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Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51

Acute myeloid leukemia (AML) remains a challenging disease to treat and urgently requires new therapies to improve its treatment outcome. In this study, we investigated the molecular mechanisms underlying the cooperative antileukemic activities of panobinostat and cytarabine or daunorubicin (DNR) in...

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Autores principales: Xie, Chengzhi, Drenberg, Christina, Edwards, Holly, Caldwell, J. Timothy, Chen, Wei, Inaba, Hiroto, Xu, Xuelian, Buck, Steven A., Taub, Jeffrey W., Baker, Sharyn D., Ge, Yubin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823972/
https://www.ncbi.nlm.nih.gov/pubmed/24244429
http://dx.doi.org/10.1371/journal.pone.0079106
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author Xie, Chengzhi
Drenberg, Christina
Edwards, Holly
Caldwell, J. Timothy
Chen, Wei
Inaba, Hiroto
Xu, Xuelian
Buck, Steven A.
Taub, Jeffrey W.
Baker, Sharyn D.
Ge, Yubin
author_facet Xie, Chengzhi
Drenberg, Christina
Edwards, Holly
Caldwell, J. Timothy
Chen, Wei
Inaba, Hiroto
Xu, Xuelian
Buck, Steven A.
Taub, Jeffrey W.
Baker, Sharyn D.
Ge, Yubin
author_sort Xie, Chengzhi
collection PubMed
description Acute myeloid leukemia (AML) remains a challenging disease to treat and urgently requires new therapies to improve its treatment outcome. In this study, we investigated the molecular mechanisms underlying the cooperative antileukemic activities of panobinostat and cytarabine or daunorubicin (DNR) in AML cell lines and diagnostic blast samples in vitro and in vivo. Panobinostat suppressed expression of BRCA1, CHK1, and RAD51 in AML cells in a dose-dependent manner. Further, panobinostat significantly increased cytarabine- or DNR-induced DNA double-strand breaks and apoptosis, and abrogated S and/or G2/M cell cycle checkpoints. Analogous results were obtained by shRNA knockdown of BRCA1, CHK1, or RAD51. Cotreatment of NOD-SCID-IL2Rγ(null) mice bearing AML xenografts with panobinostat and cytarabine significantly increased survival compared to either cytarabine or panobinostat treatment alone. Additional studies revealed that panobinostat suppressed the expression of BRCA1, CHK1, and RAD51 through downregulation of E2F1 transcription factor. Our results establish a novel mechanism underlying the cooperative antileukemic activities of these drug combinations in which panobinostat suppresses expression of BRCA1, CHK1, and RAD51 to enhance cytarabine and daunorubicin sensitivities in AML cells.
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spelling pubmed-38239722013-11-15 Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51 Xie, Chengzhi Drenberg, Christina Edwards, Holly Caldwell, J. Timothy Chen, Wei Inaba, Hiroto Xu, Xuelian Buck, Steven A. Taub, Jeffrey W. Baker, Sharyn D. Ge, Yubin PLoS One Research Article Acute myeloid leukemia (AML) remains a challenging disease to treat and urgently requires new therapies to improve its treatment outcome. In this study, we investigated the molecular mechanisms underlying the cooperative antileukemic activities of panobinostat and cytarabine or daunorubicin (DNR) in AML cell lines and diagnostic blast samples in vitro and in vivo. Panobinostat suppressed expression of BRCA1, CHK1, and RAD51 in AML cells in a dose-dependent manner. Further, panobinostat significantly increased cytarabine- or DNR-induced DNA double-strand breaks and apoptosis, and abrogated S and/or G2/M cell cycle checkpoints. Analogous results were obtained by shRNA knockdown of BRCA1, CHK1, or RAD51. Cotreatment of NOD-SCID-IL2Rγ(null) mice bearing AML xenografts with panobinostat and cytarabine significantly increased survival compared to either cytarabine or panobinostat treatment alone. Additional studies revealed that panobinostat suppressed the expression of BRCA1, CHK1, and RAD51 through downregulation of E2F1 transcription factor. Our results establish a novel mechanism underlying the cooperative antileukemic activities of these drug combinations in which panobinostat suppresses expression of BRCA1, CHK1, and RAD51 to enhance cytarabine and daunorubicin sensitivities in AML cells. Public Library of Science 2013-11-11 /pmc/articles/PMC3823972/ /pubmed/24244429 http://dx.doi.org/10.1371/journal.pone.0079106 Text en © 2013 Xie et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Xie, Chengzhi
Drenberg, Christina
Edwards, Holly
Caldwell, J. Timothy
Chen, Wei
Inaba, Hiroto
Xu, Xuelian
Buck, Steven A.
Taub, Jeffrey W.
Baker, Sharyn D.
Ge, Yubin
Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
title Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
title_full Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
title_fullStr Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
title_full_unstemmed Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
title_short Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
title_sort panobinostat enhances cytarabine and daunorubicin sensitivities in aml cells through suppressing the expression of brca1, chk1, and rad51
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823972/
https://www.ncbi.nlm.nih.gov/pubmed/24244429
http://dx.doi.org/10.1371/journal.pone.0079106
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