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.

• MeSH
• antitumorózní látky farmakologie   MeSH
• chemorezistence MeSH
• dítě MeSH
• elipticiny farmakologie   MeSH
• epigenomika MeSH
• financování organizované MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• neuroblastom genetika   terapie   MeSH
• poškození DNA MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

Valproic acid (VPA) has been used for epilepsy treatment since the 1970s. Recently, it was demonstrated that it inhibits histone deacetylases (HDAC), modulates cell cycle, induces tumor cell death and inhibits angiogenesis in various tumor models. The exact anticancer mechanisms of VPA remains unclear, but HDAC inhibition, extracellular-regulated kinase activation, protein kinase C inhibition, Wnt-signaling activation, proteasomal degradation of HDAC, possible downregulation of telomerase activity and DNA demethylation participate in its anticancer effect. Hyperacetylation of histones, as a result of HDAC inhibition, seems to be the most important mechanism of VPA's antitumor action. Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2'-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods. Clinical trials in patients with malignancies are being conducted. The use of VPA prior to or together with anticancer drugs may thus prove a beneficial treatment.

• MeSH
• acetylace účinky léků   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• azacytidin analogy a deriváty   farmakologie   MeSH
• buněčný cyklus účinky léků   fyziologie   MeSH
• chemorezistence MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• epilepsie farmakoterapie   MeSH
• histondeacetylasy účinky léků   MeSH
• histony účinky léků   fyziologie   MeSH
• inhibitory angiogeneze farmakologie   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• klinické zkoušky jako téma MeSH
• kombinovaná farmakoterapie MeSH
• kombinovaná terapie MeSH
• kyselina valproová farmakologie   MeSH
• lidé MeSH
• nádorový supresorový protein p53 účinky léků   fyziologie   MeSH
• nádory farmakoterapie   MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• synergismus léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH