Figure 3.

Candidate pathways for azanucleotide activity. Following uptake into the cell by nucleoside-specific transport, AZA and DAC enter the cell and after phosphorylation and reduction, are incorporated into DNA. Excess azanucleotides are rapidly deaminated to uracil by cytidine deaminase and excreted by the kidneys. DNMT1 is then trapped by 5-Aza-deoxinucleotides, resulting in DNA hypomethylation following replication. Mutations of epigenetic enzymes alter chromatin configuration (i.e. EZH2), methylation (DNMT1, 3A and 3B) and the production of 5hmC (IDH1/2, TET2). Azacitidine and decitabine treatment reactivate expression of most oncogenic pathways, including among others lineage commitment, cell adhesion and cycle, signal transduction, immune responses and apoptosis. Upregulation of cancer antigens has also been shown, together with induction of T-cell responses. Changes in any of these stages may influence patients’ response to hypomethylating treatment.