Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/126421
Full metadata record
DC FieldValueLanguage
dc.contributor.authorSoaresa, Joana-
dc.contributor.authorRaimundo, Liliana-
dc.contributor.authorPereira, Nuno A. L.-
dc.contributor.authordos Santos, Daniel J. V. A.-
dc.contributor.authorPérez Bosch, Maria-
dc.contributor.authorQueiroz, Glória-
dc.contributor.authorLeão, Mariana-
dc.contributor.authorSantos, Maria M. M.-
dc.contributor.authorSaraiva, Lucília-
dc.date.accessioned2018-11-23T16:00:02Z-
dc.date.available2018-11-23T16:00:02Z-
dc.date.issued2015-05-
dc.identifier.issn1043-6618-
dc.identifier.urihttp://hdl.handle.net/2445/126421-
dc.description.abstractInactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53+/+) and its p53-null isogenic derivative (HCT116 p53−/−), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53+/+, but not in p53−/−, HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ-1 against MDMXoverexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53+/+ cells, the disruption of the p53 interaction with MDMs by OXAZ- 1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53-dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53-dependent synergistic effect with conventional chemotherapeutic drugs. Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53 MDMs interaction.-
dc.format.extent11 p.-
dc.format.mimetypeapplication/pdf-
dc.language.isoeng-
dc.publisherElsevier B.V.-
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1016/j.phrs.2015.03.006-
dc.relation.ispartofPharmacological Research, 2015, vol. 95-96, p. 42-52-
dc.relation.urihttps://doi.org/10.1016/j.phrs.2015.03.006-
dc.rightscc-by-nc-nd (c) Elsevier B.V., 2015-
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es-
dc.sourceArticles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)-
dc.subject.classificationMedicaments antineoplàstics-
dc.subject.classificationCompostos orgànics-
dc.subject.classificationTriptòfan-
dc.subject.classificationLactames-
dc.subject.otherAntineoplastic agents-
dc.subject.otherOrganic compounds-
dc.subject.otherTryptophan-
dc.subject.otherLactams-
dc.titleA tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins-
dc.typeinfo:eu-repo/semantics/article-
dc.typeinfo:eu-repo/semantics/acceptedVersion-
dc.identifier.idgrec650744-
dc.date.updated2018-11-23T16:00:02Z-
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess-
dc.identifier.pmid25814188-
Appears in Collections:Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)

Files in This Item:
File Description SizeFormat 
650744.pdf491.67 kBAdobe PDFView/Open


This item is licensed under a Creative Commons License Creative Commons