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dc.contributor.authorCueva, Ana de la-
dc.contributor.authorRamírez de Molina, Ana-
dc.contributor.authorÁlvarez-Ayerza, Néstor-
dc.contributor.authorRamos, Maria Angeles-
dc.contributor.authorCebrián, Arancha-
dc.contributor.authorGómez del Pulgar, Teresa-
dc.contributor.authorLacal, Juan Carlos-
dc.date.accessioned2015-10-26T14:03:39Z-
dc.date.available2015-10-26T14:03:39Z-
dc.date.issued2013-
dc.identifierdoi: 10.1371/journal.pone.0064961-
dc.identifierissn: 1932-6203-
dc.identifier.citationPLoS ONE 8(6): e64961 (2013)-
dc.identifier.urihttp://hdl.handle.net/10261/123856-
dc.descriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.-
dc.description.abstract[Background]: Colorectal cancer (CRC) is the third major cause of cancer related deaths in the world. 5-fluorouracil (5-FU) is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. Choline kinase alpha (ChoKα), an enzyme that plays a role in cell proliferation and transformation, has been reported overexpressed in many different tumors, including colorectal tumors. ChoKα inhibitors have recently entered clinical trials as a novel antitumor strategy. [Methodology/Principal Findings]: ChoKα specific inhibitors, MN58b and TCD-717, have demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines. The effect of ChoKα inhibitors in combination with 5-FU as a new alternative for the treatment of colon tumors has been investigated both in vitro in CRC-tumour derived cell lines, and in vivo in mouse xenografts models. The effects on thymidilate synthase (TS) and thymidine kinase (TK1) levels, two enzymes known to play an essential role in the mechanism of action of 5-FU, were analyzed by western blotting and quantitative PCR analysis. The combination of 5-FU with ChoKα inhibitors resulted in a synergistic effect in vitro in three different human colon cancer cell lines, and in vivo against human colon xenografts in nude mice. ChoKα inhibitors modulate the expression levels of TS and TK1 through inhibition of E2F production, providing a rational for its mechanism of action. [Conclusion/Significance ]: Our data suggest that both drugs in combination display a synergistic antitumoral effect due to ChoKα inhibitors-driven modulation of the metabolization of 5-FU. The clinical relevance of these findings is strongly supported since TCD-717 has recently entered Phase I clinical trials against solid tumors. © 2013 de la Cueva et al.-
dc.description.sponsorshipThis work has been funded by the following grants: Comunidad de Madrid (S-BIO/0280/2006 and S2010/BMD-2326), Ministerio de Ciencia e Innovación (SAF2008-03750, SAF2011-29699, RD06-0020-0016 and RD12/0036/0019) and EU #259737.-
dc.publisherPublic Library of Science-
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/259737-
dc.relationS2010/BMD-2326/INMUNOTHERCAN-
dc.relation.isversionofPublisher's version-
dc.rightsopenAccess-
dc.titleCombined 5-FU and ChoKα inhibitors as a new alternative therapy of colorectal cancer: Evidence in human tumor-derived cell lines and mouse xenografts-
dc.typeartículo-
dc.identifier.doi10.1371/journal.pone.0064961-
dc.relation.publisherversionhttp://dx.doi.org/10.1371/journal.pone.0064961-
dc.date.updated2015-10-26T14:03:39Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.rights.licensehttp://creativecommons.org/licenses/by/4.0/-
dc.contributor.funderEuropean Commission-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderComunidad de Madrid-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004837es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100012818es_ES
dc.identifier.pmid23762272-
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.openairetypeartículo-
item.cerifentitytypePublications-
item.grantfulltextopen-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextWith Fulltext-
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