title: PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma.
abstract: In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease.
authors.affiliation: Helen DeVos Children's Hospital/Michigan State University College of Medicine, Grand Rapids, MI.
authors.forename: Giselle Saulnier
authors.initials: GS
authors.lastname: Sholler
authors.affiliation: Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Currier
authors.affiliation: Helen DeVos Children's Hospital/Michigan State University College of Medicine, Grand Rapids, MI.
authors.forename: Akshita
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Marni A
authors.initials: MA
authors.lastname: Slavik
authors.affiliation: Department of Research and Development, Haemtologic Technologies Inc., Essex Junction, VT.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Illenye
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD.
authors.forename: Maria Cecilia F
authors.initials: MC
authors.lastname: Mendonca
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Julie
authors.initials: J
authors.lastname: Dragon
authors.affiliation: Department of Pediatrics Neuroblastoma Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Roberts
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bond
keywords: Neuroblastoma; PCI-24781 (abexinostat); ROS; apoptosis; bortezomib