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http://hdl.handle.net/10261/39946
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Campo DC | Valor | Lengua/Idioma |
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dc.contributor.author | Fernández, Yolanda | - |
dc.contributor.author | Miller, Thomas P. | - |
dc.contributor.author | Denoyelle, Christophe | - |
dc.contributor.author | Esteban, José A. | - |
dc.contributor.author | Tang, Wen-Hua | - |
dc.contributor.author | Bengston, Audrey L. | - |
dc.contributor.author | Soengas, María S. | - |
dc.date.accessioned | 2011-09-23T18:18:16Z | - |
dc.date.available | 2011-09-23T18:18:16Z | - |
dc.date.issued | 2006-01-13 | - |
dc.identifier.citation | Journal of Biological Chemistry 281: 1107-1118 (2006) | es_ES |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.uri | http://hdl.handle.net/10261/39946 | - |
dc.description.abstract | The proteasome inhibitor bortezomib is emerging as a potent anti-cancer agent. Still, recent clinical trials have revealed a significant secondary toxicity of bortezomib. Consequently, there is much interest in dissecting the mechanism of action of this compound to rationally improve its therapeutic index. The cytotoxic effect of bortezomib is frequently characterized by interfering with downstream events derived from the accumulation of proteasomal targets. Here we identify the first chemical agent able to act upstream of the proteasome to prevent cell killing by bortezomib. Specifically, we show that the polyhydroxyl compound Tiron can function as a competitive inhibitor of bortezomib. This effect of Tiron was surprising, since it is a classical radical spin trap and was expected to scavenge reactive oxygen species produced as a consequence of bortezomib action. The inhibitory effect of Tiron against bortezomib was selective, since it was not shared by other antioxidants, such as vitamin E, MnTBAP, L-N-acetyl-cysteine, and FK-506. Comparative analyses with nonboronated proteasome inhibitors (i.e. MG132) revealed a specificity of Tiron for bortezomib. We exploited this novel feature of Tiron to define the “point of no return” of proteasome inhibition in melanoma cells and to block cell death in a three-dimensional model of human skin. Cells from T-cell lymphoma, breast carcinoma, and non-small cell lung cancer were also responsive to Tiron, suggesting a broad impact of this agent as a bortezomib blocker. These results may have important implications for the analysis of bortezomib in vivo and for the design of drug mixtures containing proteasome inhibitors. | es_ES |
dc.description.sponsorship | This work was supported by a Dermatology Foundation Career Development Award and National Institutes of Health Grant R01 CA107237 (to M. S. S). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Society for Biochemistry and Molecular Biology | es_ES |
dc.rights | closedAccess | es_ES |
dc.subject | Bortezomib | es_ES |
dc.subject | Tiron | es_ES |
dc.subject | L-N-acetyl-cysteine | es_ES |
dc.title | Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib | es_ES |
dc.type | artículo | es_ES |
dc.identifier.doi | 10.1074/jbc.M511607200 | - |
dc.description.peerreviewed | Peer reviewed | es_ES |
dc.relation.publisherversion | http://dx.doi.org/10.1074/jbc.M511607200 | es_ES |
dc.contributor.funder | National Institutes of Health (US) | - |
dc.contributor.funder | Dermatology Foundation | - |
dc.identifier.funder | http://dx.doi.org/10.13039/100000002 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100001582 | es_ES |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.grantfulltext | none | - |
item.fulltext | No Fulltext | - |
item.languageiso639-1 | en | - |
item.cerifentitytype | Publications | - |
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