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.

• Keywords
• DNA damage, acetylation of histones, apoptosis, ellipticine, neuroblastoma, valproate,
• MeSH
• Apoptosis MeSH
• Ellipticines toxicity   MeSH
• Histone Deacetylase Inhibitors toxicity   MeSH
• Valproic Acid toxicity   MeSH
• Humans MeSH
• Mutagens toxicity   MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma metabolism   MeSH
• Neurons drug effects   metabolism   MeSH
• Drug Synergism MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ellipticines MeSH
• ellipticine MeSH Browser
• Histone Deacetylase Inhibitors MeSH
• Valproic Acid MeSH
• Mutagens MeSH

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

• Keywords
• anti-angiogenic effect, apoptosis, autophagy, cancer, cell cycle arrest, drug combinations, histone deacetylase inhibitors, histone deacetylases,
• MeSH
• Acetylation drug effects   MeSH
• Apoptosis drug effects   MeSH
• Autophagy drug effects   MeSH
• Epigenesis, Genetic drug effects   MeSH
• Immunomodulation drug effects   MeSH
• Angiogenesis Inhibitors pharmacology   therapeutic use   MeSH
• Histone Deacetylase Inhibitors pharmacology   therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Cell Cycle Checkpoints drug effects   MeSH
• Humans MeSH
• Drug Evaluation, Preclinical MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Angiogenesis Inhibitors MeSH
• Histone Deacetylase Inhibitors MeSH
• Antineoplastic Agents MeSH

Ellipticine is a DNA-damaging agent acting as a prodrug whose pharmacological efficiencies and genotoxic side effects are dictated by activation with cytochrome P450 (CYP). Over the last decade we have gained extensive experience in using pure enzymes and various animal models that helped to identify CYPs metabolizing ellipticine. In this review we focus on comparison between the in vitro and in vivo studies and show a necessity of both approaches to obtain valid information on CYP enzymes contributing to ellipticine metabolism. Discrepancies were found between the CYP enzymes activating ellipticine to 13-hydroxy- and 12-hydroxyellipticine generating covalent DNA adducts and those detoxifying this drug to 9-hydroxy- and 7-hydroellipticine in vitro and in vivo. In vivo, formation of ellipticine-DNA adducts is dependent not only on expression levels of CYP3A, catalyzing ellipticine activation in vitro, but also on those of CYP1A that oxidize ellipticine in vitro mainly to the detoxification products. The finding showing that cytochrome b5 alters the ratio of ellipticine metabolites generated by CYP1A1/2 and 3A4 explained this paradox. Whereas the detoxification of ellipticine by CYP1A and 3A is either decreased or not changed by cytochrome b5, activation leading to ellipticine-DNA adducts increased considerably. We show that (I) the pharmacological effects of ellipticine mediated by covalent ellipticine-derived DNA adducts are dictated by expression levels of CYP1A, 3A and cytochrome b5, and its own potency to induce these enzymes in tumor tissues, (II) animal models, where levels of CYPs are either knocked out or induced are appropriate to identify CYPs metabolizing ellipticine in vivo, and (III) extrapolation from in vitro data to the situation in vivo is not always possible, confirming the need for these animal models.

• MeSH
• Cytochrome P-450 CYP1A1 deficiency   genetics   metabolism   MeSH
• Ellipticines pharmacology   MeSH
• Hepatocytes drug effects   metabolism   MeSH
• Rats MeSH
• Mice MeSH
• DNA Damage * MeSH
• Antineoplastic Agents pharmacology   MeSH
• Uncoupling Agents pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cytochrome P-450 CYP1A1 MeSH
• Ellipticines MeSH
• ellipticine MeSH Browser
• Antineoplastic Agents MeSH
• Uncoupling Agents MeSH