Evaluation of benzyl selenocyanate glutathione conjugate for potential chemopreventive properties in colon carcinogenesis.
Observational, clinical and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. Since toxicity and chemopreventive efficacy of selenium compounds depend to a large extent, on the form of selenium the development of efficacious organoselenium compounds with low toxicity is being pursued in our laboratory. We have assessed the chemopreventive properties of a newly synthesized organoselenium compound, benzyl selenocyanate glutathione conjugate (BSeSG), and of benzyl selenocyanate (BSC), as a positive control, using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 10 or 20 ppm BSeSG (1.7 and 3.4 ppm as Se, respectively), or 10 ppm BSC (4.1 ppm as Se). One week later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg of body weight, once weekly for 2 weeks). All animals were sacrificed 7 weeks after the last AOM injection, and the ACF, levels of prostaglandin E2 (PGE2), cyclooxygenase protein expression (COX-1 and -2), and glutathione S-transferase type mu (GST-mu) were determined in the colon. As expected, dietary administration of BSC suppressed ACF development by about 37%. In rats administered 10 or 20 ppm BSeSG, the frequencies of AOM-induced colonic ACF were significantly decreased compared to those of rats given AOM and control diet by about 41% (P<0.01) and 61% (P<0.001), respectively. Administration of BSeSG inhibited PGE2 production (81-88% inhibition) via COX-2 synthesis in the colonic mucosa (18-60% inhibition). Also, BSeSG increased GST-mu protein activity in colonic mucosa (30-32% increase). These data suggest that a newly synthesized organoselenium compound, BSeSG might be a promising chemopreventive agent against colon carcinogenesis.
Kawamori
T
T
Division of Nutritional Carcinogenesis and Division of Cancer Etiology and Prevention, American Health Foundation, Valhalla, NY 10595, USA.
El-Bayoumy
K
K
Ji
B Y
BY
Rodriguez
J G
JG
Rao
C V
CV
Reddy
B S
BS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001397:Azoxymethane; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D003485:Cyanates / Q000737:chemistry / Q000627:therapeutic use*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005982:Glutathione Transferase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D016566:Organoselenium Compounds / Q000737:chemistry / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D016588:Anticarcinogenic Agents; D003485:Cyanates; D007527:Isoenzymes; D008565:Membrane Proteins; C113713:N-(2-(carboxymethyl)amino-2-oxo-1-((((phenylmethyl)seleno)thio)methyl)ethyl)glutamine; D016566:Organoselenium Compounds; C054108:benzyl selenocyanate; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D005982:Glutathione Transferase; D005978:Glutathione; D015232:Dinoprostone; D001397:Azoxymethane