Fig. 2

Azanucleoside uptake and intracellular metabolism. Human equilibrative and concentrative nucleoside transporters (hENT/SLC29A and hCNT/SLC28A, respectively) and the SLC15 and SLC22 transporter families mediate azanucleosides (5-aza and 5-aza-dC) uptake. Once inside the cell, the drugs are activated through consecutive ATP-dependent phosphorylation steps: the first one is mediated by uridine-cytidine kinase (UCK) for 5-aza and by deoxycytidine kinase (DCK) in the case of 5-aza-dC; the enzyme nucleoside monophosphate kinase (NMPK) incorporates the second phosphate group in both drugs; then, ribonucleotide reductase (RNR) partly converts (10–20 %) 5-aza-CDP into its deoxy form 5-aza-dCDP. Finally, nucleoside diphosphate kinase (NDPK) adds the third phosphate group and 5-aza-CTP is incorporated into RNA while 5-aza-dCTP is incorporated into DNA. Enzymes involved in resistance are highlighted in red, while mutated genes, which have been described to increase the sensitivity to AZN treatment or improve overall survival in patients, are highlighted in green