Mechanisms in the chemoprevention of colon cancer: Modulation of protein kinase C, tyrosine protein kinase and diacylglycerol kinase activities by 1,4-phenylenebis(methylene)selenocyanate and impact of low-fat diet

Epidemiological and experimental studies suggest an inverse relationship be tween the intake of dietary selenium and/or low fat-intake and colon cancer risk. Efficacy studies in rodents suggest that the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC), is a more effective and less toxic chemopreventive agent than other organic or inorganic selenium c ompounds such as selenomethionine and Na2SeO3. The efficacy of p-XSC agains t colon cancer is significantly augmented by a low-fat diet. To explore the mechanisms by which this combined inhibiting effect against colon carcinog enesis comes about, we have investigated protein kinase C (PKC), tyrosine p rotein kinase (TPK), diacylglycerol kinase (DGK) activities and 8-isoprosta ne levels in colonic mucosa and tumor tissues in an azoxymethane (AOM)-indu ced rat colon cancer model. Weanling male F344 rats were fed the semipurifi ed AIN-76A diet until seven weeks of age. Then various experimental groups were fed the low- or high-fat diets containing 0 or 20 ppm p-XSC (10 ppm as selenium). At seven weeks of age, groups of rats were injected s.c. with a zoxymethane (AOM; 15 mg/kg body wt., once weekly for 2 weeks) and continued on their respective experimental diets until 38 weeks after the second AOM treatment. They were then sacrificed and colonic mucosal and tumor samples were evaluated for PKC, TPK, DGK and 8-isoprostane levels. Administration of p-XSC along with a low-fat diet significantly inhibited Ca+2-dependent a nd -independent PKC (P<0.05-0.01) activities in colonic mucosa and tumors. Administration of p-XSC either low-fat or high-fat diet significantly suppr essed both colonic mucosal and tumor TPK activity (P<0.05-0.01). Suppressio n of TPK activity was more pronounced in rats maintained on a low-fat diet containing pXSC. In contrast, rats receiving p-XSC with either low- or high fat diet showed significantly increased DGK activity (P<0.01-0.0001), Rats fed low-fat or high-fat plus p-XSC had lower-levels of 8-isoprostane in th e colonic tumors than animals who had been given low- or high-fat diets wit hout the organoselenium compound. Interestingly, 8-isoprostane levels were lower in the colon tumors of the rats fed the low-fat diet than those fed t he high-fat diet. Our findings suggest that p-XSC induced down-regulation o f PKC and TPK activities and up-regulation of DGK activity. These events ma y in part be responsible for the chemopreventive activity against colon car cinogenesis. Further, this study implies that p-XSC with a low-fat dietary regimen will augment regulation of PKC, TPK and DGK activities in the colon .