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

Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O2) conditions only. Therefore, we questioned whether VPA would be equally effective under hypoxic conditions (1% O2), which is known to induce resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS, plus one cisplatin-resistant subline derived from each of the two original sensitive lines. All were treated with VPA and incubated under hypoxic conditions. Measurement of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling revealed that VPA was even more effective under hypoxic conditions. We show here that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could be overcome using VPA. We also demonstrated that apoptosis pathways induced by VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis proceeds through the mitochondrial pathway, not the extrinsic pathway (under both normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis or influence bid cleavage. Our data demonstrated that VPA is more efficient in triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma (NBL) treatment.

• MeSH
• Enzyme Activation MeSH
• Apoptosis drug effects   MeSH
• Time Factors MeSH
• Drug Resistance, Neoplasm * MeSH
• Cisplatin pharmacology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   metabolism   MeSH
• Cell Hypoxia MeSH
• Histone Deacetylase Inhibitors pharmacology   MeSH
• Caspase 8 metabolism   MeSH
• In Situ Nick-End Labeling MeSH
• Valproic Acid pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma genetics   metabolism   pathology   MeSH
• BH3 Interacting Domain Death Agonist Protein metabolism   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• Drug Synergism MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• BID protein, human MeSH Browser
• CASP8 protein, human MeSH Browser
• Cisplatin MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• HIF1A protein, human MeSH Browser
• Histone Deacetylase Inhibitors MeSH
• Caspase 8 MeSH
• Valproic Acid MeSH
• BH3 Interacting Domain Death Agonist Protein MeSH

Neuroblastoma, a tumor of the peripheral sympathetic nervous system, is the most frequent solid extra cranial tumor in children and is a major cause of death from neoplasia in infancy. Still little improvement in therapeutic options has been made, requiring a need for the development of new therapies. In our laboratory, we address still unsettled questions, which of mechanisms of action of DNA-damaging drugs both currently use for treatment of human neuroblastomas (doxorubicin, cis-platin, cyclophosphamide and etoposide) and another anticancer agent decreasing growth of neuroblastomas in vitro, ellipticine, are predominant mechanism(s) responsible for their antitumor action in neuroblastoma cell lines in vitro. Because hypoxia frequently occurs in tumors and strongly correlates with advanced disease and poor outcome caused by chemoresistance, the effects of hypoxia on efficiencies and mechanisms of actions of these drugs in neuroblastomas are also investigated. Since the epigenetic structure of DNA and its lesions play a role in the origin of human neuroblastomas, pharmaceutical manipulation of the epigenome may offer other treatment options also for neuroblastomas. Therefore, the effects of histone deacetylase inhibitors on growth of neuroblastoma and combination of these compounds with doxorubicin, cis-platin, etoposide and ellipticine as well as mechanisms of such effects in human neuroblastona cell lines in vitro are also investigated. Such a study will increase our knowledge to explain the proper function of these drugs on the molecular level, which should be utilized for the development of new therapies for neuroblastomas.

• Keywords
• DNA-damaging anticancer drugs, inhibitors of histone deacetylases, mechanisms of acticancer effects of drugs, neuroblastoma,
• Publication type
• Journal Article MeSH