DNA (cytosine) methylation in murine and human tumor cell lines treated with S-adenosylhomocysteine hydrolase inhibitors

Abstract

The effects of periodate-oxidized adenosine, 3-deaza-adenosine and 3-deaza-(+/-)aristeromycin, potent inhibitors of S-adenosylhomocysteine hydrolase activity, on DNA methylation and the intracellular ratio of S-adenosylhomocysteine and S-adenosylmethionine have been examined in a series of murine and human tumor cell lines. A 24-h exposure of murine LC3, TA3 and B16 cells and human MeWo and K562 cells to 1-10 microM periodate-oxidized adenosine had a very slight inhibitory effect upon DNA methylation. 3-Deaza-(+/-)aristeromycin and 3-deaza-adenosine (50 microM) had virtually no effect upon DNA methylation in LC3 and B16 cells. In LC3 cells, periodate-oxidized adenosine, 3-deaza-adenosine and 3-deaza-(+/-)aristeromycin reduced the intracellular ratio of S-adenosylmethionine/S-adenosylhomocysteine approximately 20-, 6- and 16-fold, respectively. In murine B16 melanoma cells, periodate-oxidised adenosine, 3-deaza-adenosine and 3-deaza-(+/-)aristeromycin reduced the intracellular ratio of S-adenosylmethionine/S-adenosylhomocysteine approximately 17-, 13- and 32-fold, respectively. These observations indicate that the cytosine methylation of DNA appears to be relatively insensitive to changes in the intracellular ratio of S-adenosylmethionine/S-adenosylhomocysteine and that such metabolic disturbances are not likely to be the major biochemical alteration responsible for the reduced level of DNA 5-methylcytosine found within transformed and malignant cells.