Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4'-tetramethoxystilbene (DMU-212) on adenoma development in the Apc(Min+) mouse and cyclooxygenase-2 in human-derived colon cancer cells.
Naturally occurring molecules with putative cancer chemopreventive properties such as the phytoalexin resveratrol (3,5,4'-trihydroxystilbene) are lead molecules that guide the design of novel agents with improved pharmacologic properties. The synthetic resveratrol analog 3,4,5,4'-tetramethoxystilbene (DMU-212) has been shown to possess stronger antiproliferative properties in human colon cancer cells than resveratrol. We tested the hypothesis that DMU-212 is also a more potent inhibitor of adenoma development in the Apc(Min+) mouse, a model of human intestinal carcinogenesis. Apc(Min+) mice received either stilbene derivative with the diet (0.2%), and adenomas were counted after experiments were terminated. Resveratrol and DMU-212 decreased adenoma load by 27% and 24%, respectively, compared to untreated controls. Cyclooxygenase (COX) enzymes are important mechanistic targets of resveratrol, and we investigated whether DMU-212 interferes with the expression and activity of COX in human colon cells. Incubation of HCA-7 cancer cells for 24-96 hr with either stilbene derivative (1-50 microM) decreased prostaglandin E-2 (PGE-2) production, but only resveratrol decreased COX-2 protein expression. In mice, which received either stilbene derivative (0.2%) for 3 weeks with their diet, PGE-2 levels in the intestinal mucosa were reduced by between 45% and 62% compared to mice on control diet. While resveratrol inhibited enzyme activity in purified COX preparations, DMU-212 failed to do so. The PGE-2 decrease seen with DMU-212 in cells and in vivo is probably mediated via its metabolites. The results suggest that alteration of the resveratrol molecule to generate DMU-212 does not abrogate its ability to decrease adenoma number in Apc(Min+) mice or to interfere with PGE-2 generation in cells.
Sale
Stewart
S
Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
Tunstall
Richard G
RG
Ruparelia
Ketan C
KC
Potter
Gerry A
GA
Steward
William P
WP
Gescher
Andreas J
AJ
D000236:Adenoma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D004032:Diet; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D017491:Genes, APC / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D000077185:Resveratrol; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013267:Stilbenes / Q000627:therapeutic use*; D014018:Tissue Distribution
C482492:3,4,5,4'-tetramethoxystilbene; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012264:Ribonucleotide Reductases; D015232:Dinoprostone; D000077185:Resveratrol