In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma

10 páginas, 5 figuras.-- et al.

Detalles Bibliográficos
Autores: Ocio, Enrique M., Vilanova, David, Maiso, Patricia, Crusoe, Edvan, Fernández-Lázaro, Diego, Garayoa, Mercedes, San-Segundo, Laura, Hernández, Mª Teresa, San Miguel, Jesús F.
Tipo de recurso: artículo
Fecha de publicación:2010
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/45724
Acceso en línea:http://hdl.handle.net/10261/45724
Access Level:acceso abierto
Palabra clave:Panobinostat
LBH589
Multiple myeloma
HDAC Inhibitors
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spelling In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myelomaOcio, Enrique M.Vilanova, DavidMaiso, PatriciaCrusoe, EdvanFernández-Lázaro, DiegoGarayoa, MercedesSan-Segundo, LauraHernández, Mª TeresaSan Miguel, Jesús F.PanobinostatLBH589Multiple myelomaHDAC Inhibitors10 páginas, 5 figuras.-- et al.[Background]: Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile. [Design and Methods]: The activity of these combinations was explored in vitro in cell lines by using MTT and annex-in V, ex vivo by flow cytometry, and in vivo using two different murine models of human myeloma: one bearing a subcutaneous plasmacytoma and another with a disseminated myeloma. Moreover, gene expression profiling and immunohistochemical studies were performed. [Results]: The addition of panobinostat (LBH589) to dexamethasone and either bortezomib or lenalidomide resulted in clear potentiation in multiple myeloma cell lines, freshly isolated plasma cells, and murine models of multiple myeloma. The quantification of the potency of these combinations by using the Chou-Talalay method showed synergistic combination indices for all of them. This effect derived from the deregulation of a cluster of genes that was completely different from the sum of genes affected by the single agents (895 and 1323 genes exclusively deregulated by panobinostat and dexamethasone plus bortezomib or lenalidomide, respectively). Functional experiments, such as annexin V staining, cell cycle analysis, and immunohistochemical studies also supported this potentiation. Anti-myeloma efficacy was confirmed in an extramedullary plasmacytoma model and a disseminated luciferized model, in which panobinostat also provided a marked benefit in bone disease. [Conclusions]: The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in multiple myeloma.This work was supported by grants from the Ministry of Education and Science of Spain (BFU2006-01813/BMC, RD06/0020/0041, and RD06/0020/0059). The CIC receives support from the European Community through the regional development funding program (FEDER). This work was also supported by the ‘Acción Transversal del Cáncer’ project, through an agreement between Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, and the Cancer Research Foundation of Salamanca University. Our group also receives support from the Junta de Castilla y Léon through ‘Ayudas destinadas a financiar programas de actividad investigadora a realizar por grupos de investigación de excelencia de Castilla y León.Peer reviewedFerrata Storti Foundation201220122010info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/45724reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.3324/haematol.2009.015495info:eu-repo/semantics/openAccessoai:digital.csic.es:10261/457242026-05-22T06:33:51Z
dc.title.none.fl_str_mv In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
title In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
spellingShingle In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
Ocio, Enrique M.
Panobinostat
LBH589
Multiple myeloma
HDAC Inhibitors
title_short In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
title_full In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
title_fullStr In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
title_full_unstemmed In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
title_sort In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma
dc.creator.none.fl_str_mv Ocio, Enrique M.
Vilanova, David
Maiso, Patricia
Crusoe, Edvan
Fernández-Lázaro, Diego
Garayoa, Mercedes
San-Segundo, Laura
Hernández, Mª Teresa
San Miguel, Jesús F.
author Ocio, Enrique M.
author_facet Ocio, Enrique M.
Vilanova, David
Maiso, Patricia
Crusoe, Edvan
Fernández-Lázaro, Diego
Garayoa, Mercedes
San-Segundo, Laura
Hernández, Mª Teresa
San Miguel, Jesús F.
author_role author
author2 Vilanova, David
Maiso, Patricia
Crusoe, Edvan
Fernández-Lázaro, Diego
Garayoa, Mercedes
San-Segundo, Laura
Hernández, Mª Teresa
San Miguel, Jesús F.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Panobinostat
LBH589
Multiple myeloma
HDAC Inhibitors
topic Panobinostat
LBH589
Multiple myeloma
HDAC Inhibitors
description 10 páginas, 5 figuras.-- et al.
publishDate 2010
dc.date.none.fl_str_mv 2010
2012
2012
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/45724
url http://hdl.handle.net/10261/45724
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.3324/haematol.2009.015495
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Ferrata Storti Foundation
publisher.none.fl_str_mv Ferrata Storti Foundation
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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