Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/169241
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dc.contributor.authorRojas, Elizabeta A.-
dc.contributor.authorCorchete, Luis A.-
dc.contributor.authorSan-Segundo, Laura-
dc.contributor.authorMartínez-Blanch, Juan F.-
dc.contributor.authorCodoñer, Francisco M.-
dc.contributor.authorPaíno, Teresa-
dc.contributor.authorPuig, Noemi-
dc.contributor.authorGarcía-Sanz, Ramón-
dc.contributor.authorMateos, Maria Victoria-
dc.contributor.authorOcio, Enrique M.-
dc.contributor.authorMisiewicz-Krzeminska, Irena-
dc.contributor.authorGutiérrez, Norma Carmen-
dc.date.accessioned2018-08-30T07:42:13Z-
dc.date.available2018-08-30T07:42:13Z-
dc.date.issued2017-
dc.identifierdoi: 10.1158/1078-0432.CCR-17-0678-
dc.identifiere-issn: 1557-3265-
dc.identifierissn: 1078-0432-
dc.identifier.citationClinical Cancer Research 23(21): 6602-6615 (2017)-
dc.identifier.urihttp://hdl.handle.net/10261/169241-
dc.description.abstract[Purpose]: The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent antimyeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. [Experimental Design]: Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq experiments, qRT-PCR, immunoblotting, and immunofluorescence assays. [Results]: Amiloride-induced apoptosis was observed in a broad panel of multiple myeloma cell lines and in a xenograft mouse model. Moreover, amiloride also had a synergistic effect when combined with dexamethasone, melphalan, lenalidomide, and pomalidomide. RNA-Seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. In addition, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, we did not find a significant systemic toxicity in mice treated with amiloride. [Conclusions]: Overall, our results demonstrate the antimyeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option for relapsed multiple myeloma patients, especially those with 17p deletion or TP53 mutations that are resistant to current therapies.-
dc.description.sponsorshipThis study was partially supported by the Instituto de Salud Carlos III-Cofinanciacion with funding from FEDER (PI13/00111 and PI16/01074), Asociacion Española Contra el Cancer (AECC, GCB120981SAN), Gerencia Regional de Salud, Junta de Castilla y Leon (BIO/SA57/13 and BIO/SA22/15), and the INNOCAMPUS Program (CEI10-1-0010). I. Misiewicz-Krzeminska was supported by a Black Swan R esearch Initiative grant from the International Myeloma Foundation. L.A. Corchete was supported by a grant from the Fundacion Española de Hematología y Hemoterapia.-
dc.publisherAmerican Association for Cancer Research-
dc.rightsclosedAccess-
dc.titleAmiloride, an old diuretic drug, is a potential therapeutic agent for multiple myeloma-
dc.typeartículo-
dc.identifier.doi10.1158/1078-0432.CCR-17-0678-
dc.date.updated2018-08-30T07:42:13Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.contributor.funderAsociación Española Contra el Cáncer-
dc.contributor.funderJunta de Castilla y León-
dc.contributor.funderInternational Myeloma Foundation-
dc.contributor.funderFundacion de la Sociedad Española de Hematología y Hemoterapia-
dc.contributor.funderEuropean Commission-
dc.contributor.funderInstituto de Salud Carlos III-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100003887es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100014180es_ES
dc.identifier.pmid28790111-
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.openairetypeartículo-
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