title: The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.
abstract: 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.
authors: Molecular Medicine, City of Hope Beckman Research Institute and National Medical Center, Duarte, CA, USA.
authors: Anna
authors: A
authors: Scuto
authors: Mark
authors: M
authors: Kirschbaum
authors: Claudia
authors: C
authors: Kowolik
authors: Leo
authors: L
authors: Kretzner
authors: Agnes
authors: A
authors: Juhasz
authors: Peter
authors: P
authors: Atadja
authors: Vinod
authors: V
authors: Pullarkat
authors: Ravi
authors: R
authors: Bhatia
authors: Stephen
authors: S
authors: Forman
authors: Yun
authors: Y
authors: Yen
authors: Richard
authors: R
authors: Jove
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000077767:Panobinostat; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
chemical_list: D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D000077767:Panobinostat; C485654:GADD45G protein, human; D000097642:GADD45 Proteins