tucson, Arizona 85724, USA.
Lawson
K R
KR
Ignatenko
N A
NA
Marek
S E
SE
Stringer
D E
DE
Skovan
B A
BA
Gerner
E W
EW
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002999:Clone Cells; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D011905:Genes, ras / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013467:Sulindac; C025462:sulindac sulfide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C025463:sulindac sulfone; D015232:Dinoprostone