Bone Marrow Stromal Cells Modulate Mouse ENT1 Activity and Protect Leukemia Cells from Cytarabine Induced Apoptosis

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dc.contributor.authorMacanas Pirard, Patricia
dc.contributor.authorLeisewitz, Andrea
dc.contributor.authorBroekhuizen, Richard
dc.contributor.authorCautivo, Kelly
dc.contributor.authorBarriga, Francisco M.
dc.contributor.authorLeisewitz, Francisco
dc.contributor.authorGidi, Victoria
dc.contributor.authorRiquelme, Erick
dc.contributor.authorMontecinos, Viviana P.
dc.contributor.authorSwett, Pilar
dc.contributor.authorBesa, Pelayo
dc.contributor.authorRamirez, Pablo
dc.contributor.authorOcqueteau, Mauricio
dc.contributor.authorKalergis, Alexis M.
dc.contributor.authorHolt, Matthew
dc.contributor.authorRettig, Michael
dc.contributor.authorDiPersio, John F.
dc.contributor.authorNervi, Bruno
dc.date.accessioned2024-01-10T12:04:30Z
dc.date.available2024-01-10T12:04:30Z
dc.date.issued2012
dc.description.abstractBackground: Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells.
dc.description.abstractMethods: Using a leukemia mouse model and a human leukemia cell line, we studied the interaction of leukemia cells with the BM microenvironment. We evaluated in vivo and in vitro leukemia cell chemoprotection to different cytotoxic agents mediated by the BM stroma. Leukemia cell apoptosis was assessed by flow cytometry and western blotting. The activity of the equilibrative nucleoside transporter 1 (ENT1), responsible for cytarabine cell incorporation, was investigated by measuring transport and intracellular accumulation of H-3-adenosine.
dc.description.abstractResults: Leukemia cell mobilization from the bone marrow into peripheral blood in vivo using a CXCR4 inhibitor induced chemo-sensitization of leukemia cells to cytarabine, which translated into a prolonged survival advantage in our mouse leukemia model. In vitro, the BM stromal cells secreted a soluble factor that mediated significant chemoprotection to leukemia cells from cytarabine induced apoptosis. Furthermore, the BM stromal cell supernatant induced a 50% reduction of the ENT1 activity in leukemia cells, reducing the incorporation of cytarabine. No protection was observed when radiation or other cytotoxic agents such as etoposide, cisplatin and 5-fluorouracil were used.
dc.description.abstractConclusion: The BM stroma secretes a soluble factor that significantly protects leukemia cells from cytarabine-induced apoptosis and blocks ENT1 activity. Strategies that modify the chemo-protective effects mediated by the BM microenvironment may enhance the benefit of conventional chemotherapy for patients with AML.
dc.description.funderChilean National Commission for Scientific Research and Technology CONICYT (FONDECYT)
dc.description.funderMillennium Institute on Immunology and Immunotherapy
dc.format.extent11 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1371/journal.pone.0037203
dc.identifier.issn1932-6203
dc.identifier.pubmedidMEDLINE:22629369
dc.identifier.urihttps://doi.org/10.1371/journal.pone.0037203
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/75817
dc.identifier.wosidWOS:000305345300026
dc.information.autorucMedicina;Besa P ;S/I;57605
dc.information.autorucCiencias Biológicas;Cautivo K ;S/I;189036
dc.information.autorucCiencias Biológicas;Gidi V;S/I;171969
dc.information.autorucCiencias Biológicas;Kalergis A;S/I;90610
dc.information.autorucMedicina;Leisewitz A ;S/I;94860
dc.information.autorucMedicina;Macanas P ;S/I;1006859
dc.information.autorucMedicina;Montecinos V;S/I;111594
dc.information.autorucMedicina;Nervi B ;S/I;604
dc.information.autorucMedicina;Ocqueteau M;S/I;71377
dc.information.autorucMedicina;Ramirez P ;S/I;1242
dc.information.autorucCiencias Biológicas;Riquelme E ;S/I;1001194
dc.information.autorucBachillerato;Swett P ;S/I;163544
dc.issue.numero5
dc.language.isoen
dc.nota.accesoSin adjunto
dc.publisherPUBLIC LIBRARY SCIENCE
dc.revistaPLOS ONE
dc.rightsregistro bibliográfico
dc.subjectACUTE MYELOID-LEUKEMIA
dc.subjectMULTIDRUG-RESISTANCE PROTEIN-1
dc.subjectACUTE MYELOGENOUS LEUKEMIA
dc.subjectHEMATOPOIETIC STEM-CELLS
dc.subjectARA-C
dc.subjectDEOXYCYTIDINE KINASE
dc.subjectCYTOSINE-ARABINOSIDE
dc.subjectDRUG-RESISTANCE
dc.subjectCXCR4
dc.subjectMICROENVIRONMENT
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleBone Marrow Stromal Cells Modulate Mouse ENT1 Activity and Protect Leukemia Cells from Cytarabine Induced Apoptosis
dc.typeartículo
dc.volumen7
sipa.codpersvinculados57605
sipa.codpersvinculados189036
sipa.codpersvinculados171969
sipa.codpersvinculados90610
sipa.codpersvinculados94860
sipa.codpersvinculados1006859
sipa.codpersvinculados111594
sipa.codpersvinculados604
sipa.codpersvinculados71377
sipa.codpersvinculados1242
sipa.codpersvinculados1001194
sipa.codpersvinculados163544
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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