A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers

Abstract

The azanucleosides azacitidine and decitabine are currently used for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients not only eligible for intensive chemotherapy but are also being explored in other hematologic and solid cancers. Based on their capacity to interfere with the DNA methylation machinery, these drugs are also referred to as hypomethylating agents (HMAs). As DNA methylation contributes to epigenetic regulation, azanucleosides are further considered to be among the first true "epigenetic drugs" that have reached clinical application. However, intriguing new evidence suggests that DNA hypomethylation is not the only mechanism of action for these drugs. This review summarizes the experience from more than 10 years of clinical practice with azanucleosides and discusses their molecular actions, including several not related to DNA methylation. A particular focus is placed on possible causes of primary and acquired resistances to azanucleoside treatment. We highlight current limitations for the success and durability of azanucleoside-based therapy and illustrate that a better understanding of the molecular determinants of drug response holds great potential to overcome resistance.

Keywords: AML; Azacitidine; Azanucleoside; Chromatin; Decitabine; HMA; MDS; Methylation.

Fig. 1

Cytidine nucleoside (a) and azanucleoside (b, c) chemical structures. Sugar moieties are indicated in grey and chemical changes between cytidine nucleoside and azanucleosides are highlighted in red

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