Table 3.
A Summary of Anti-AML Drugs, Targets and Mechanisms of Action
| Drug | Targets | Mechanism of Action |
|---|---|---|
| Deoxycytidine analogues | ||
| Azacitidine, decitabine, cytarabine | DNMT (low dose)29 | Inhibiting DNA methylation, activating CDKN1C (the cell-cycle regulator p57KIP2), RAR genes, growth factor- families (DLK1, HGF), S-phase-active chemotherapeutic agents6,29 |
| DNA Pol (primary target) | Inhibiting DNA replication & inducing apoptosis,1,6,20 impairment of DNA repair, inhibiting DNPS pathway6,7 | |
| dCK | Phosphorylating all deoxynucleoside analogues, converting to deoxynucleotides which compete with natural substrates & incorporating into DNA6,20 | |
| RNR | Depleting the deoxynucleotide pool, limiting DNA synthesis,6,7 | |
| Purine analogues | ||
| Thiopurines | PRT (primary target) | Activating antimetabolites,6,20 |
| HGPRT | Converted to 6-thioguanosine-5′-triphosphate which is readily incorporated into RNA6,23 | |
| RNR | Incorporation into DNA & inhibiting DNA methylation, impairing DNA repair by futile cycle6,23,29 | |
| DNPS (secondary target) | Greater antileukemic effects, purine deprivation, leading to inhibition of DNA synthesis6,23 | |
| Purine nucleoside analogues | ||
| Fludarabine, cladribine, clofarabine | DNA Pol (primary target) | Inhibiting DNA replication & inducing apoptosis,1,6,20 impairment of DNA repair6,7 |
| dCK | Phosphorylating all deoxynucleoside analogues which compete with natural substrates,6,20 inhibiting DNPS pathway | |
| RNR | Conversion to deoxynucleotides & incorporation into DNA, inhibiting DNA methylation,6,20,29 inhibiting RNR, depleting the deoxynucleotide pool, limiting DNA synthesis,6,7 impairing DNA repair by a futile cycle | |
| Nucleoside transporters | Increasing the cellular uptake as well as accumulation of Ara-CTP in leukemic blasts1 | |
| Anthracyclines | ||
| Aclarubicin, doxorubicin, Daunorubicin, idarubicin, mitoxantrone | DNA intercalating agents | DNA strands break inducers by inhibiting TOP I/II, DNA Pol and DNA repair enzymes, with cytarabine enhanced DNA breaks due to inhibiting repair of DNA in leukemia cells, G1 block facilitators1,16 |
| Etoposide | TOP I/II | Like as anthracyclines1 |
| Antagonists of surface growth receptors | ||
| Midostaurin, Sorafenib, Gilteritinib, Crenolanib | TKs: FLT3 kinase, KIT, VEGFR, PDGFR; kinase C | Inhibiting a cascade of downstream pathways including the RAS, Src/JAK (Janus kinase), and PI3K pathways that signal cell proliferation5,10,17 |
| G-CSF | G-CSF receptors | Frequently expressed in leukemic blasts than in healthy BM cells, increasing leukemic blasts in the S-phase, enhancing the cytotoxicity of S-phase-active chemotherapeutic agents such as cytarabine, promoting differentiation in myeloid cells1,12 |
| HHT | DNA incorporation into the DNA | Inhibits DNA synthesis, induces apoptosis in a variety of AML cells in a dose dependent manner, a G1/G2 phase-specific chemotherapeutic agent12 |
| Cisplatin | Cross-linking DNA, forming intra- and interstrand adducts | DNA-damaging, cytotoxic & carcinogenic potential, effective salvage chemotherapy in high-risk relapsed or refractory AML in combination with high dose cytarabine and etoposide, attracting high-mobility-group proteins, activating ATF, p53, p73, and MAPK15 |
| ATRA | RAR-RXR | Forming a transcription activator to activate the genes required for promyelocyte differentiation30 |
| HDACi | HDACs | Opening chromatin & double strand breaks, increasing p53, acetylated p53, p21 Bad, Bim, Bix, Noxa expression, and enhances the apoptotic response of AML cells, G1/S or G2/M transition blockage9,29 in rational combination with docetaxel, doxorubicin, etoposide, and cisplatin shows additive or synergistic effects15,24 |
Abbreviations: DNA Pol, DNA polymerase; DNMT, DNA methyltransferase; RNR, ribonucleotide reductase; dCK, deoxycytidine kinase; RAR, retinoic-acid-responsive; PRT, phosphoribosyl transferase; G-CSF, granulocyte colony-stimulating factor; HHT, homoharringtonine; DNPS, de novo purine synthesis; TOP I/II, topoisomerase I and II; ATRA, all-trans retinoic acid; RAR-RXR, retinoic acid receptor α-retinoid X receptor heterodimer protein; HDACs, histone deacetylases; HDACi, histone deacetylase inhibitors; HMTs, histone methyltransferases; Bad, BH3-only pro-apoptotic protein-encoding genes; TKs, tyrosine kinases.