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http://hdl.handle.net/10261/77449
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dc.contributor.author | González-Santiago, L. | - |
dc.contributor.author | Suárez, Yajaira | - |
dc.contributor.author | Muñoz-Alonso, María J. | - |
dc.contributor.author | Cuadrado, Ana | - |
dc.contributor.author | Martínez, Teresa | - |
dc.contributor.author | Goya, Luis | - |
dc.contributor.author | Rojas, José María | - |
dc.contributor.author | Muñoz Terol, Alberto | - |
dc.date.accessioned | 2013-06-04T09:37:01Z | - |
dc.date.available | 2013-06-04T09:37:01Z | - |
dc.date.issued | 2006 | - |
dc.identifier | doi: 10.1038/sj.cdd.4401898 | - |
dc.identifier | issn: 1350-9047 | - |
dc.identifier.citation | Cell Death and Differentiation 13(11): 1968-1981 (2006) | - |
dc.identifier.uri | http://hdl.handle.net/10261/77449 | - |
dc.description.abstract | Aplidin® is an antitumor agent in phase II clinical trials that induces apoptosis through the sustained activation of Jun N-terminal kinase (JNK). We report that Aplidin® alters glutathione homeostasis increasing the ratio of oxidized to reduced forms (GSSG/GSH). Aplidin® generates reactive oxygen species and disrupts the mitochondrial membrane potential. Exogenous GSH inhibits these effects and also JNK activation and cell death. We found two mechanisms by which Aplidin® activates JNK: rapid activation of Rac1 small GTPase and downregulation of MKP-1 phosphatase. Rac1 activation was diminished by GSH and enhanced by L-buthionine (SR)-sulfoximine, which inhibits GSH synthesis. Downregulation of Rac1 by transfection of small interfering RNA (siRNA) duplexes or the use of a specific Rac1 inhibitor decreased Aplidin®-induced JNK activation and cytotoxicity. Our results show that Aplidin® induces apoptosis by increasing the GSSG/GSH ratio, a necessary step for induction of oxidative stress and sustained JNK activation through Rac1 activation and MKP-1 downregulation. | - |
dc.description.sponsorship | This study was supported in part by Grant SAF04- 01015 (to AM) and SAF03-02604 (to JMR) from Ministerio de Educación y Ciencia and FIS03-C03/10 and Intramural ISCIII (03/ESP27) from Instituto de Salud Carlos III. | - |
dc.language.iso | eng | - |
dc.publisher | Nature Publishing Group | - |
dc.rights | closedAccess | - |
dc.title | Aplidin® induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1038/sj.cdd.4401898 | - |
dc.date.updated | 2013-06-04T09:37:01Z | - |
dc.description.version | Peer Reviewed | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | No Fulltext | - |
item.languageiso639-1 | en | - |
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accesoRestringido.pdf | 15,38 kB | Adobe PDF | Visualizar/Abrir |
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