Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies

Detalhes bibliográficos
Autor(a) principal: Silva, Gabriela de Medeiros
Data de Publicação: 2013
Outros Autores: Cardoso, Bruno, Belo, Hélio, Almeida, António
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/22414
Resumo: This study was funded by a research grant from the Portuguese Association Against Leukemia, from the IPOLFG Oncology Research Fund, and a post-doctoral fellowship from "Fundacao para a Ciencia e Tecnologia" (SFRH/BPD/46494/2008) for GS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr AMA receives consulting fees from Celgene and Novartis and is on the board of speakers for Bristol-Meyer Squibb, Shire and Amgen. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
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spelling Vorinostat Induces Apoptosis and Differentiation in Myeloid MalignanciesGenetic and Molecular MechanismsCANCER-CELLSCELL LYMPHOMAHISTONE DEACETYLASE INHIBITORBONE-MARROWMYELODYSPLASTIC SYNDROMESTRANSCRIPTION FACTORSCD34(+) CELLSSP FAMILYDOWN-REGULATIONSUBEROYLANILIDE HYDROXAMIC ACIDHISTONE DEACETYLASE INHIBITORSUBEROYLANILIDE HYDROXAMIC ACIDMYELODYSPLASTIC SYNDROMESDOWN-REGULATIONBONE-MARROWTRANSCRIPTION FACTORSCELL LYMPHOMACD34(+) CELLSCANCER-CELLSSP FAMILYSDG 3 - Good Health and Well-beingThis study was funded by a research grant from the Portuguese Association Against Leukemia, from the IPOLFG Oncology Research Fund, and a post-doctoral fellowship from "Fundacao para a Ciencia e Tecnologia" (SFRH/BPD/46494/2008) for GS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr AMA receives consulting fees from Celgene and Novartis and is on the board of speakers for Bristol-Meyer Squibb, Shire and Amgen. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.Background: Aberrant epigenetic patterns are central in the pathogenesis of haematopoietic diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Vorinostat is a HDACi which has produced responses in these disorders. The purpose of this study was to address the functional effects of vorinostat in leukemic cell lines and primary AML and MDS myeloid cells and to dissect the genetic and molecular mechanisms by which it exerts its action. Methodology/Principal Findings: Functional assays showed vorinostat promoted cell cycle arrest, inhibited growth, and induced apoptosis and differentiation of K562, HL60 and THP-1 and of CD33(+) cells from AML and MDS patients. To explore the genetic mechanism for these effects, we quantified gene expression modulation by vorinostat in these cells. Vorinostat increased expression of genes down-regulated in MDS and/or AML (cFOS, COX2, IER3, p15, RAI3) and suppressed expression of genes over-expressed in these malignancies (AXL, c-MYC, Cyclin D1) and modulated cell cycle and apoptosis genes in a manner which would favor cell cycle arrest, differentiation, and apoptosis of neoplastic cells, consistent with the functional assays. Reporter assays showed transcriptional effect of vorinostat on some of these genes was mediated by proximal promoter elements in GC-rich regions. Vorinostat-modulated expression of some genes was potentiated by mithramycin A, a compound that interferes with SP1 binding to GC-rich DNA sequences, and siRNA-mediated SP1 reduction. ChIP assays revealed vorinostat inhibited DNA binding of SP1 to the proximal promoter regions of these genes. These results suggest vorinostat transcriptional action in some genes is regulated by proximal promoter GC-rich DNA sequences and by SP1. Conclusion: This study sheds light on the effects of vorinostat in AML and MDS and supports the implementation of clinical trials to explore the use of vorinostat in the treatment of