Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy

Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR)...

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Autores: Rodríguez Macías, Gabriela, Briz, Oscar, Cives Losada, Candela, Chillón, María, Martínez Laperche, Carolina, Martínez Arranz, Ibon, Buño Borde, Ismael, González Díaz, Marcos, Díez Martín, José Luis, Marin, Jose J. G., Macias, Rocio I. R.
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/103517
Acceso en línea:https://hdl.handle.net/20.500.14352/103517
Access Level:acceso abierto
Palabra clave:616.155.392
AML
Blood cancer
Chemotherapy
Chemoresistance
Prognosis
Bioquímica (Medicina)
3201.03 Microbiología Clínica
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network_name_str España
repository_id_str
spelling Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction ChemotherapyRodríguez Macías, GabrielaBriz, OscarCives Losada, CandelaChillón, MaríaMartínez Laperche, CarolinaMartínez Arranz, IbonBuño Borde, IsmaelGonzález Díaz, MarcosDíez Martín, José LuisMarin, Jose J. G.Macias, Rocio I. R.616.155.392AMLBlood cancerChemotherapyChemoresistancePrognosisBioquímica (Medicina)3201.03 Microbiología ClínicaDespite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.MDPIUniversidad Complutense de Madrid20232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/103517reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI20 00189Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI19 00189open accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1035172026-06-02T12:44:21Z
dc.title.none.fl_str_mv Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
title Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
spellingShingle Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
Rodríguez Macías, Gabriela
616.155.392
AML
Blood cancer
Chemotherapy
Chemoresistance
Prognosis
Bioquímica (Medicina)
3201.03 Microbiología Clínica
title_short Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
title_full Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
title_fullStr Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
title_full_unstemmed Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
title_sort Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy
dc.creator.none.fl_str_mv Rodríguez Macías, Gabriela
Briz, Oscar
Cives Losada, Candela
Chillón, María
Martínez Laperche, Carolina
Martínez Arranz, Ibon
Buño Borde, Ismael
González Díaz, Marcos
Díez Martín, José Luis
Marin, Jose J. G.
Macias, Rocio I. R.
author Rodríguez Macías, Gabriela
author_facet Rodríguez Macías, Gabriela
Briz, Oscar
Cives Losada, Candela
Chillón, María
Martínez Laperche, Carolina
Martínez Arranz, Ibon
Buño Borde, Ismael
González Díaz, Marcos
Díez Martín, José Luis
Marin, Jose J. G.
Macias, Rocio I. R.
author_role author
author2 Briz, Oscar
Cives Losada, Candela
Chillón, María
Martínez Laperche, Carolina
Martínez Arranz, Ibon
Buño Borde, Ismael
González Díaz, Marcos
Díez Martín, José Luis
Marin, Jose J. G.
Macias, Rocio I. R.
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 616.155.392
AML
Blood cancer
Chemotherapy
Chemoresistance
Prognosis
Bioquímica (Medicina)
3201.03 Microbiología Clínica
topic 616.155.392
AML
Blood cancer
Chemotherapy
Chemoresistance
Prognosis
Bioquímica (Medicina)
3201.03 Microbiología Clínica
description Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/103517
url https://hdl.handle.net/20.500.14352/103517
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI20 00189
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI19 00189
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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