ITF2357 interferes with apoptosis and inflammatory pathways in the HL-60 model: a gene expression study.
BACKGROUND
Cytotoxic and pro-apoptotic effects exerted by the histone deacetylase inhibitor ITF2357 have been reported in acute myeloid leukemia HL-60 cells. In the current study, its mechanism of action was investigated at the molecular level.


METHODS
Cell proliferation was evaluated by methyl thiazol tetrazolium bromide reduction; apoptosis by annexin V, mitochondrial transmembrane potential by tetramethylrhodamine ethyl ester. Functional experiments and gene expression evaluations were performed by flow cytometry, microarray, and quantitative polymerase chain reaction.


RESULTS
Significant cell growth inhibition and increased apoptosis were observed. ITF2357 reduced protein levels of BCL-2, MCL-1, and BCL-X, and increased levels of BAK. Exposure to ITF2357 did not abrogate NF-κB DNA binding. After microarray analysis, interleukin-10, interleukin-6, epidermal growth factor, peroxisome proliferator-activated receptor (PPAR), transforming growth factor β, P38 mitogen-activated protein kinase, aryl hydrocarbon receptor, xenobiotic metabolism, PPAR/retinoic acid receptor, NF-κB, apoptosis, lipopolysaccharide/interleukin-1, G-protein receptor, T-cell receptor, and platelet-derived growth factor were the de-regulated pathways.


CONCLUSIONS
This study shows that ITF2357 influences both proliferation and inflammatory pathways in HL-60 cells; this observation could have possible applications in clinical practice.
Department of Oncology, Transplant and Advances in Medicine, Section of Hematology, University of Pisa, Ospedale S Chiara, Via Roma 67, 56126 Pisa, Italy. s.galimberti@med.unipi.it
Sara
S
Galimberti
Martina
M
Canestraro
Hakan
H
Savli
Giuseppe Alberto
GA
Palumbo
Daniele
D
Tibullo
Balint
B
Nagy
Simona
S
Piaggi
Francesca
F
Guerrini
Naci
N
Cine
Maria Rita
MR
Metelli
Mario
M
Petrini
D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D012333:RNA, Messenger; C502418:givinostat hydrochloride