5-Azacytidine is able to induce the conversion of teratocarcinoma-derived mesenchymal cells into epithelia cells.

Abstract

The inhibitor of DNA-methylation, 5-azacytidine (5-AzaC) induced the appearance of cytokeratin-containing cells in several mesenchymal cell lines such as teratocarcinomaderived fibroblasts, preadipocytes and myoblasts, NIH-3T3 fibroblasts and human embryonic fibroblasts. At optimal 5-AzaC concentrations the proportion of such cells was in the range of 10-1 compared with 10-6-10-4 in non-treated cultures. Dose-response curves indicated that the induction of cytokeratin was the result of an interaction of the drug with few targets. Stable, mature, keratinocyte cell lines, as well as lines of myoblasts and astrocytes, could be isolated from a teratocarcinoma-derived preadipocyte line, showing that 5-AzaC is able to provoke a wide range of complete phenotypic conversions. In these cell lines, the intermediate filaments corresponded to the morphological phenotype. Altogether, the results suggest that 5-AzaC preferentially activates certain genes.

Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells

“…These interesting observations were based on spontaneous differentiation of immortalized (28) or tumor-derived cell lines (13,29) occurring several days after the exposure to the drug, which lead to a conversion process characterized by variable efficiency and stability, as well as being mainly limited within the mesoderm linages.…”

“…Therefore, we tested whether a short exposure to a demethylating agent is sufficient to allow the direct conversion of an adult mature cell into another differentiated cell type. To this purpose, we selected the cytidine analog 5-azacytidine (5-aza-CR), a well-characterized DNA methyltransferase inhibitor known to activate the expression of silent genes (11) and to alter the differentiation state of embryonic (12) and mesenchymal cell lines (13).…”

Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

“…On the one hand, 5-azacytidine is capable of enhancing or inducing the metastatic capacity of various tumour cell lines (Olsson & Forchammer, 1984;Trainer et al, 1985;Ormerod et al, 1986), activating silent retroviral genomes (Jaenisch et al, 1985), enhancing the induction by various carcinogens of gamma-glutamyltransferase positive liver foci (Denda et al, 1985), of altering cellular DNA which is incapable of inducing transformation (Venolia et al, 1982), and of inducing tumorigenesis in various cells in culture (Venolia et al, 1982;Harrison et al, 1983;Benedict et al, 1977;Marquardt & Marquardt, 1977), even though it does not appear to be a significant mutagen in mammalian cells (Landolph & Jones, 1982;Frost et al, 1984;Momparler et al, 1984;Delers et al, 1984;Bouck et al, 1984;Jones, 1984). On the other hand, 5-azacytidine has been shown to induce differentiation in both non-transformed as well as in neoplastic cells in culture (Constantinides et al, 1977(Constantinides et al, , 1978Jones & Taylor, 1980;Walker et al, 1984;Creusot et al, 1982;Darmon et al, 1984;Pinto et al, 1984). 5-Azacytidine is a cell toxin and has been used to treat leukaemia (von Hoff et al, 1976) and can induce the expression of new cell surface antigens and thus increase the effectiveness of immunosurveillance in immunocompetent animals (Frost et al, 1984).…”

DNA Methylation and Differentiation

“…In addition, functionally differentiated adipocytes and chondrocytes also emerged after 5-aza-CR treatment of 10T½/ cells, so that alterations in differentiation were not restricted to the muscle phenotype (83). Phenotypic changes were not even confined to the developmental lineage of the treated precursor cell since epithelial cells were induced from 5-aza-CR-treated teratocarcinoma-derived mesenchymal cells (84). The differentiation of nonmesenchymal cells is also dramatically altered by exposure to 5-aza-CR, as exemplified by various leukemia cell differentiation models (73,85,86).…”