Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance

Table 1 Properties of the chemotherapeutic drugs used in AML

Drug	Target	Influx	Metabolism^a	Efflux	Refs.
Cytarabine (Ara-C)	DNA polymerases	ENT1, CNT3, OCTN1	Activation: dCK, dCMPK, NDK. Inactivation: CDA, dCMPD, PN-I.	MRP4,7,8	[14, 30,31,32,33, 78,79,80]
Daunorubicin (DNR)	DNA, Topoisomerase II	Passive diffusion		P-gp, MRP1,7, BCRP	[44, 51, 81,82,83,84]
Mitoxantrone (MX)	DNA, Topoisomerase II	Passive diffusion		P-gp, MRP1, BCRP	[44, 85,86,87,88,89,90]
Etoposide (VP-16)	Topoisomerase II	Passive diffusion		P-gp, MRP1-3,6, BCRP	[16, 91, 92]
Methotrexate (MTX)	DHFR, TS, AICARFT	RFC, PCFT	Aldehyde oxidase, FPGS (polyglutamylation)	P-gp, MRP1-5, BCRP	[16, 93, 94]
Venetoclax (VEN)	Bcl-2	Passive diffusion		P-gp	[72, 95]
Gemtuzumab Ozogamicin (GO)	DNA	Ab-mediated endocytosis	Lysosomal Calicheamicin cleavage from Ab, glutathione	P-gp, MRP1	[73, 77]

DHFR, dihydrofolate reductase; TS, thymidylate synthase; AICARFT, aminoimidazole-4-carboxamide ribonucleotide formyltransferase; Bcl-2, B-cell leukemia/lymphoma 2; ENT1, equilibrative nucleoside transporter 1; CNT3, concentrative nucleoside transporter 3; OCTN1, organic cation transporter, novel, type 1; RFC, reduced folate carrier; PCFT, proton coupled folate transporter; dCK, deoxycytidine kinase; dCMPK, deoxycytidylate kinase; NDK, nucleoside diphosphate kinase; CDA, cytidine deaminase; dCMPD, deoxycytidylate deaminase; PN-I, cytosolic 5-nuleotidase 3A; FPGS, folylpoly-ɣ-glutamate synthetase; MRP, multidrug resistance-associated protein; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein.
^aOccuring in leukemic cells.

ISSN: 1475-2867