The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph− acute lymphoblastic leukemia cells
Open accessAbstract
We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome-negative (Ph(-)) acute lymphoblastic leukemia (ALL). Two model human Ph(-) ALL cell lines (T-cell MOLT-4 and pre-B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC(50): 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph(-) ALL cells, including those from a relapsed patient, inducing loss of cell viability (up to 70%) and induction of GADD45G mRNA expression (up to 35-fold). Thus, LBH589 possesses potent growth inhibitory activity against including Ph(-) ALL cells associated with up-regulation of genes critical for DNA damage response and growth arrest. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph(-) ALL.
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“Previous studies showed that enhanced histone acetylation induced by HDACi allowed the overexpression of genes involved in cell cycle arrest such as cyclin-dependent kinase inhibitors or the growth arrest and DNA damage-inducible protein GADD45 gene family (11, 28, 40, 45-49).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [49]
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Metadata
- Authors
- Scuto, A., Kirschbaum, M., Kowolik, C., Kretzner, L., Juhasz, A., Atadja, P., Pullarkat, V., Bhatia, R., Forman, S., Yen, Y., & Jove, R.
- Affiliations
- City Of Hope National Medical Center (US)
- Novartis Pharmaceuticals, Cambridge, MA
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-05-15
- Volume
- 111
- Issue
- 10
- Pages
- 5093-5100
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2384136
- OpenAlex
- W2086799752
- Cited by
- 141
- References
- 53
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 13 · 2019: 9 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 8 · 2013: 8 · 2012: 15
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W. M. Keck Foundation
- National Institutes of Health
- National Cancer Institute (R01CA055652)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- panobinostat, histone deacetylase inhibitors, Philadelphia chromosome-negative acute lymphoblastic leukemia, DNA damage response, apoptosis, GADD45G, histone acetylation, H2AX phosphorylation, FOXO3, cell cycle arrest, MOLT-4 cells, REH cells, relapsed leukemia
- MeSH terms
- Panobinostat, GADD45 Proteins, Acetylation, DNA Damage, Gene Expression Regulation, Histones, Humans, Hydroxamic Acids, Indoles, Tumor Cells, Cultured, Apoptosis, Intracellular Signaling Peptides and Proteins, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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