Equitoxic Doses of 5-Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the TranscriptomeReportar como inadecuado




Equitoxic Doses of 5-Azacytidine and 5-Aza-2′Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

The hypomethylating agent 5-Azacytidine 5-Aza-CR is the first drug to prolong overall survival in patients with myelodysplastic syndrome MDS. Surprisingly, the deoxyribonucleoside analog 5-Aza-2′deoxycytidine 5-Aza-CdR did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase DNMT. While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs miRNA, which may potentially affect the activities of the drugs in patients.

Methodology-Principal Findings

A hematopoietic HL-60; acute myeloid leukemia and a solid T24; transitional cell carcinoma cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate day 2 and lasting day 8 effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells.

Conclusions-Significance

Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping.



Autor: Xiangning Qiu , Christoffer Hother , Ulrik M. Ralfkiær, Alexandra Søgaard, Qianjin Lu, Christopher T. Workman, Gangning Liang,

Fuente: http://plos.srce.hr/



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