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2-Deoxy-D-glucose cooperates with arsenic trioxide to induce apoptosis in leukemia cells: Involvement of IGF-1R-regulated Akt/mTOR, MEK/ERK and LKB-1/ AMPK signaling pathways

dc.contributor.authorEstañ, María Cristina
dc.contributor.authorCalviño, Eva
dc.contributor.authorBlas, Elena de
dc.contributor.authorBoyano Adánez, María del Carmen
dc.contributor.authorMena, María Luz
dc.contributor.authorGómez Gómez, M.Milagros
dc.contributor.authorRial, Eduardo
dc.contributor.authorAller, Patricio
dc.date.accessioned2023-06-20T00:29:21Z
dc.date.available2023-06-20T00:29:21Z
dc.date.issued2012
dc.description.abstractWhile the anti-tumor efficacy of 2-deoxy-D-glucose (2-DG) is normally low in monotherapy, it may represent a valuable radio- and chemo-sensitizing agent. We here demonstrate that 2–10 mM 2-DG cooperates with arsenic trioxide (ATO) and other antitumor drugs to induce apoptosis in human myeloid leukemia cell lines. Using ATO and HL60 as drug and cell models, respectively, we observed that 2-DG/ ATO combination activates the mitochondrial apoptotic pathway, as indicated by Bid-, and Baxregulated cytochrome c and Omi/HtrA2 release, XIAP down-regulation, and caspase-9/-3 pathway activation. 2-DG neither causes oxidative stress nor increases ATO uptake, but causes inner mitochondria membrane permeabilization as well as moderate ATP depletion, which nevertheless do not satisfactorily explain the pro-apoptotic response. Surprisingly 2-DG causes cell line-specific decrease in LKB-1/AMPK phosphorylation/activation, and also causes Akt/mTOR/p70S6K and MEK/ERK activation, which is prevented by co-treatment with ATO. The use of kinase-specific pharmacologic inhibitors and/or siRNAs reveals that apoptosis is facilitated by AMPK inactivation and restrained by Akt and ERK activation, and that Akt and ERK activation mediates AMPK inhibition. Finally, 2-DG stimulates IGF-1R phosphorylation/activation, and co-treatment with IGF-1R inhibitor prevents 2-DG effects on Akt, ERK and AMPK, and facilitates 2-DG-provoked apoptosis. In summary 2-DG elicits IGF-1R-mediated AMPK inactivation and Akt and ERK activation, which facilitates or restrain apoptosis, respectively. 2-DG-provoked AMPK inactivation increases the apoptotic efficacy of ATO, while in turn ATO-provoked Akt and ERK inactivation may increase the efficacy of 2-DG as anti-tumor drug.
dc.description.departmentDepto. de Química Analítica
dc.description.facultyFac. de Ciencias Químicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)
dc.description.sponsorshipPrograma Consolider-Ingenio 2010
dc.description.sponsorshipConsejo Superior de Investigaciones Científicas
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/42119
dc.identifier.doidoi.org/10.1016/j.bcp.2012.09.022
dc.identifier.issn0006-2952(Print) 1873-2968 (Online)
dc.identifier.officialurlhttp://www.sciencedirect.com/science/article/pii/S0006295212006533
dc.identifier.urihttps://hdl.handle.net/20.500.14352/42639
dc.issue.number12
dc.journal.titleBiochemical pharmacology
dc.language.isoeng
dc.page.final1616
dc.page.initial1604
dc.publisherElsevier
dc.relation.projectID(SAF2010-20256)
dc.relation.projectID(CSD2007-00020)
dc.relation.projectID(201020E037)
dc.rights.accessRightsrestricted access
dc.subject.cdu543
dc.subject.keyword2-Deoxy-D-glucose
dc.subject.keywordArsenic trioxide
dc.subject.keywordApoptosis
dc.subject.keywordProtein kinases
dc.subject.keywordLeukemia cells
dc.subject.ucmQuímica analítica (Química)
dc.subject.unesco2301 Química Analítica
dc.title2-Deoxy-D-glucose cooperates with arsenic trioxide to induce apoptosis in leukemia cells: Involvement of IGF-1R-regulated Akt/mTOR, MEK/ERK and LKB-1/ AMPK signaling pathways
dc.typejournal article
dc.volume.number84
dspace.entity.typePublication
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