2. Department of Pediatrics, Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
3. Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT, USA.
4. Department of Research and Development, Haemtologic Technologies Inc., Essex Junction, VT, USA.
5. Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
6. Department of Pediatrics Neuroblastoma Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
In this study, we investigated the cytotoxic effects of a broad-spectrumhistone 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 animal streated 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.
Keywords: Neuroblastoma, apoptosis, PCI-24781 (abexinostat), bortezomib, ROS