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Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
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Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
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Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
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Journal Article
Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
2013
Overview
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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Animals
/ Antibiotics, Antineoplastic - pharmacology
/ Antimetabolites, Antineoplastic - pharmacology
/ BRCA1 Protein - biosynthesis
/ Child
/ DNA
/ Female
/ G2 Phase Cell Cycle Checkpoints - drug effects
/ Gene Expression Regulation, Leukemic - drug effects
/ Humans
/ Hydroxamic Acids - pharmacology
/ Hypoxia
/ Kinases
/ Leukemia
/ Leukemia, Myeloid, Acute - drug therapy
/ Leukemia, Myeloid, Acute - metabolism
/ Leukemia, Myeloid, Acute - pathology
/ M Phase Cell Cycle Checkpoints - drug effects
/ Male
/ Medicine
/ Mice
/ Mutation
/ Oncology
/ Protein Kinases - biosynthesis
/ Rad51 Recombinase - biosynthesis
/ Tumors