these diseases.Centro de Estudos de Doenças Crónicas (CEDOC)NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)RUNSilva, Gabriela de MedeirosCardoso, BrunoBelo, HélioAlmeida, António2017-08-02T22:00:29Z2013-01-082013-01-08T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/22414eng1932-6203PURE: 154938https://doi.org/10.1371/journal.pone.0053766info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:09:55Zoai:run.unl.pt:10362/22414Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:27:17.178146Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
Genetic and Molecular Mechanisms
title Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
spellingShingle Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
Silva, Gabriela de Medeiros
CANCER-CELLS
CELL LYMPHOMA
HISTONE DEACETYLASE INHIBITOR
BONE-MARROW
MYELODYSPLASTIC SYNDROMES
TRANSCRIPTION FACTORS
CD34(+) CELLS
SP FAMILY
DOWN-REGULATION
SUBEROYLANILIDE HYDROXAMIC ACID
HISTONE DEACETYLASE INHIBITOR
SUBEROYLANILIDE HYDROXAMIC ACID
MYELODYSPLASTIC SYNDROMES
DOWN-REGULATION
BONE-MARROW
TRANSCRIPTION FACTORS
CELL LYMPHOMA
CD34(+) CELLS
CANCER-CELLS
SP FAMILY
SDG 3 - Good Health and Well-being
title_short Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
title_full Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
title_fullStr Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
title_full_unstemmed Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
title_sort Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies
author Silva, Gabriela de Medeiros
author_facet Silva, Gabriela de Medeiros
Cardoso, Bruno
Belo, Hélio
Almeida, António
author_role author
author2 Cardoso, Bruno
Belo, Hélio
Almeida, António
author2_role author
author
author
dc.contributor.none.fl_str_mv Centro de Estudos de Doenças Crónicas (CEDOC)
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
RUN
dc.contributor.author.fl_str_mv Silva, Gabriela de Medeiros
Cardoso, Bruno
Belo, Hélio
Almeida, António
dc.subject.por.fl_str_mv CANCER-CELLS
CELL LYMPHOMA
HISTONE DEACETYLASE INHIBITOR
BONE-MARROW
MYELODYSPLASTIC SYNDROMES
TRANSCRIPTION FACTORS
CD34(+) CELLS
SP FAMILY
DOWN-REGULATION
SUBEROYLANILIDE HYDROXAMIC ACID
HISTONE DEACETYLASE INHIBITOR
SUBEROYLANILIDE HYDROXAMIC ACID
MYELODYSPLASTIC SYNDROMES
DOWN-REGULATION
BONE-MARROW
TRANSCRIPTION FACTORS
CELL LYMPHOMA
CD34(+) CELLS
CANCER-CELLS
SP FAMILY
SDG 3 - Good Health and Well-being
topic CANCER-CELLS
CELL LYMPHOMA
HISTONE DEACETYLASE INHIBITOR
BONE-MARROW
MYELODYSPLASTIC SYNDROMES
TRANSCRIPTION FACTORS
CD34(+) CELLS
SP FAMILY
DOWN-REGULATION
SUBEROYLANILIDE HYDROXAMIC ACID
HISTONE DEACETYLASE INHIBITOR
SUBEROYLANILIDE HYDROXAMIC ACID
MYELODYSPLASTIC SYNDROMES
DOWN-REGULATION
BONE-MARROW
TRANSCRIPTION FACTORS
CELL LYMPHOMA
CD34(+) CELLS
CANCER-CELLS
SP FAMILY
SDG 3 - Good Health and Well-being
description This study was funded by a research grant from the Portuguese Association Against Leukemia, from the IPOLFG Oncology Research Fund, and a post-doctoral fellowship from "Fundacao para a Ciencia e Tecnologia" (SFRH/BPD/46494/2008) for GS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr AMA receives consulting fees from Celgene and Novartis and is on the board of speakers for Bristol-Meyer Squibb, Shire and Amgen. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
publishDate 2013
dc.date.none.fl_str_mv 2013-01-08
2013-01-08T00:00:00Z
2017-08-02T22:00:29Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/22414
url http://hdl.handle.net/10362/22414
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1932-6203
PURE: 154938
https://doi.org/10.1371/journal.pone.0053766
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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