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http://hdl.handle.net/2445/126421
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DC Field | Value | Language |
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dc.contributor.author | Soaresa, Joana | - |
dc.contributor.author | Raimundo, Liliana | - |
dc.contributor.author | Pereira, Nuno A. L. | - |
dc.contributor.author | dos Santos, Daniel J. V. A. | - |
dc.contributor.author | Pérez Bosch, Maria | - |
dc.contributor.author | Queiroz, Glória | - |
dc.contributor.author | Leão, Mariana | - |
dc.contributor.author | Santos, Maria M. M. | - |
dc.contributor.author | Saraiva, Lucília | - |
dc.date.accessioned | 2018-11-23T16:00:02Z | - |
dc.date.available | 2018-11-23T16:00:02Z | - |
dc.date.issued | 2015-05 | - |
dc.identifier.issn | 1043-6618 | - |
dc.identifier.uri | http://hdl.handle.net/2445/126421 | - |
dc.description.abstract | Inactivation 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.extent | 11 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Elsevier B.V. | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1016/j.phrs.2015.03.006 | - |
dc.relation.ispartof | Pharmacological Research, 2015, vol. 95-96, p. 42-52 | - |
dc.relation.uri | https://doi.org/10.1016/j.phrs.2015.03.006 | - |
dc.rights | cc-by-nc-nd (c) Elsevier B.V., 2015 | - |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es | - |
dc.source | Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia) | - |
dc.subject.classification | Medicaments antineoplàstics | - |
dc.subject.classification | Compostos orgànics | - |
dc.subject.classification | Triptòfan | - |
dc.subject.classification | Lactames | - |
dc.subject.other | Antineoplastic agents | - |
dc.subject.other | Organic compounds | - |
dc.subject.other | Tryptophan | - |
dc.subject.other | Lactams | - |
dc.title | A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 650744 | - |
dc.date.updated | 2018-11-23T16:00:02Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 25814188 | - |
Appears in Collections: | Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia) |
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650744.pdf | 491.67 kB | Adobe PDF | View/Open |
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