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Int. J. Mol. Sci. 2018, 19(1), 164;

The Histone Deacetylase Inhibitor Valproic Acid Exerts a Synergistic Cytotoxicity with the DNA-Damaging Drug Ellipticine in Neuroblastoma Cells

Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128 43 Prague 2, Czech Republic
Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Uvalu 84/1, CZ-150 06 Prague 5, Czech Republic
Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King’s College London, London WC2R 2LS, UK
NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King’s College London in Partnership with Public Health England, London WC2R 2LS, UK
Author to whom correspondence should be addressed.
Received: 25 November 2017 / Revised: 22 December 2017 / Accepted: 28 December 2017 / Published: 5 January 2018
(This article belongs to the Section Biochemistry)
Full-Text   |   PDF [3580 KB, uploaded 5 January 2018]   |  


Neuroblastoma (NBL) originates from undifferentiated cells of the sympathetic nervous system. Chemotherapy is judged to be suitable for successful treatment of this disease. Here, the influence of histone deacetylase (HDAC) inhibitor valproate (VPA) combined with DNA-damaging chemotherapeutic, ellipticine, on UKF-NB-4 and SH-SY5Y neuroblastoma cells was investigated. Treatment of these cells with ellipticine in combination with VPA led to the synergism of their anticancer efficacy. The effect is more pronounced in the UKF-NB-4 cell line, the line with N-myc amplification, than in SH-SY5Y cells. This was associated with caspase-3-dependent induction of apoptosis in UKF-NB-4 cells. The increase in cytotoxicity of ellipticine in UKF-NB-4 by VPA is dictated by the sequence of drug administration; the increased cytotoxicity was seen only after either simultaneous exposure to these drugs or after pretreatment of cells with ellipticine before their treatment with VPA. The synergism of treatment of cells with VPA and ellipticine seems to be connected with increased acetylation of histones H3 and H4. Further, co-treatment of cells with ellipticine and VPA increased the formation of ellipticine-derived DNA adducts, which indicates an easier accessibility of ellipticine to DNA in cells by its co-treatment with VPA and also resulted in higher ellipticine cytotoxicity. The results are promising for in vivo studies and perhaps later for clinical studies of combined treatment of children suffering from high-risk NBL. View Full-Text
Keywords: neuroblastoma; ellipticine; valproate; DNA damage; acetylation of histones; apoptosis neuroblastoma; ellipticine; valproate; DNA damage; acetylation of histones; apoptosis

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Cerna, T.; Hrabeta, J.; Eckschlager, T.; Frei, E.; Schmeiser, H.H.; Arlt, V.M.; Stiborová, M. The Histone Deacetylase Inhibitor Valproic Acid Exerts a Synergistic Cytotoxicity with the DNA-Damaging Drug Ellipticine in Neuroblastoma Cells. Int. J. Mol. Sci. 2018, 19, 164.

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