PloS one, 2013-11, Vol.8 (11), p.e79106
2013
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- Autor(en) / Beteiligte
- Titel
- Panobinostat enhances cytarabine and daunorubicin sensitivities in AML cells through suppressing the expression of BRCA1, CHK1, and Rad51
- Ist Teil von
- PloS one, 2013-11, Vol.8 (11), p.e79106
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Quelle
- Electronic Journals Library
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0079106Titel-ID: cdi_plos_journals_1450016269
- Format
- –
- Schlagworte
- Acute myeloid leukemia, Animals, Antibiotics, Antineoplastic - pharmacology, Anticancer properties, Antimetabolites, Antineoplastic - pharmacology, Apoptosis, BRCA1 protein, BRCA1 Protein - biosynthesis, Breast cancer, Cancer therapies, Cell cycle, Checkpoint Kinase 1, Chemotherapy, Child, Child, Preschool, CHK1 protein, Combination drug therapy, Cytarabine, Cytarabine - pharmacology, Daunorubicin, Daunorubicin - agonists, Daunorubicin - pharmacology, Deoxyribonucleic acid, Diagnostic systems, DNA, DNA damage, DNA repair, Down syndrome, Drug Agonism, Female, G2 Phase Cell Cycle Checkpoints - drug effects, Gene expression, Gene Expression Regulation, Leukemic - drug effects, Hematology, Heterografts, Humans, Hydroxamic Acids - pharmacology, Hypoxia, Indoles - pharmacology, Kinases, Laboratories, Leukemia, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - metabolism, Leukemia, Myeloid, Acute - pathology, Life sciences, M Phase Cell Cycle Checkpoints - drug effects, Male, Medicine, Mice, Mice, Inbred NOD, Mice, SCID, Molecular modelling, Mutation, Myeloid leukemia, Neoplasm Transplantation, Oncology, Panobinostat, Pediatrics, Pharmaceutical sciences, Protein Kinases - biosynthesis, Rad51 Recombinase - biosynthesis, Tumors, U937 Cells, Xenografts, Xenotransplantation