Dietary selenite and azadeoxycytidine treatments affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells.
Several observations implicate a role for altered DNA methylation in cancer pathogenesis. The global level of DNA methylation is generally lower; however, DNA methyltransferase (Dnmt1) activity is usually higher in tumor cells than in normal cells. The purpose of this study was to investigate whether the Dnmt1 inhibitor, 5-aza-2'-deoxycytidine (aza-dC) would alter the effect of dietary selenium on the formation of aberrant crypts. Weanling rats (n = 60) were fed three concentrations of selenium (deficient, 0.1 and 2.0 mg/kg diet) in a Torula yeast-based diet. Half of the rats were injected weekly with aza-dC (1 mg/kg, subcutaneously) and half were injected with the vehicle control (PBS). After 3.5 wk of consuming the experimental diets, the rats were given two injections of dimethylhydrazine (DMH; 25 mg/kg, intraperitoneally). Rats fed the selenium-deficient diet and injected with PBS had significantly (P < 0.006) more aberrant crypts than rats fed 0.1 or 2.0 mg selenium/kg diet (244 +/- 21 vs. 165 +/- 9 and 132 +/- 14, respectively). In contrast, when rats were injected with aza-dC, there was a significant (P < 0.0001) reduction in aberrant crypt formation and dietary selenium had no effect (62 +/- 8 vs. 77 +/- 13 vs. 54 +/- 8, in rats fed 0, 0.1 and 2.0 mg selenium/kg diet, respectively). HT-29 cells cultured in the absence of selenium had significantly hypomethylated DNA but significantly more Dnmt1 protein expression than cells cultured in the presence of 1 or 2 micromol/L selenium. These results suggest that aza-dC treatment may protect selenium-deficient rats against carcinogen-induced aberrant crypt formation.
Davis
Cindy D
CD
U.S. Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034, USA. cdavis@gfhnrc.ars.usda.gov
Uthus
Eric O
EO
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004127:Dimethylhydrazines / Q000633:toxicity; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D018038:Sodium Selenite / Q000008:administration & dosage / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D002273:Carcinogens; D004127:Dimethylhydrazines; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619382:Dnmt1 protein, rat; D018038:Sodium Selenite; D001374:Azacitidine