Hypomethylation and apoptosis in 5-azacytidine-treated myeloid cells

Experimental Hematology
Rasheed KhanEva Hellstrom-Lindberg

Abstract

Although clinically approved for myelodysplastic syndromes (MDS), the mode of action of 5-azacytidine has not been well understood at the cellular level. The present study aimed at characterizing the mechanisms for 5-azacytidine-induced apoptosis, as well as the presence of a possible link between apoptosis and DNA hypomethylation. We investigated the effects of 5-azacytidine on a spectrum of specific apoptotic pathways, as well as on global DNA methylation, assessed by luminometric methylation assay, in myeloid (P39, HL60) and T cells (Jurkat). 5-Azacytidine induced dose-dependent apoptosis as well as non-dose-dependent global DNA hypomethylation at concentrations >or=0.5 microM. Hypomethylation was observed in the sorted apoptotic fraction (41% decrease with 1 microM after 24 hours), while nonapoptotic cells retained a methylation pattern similar to untreated cells (+/-6%). The induced apoptotic pattern involved several pathways: cleavage of Bcl-2 family proteins, activation of caspase-2 and -3-like, mitochondrial involvement characterized by loss of transmembrane potential (tetramethylrhodamine ethyl ester [TMRE]) and cytochrome release, and acidification of cytosol. Selective inhibition of caspase-3-like, -2, -8, -9, and pa...Continue Reading

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