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Epigenetic and Cytotoxic Effects of Histone Deacetylase Inhibitors in Combination with Cytostatics on Neuroblasma
Abdel Rahman, Mohamed Ashraf Khalil ; Eckschlager, Tomáš (advisor) ; Mandys, Václav (referee) ; Krsková, Lenka (referee)
The enhanced expression of histone deacetylases (HDACs) in a variety of malignancies drew attention to investigate a new category of anti-cancer drugs that are based on the inhibition of those enzymes. Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through inhibition of HDACs class I and IIa. Cancer stem cells (CSCs) have been recognized to drive the tumor growth and progression hence; attention has been given to target this small subpopulation of CSCs rather than the whole bulk tumor cells. CD133 is considered to be a CSC marker in several tumors and its transcription is strongly influenced by epigenetic changes that will be altered upon administration of histone deacetylase inhibitors (HDACi) in cancer treatment. Therefore, we evaluated the epigenetic and cytotoxic effects of treatment with 1 mM VPA in combination with other chemotherapeutics and its influence on the expression of CD133 in human neuroblastoma (NB) cell lines. Our results revealed that addition of VPA to DNA-damaging chemotherapeutics induced a synergistic anti-tumor effect that was associated with caspase-3 dependent induction of apoptosis in UKF-NB-4 cells. This synergism was related to the increase of the acetylation status of histones H3 and H4 and was only produced either by...
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Epigenetic and Cytotoxic Effects of Histone Deacetylase Inhibitors in Combination with Cytostatics on Neuroblasma
Abdel Rahman, Mohamed Ashraf Khalil ; Eckschlager, Tomáš (advisor) ; Mandys, Václav (referee) ; Krsková, Lenka (referee)
The enhanced expression of histone deacetylases (HDACs) in a variety of malignancies drew attention to investigate a new category of anti-cancer drugs that are based on the inhibition of those enzymes. Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through inhibition of HDACs class I and IIa. Cancer stem cells (CSCs) have been recognized to drive the tumor growth and progression hence; attention has been given to target this small subpopulation of CSCs rather than the whole bulk tumor cells. CD133 is considered to be a CSC marker in several tumors and its transcription is strongly influenced by epigenetic changes that will be altered upon administration of histone deacetylase inhibitors (HDACi) in cancer treatment. Therefore, we evaluated the epigenetic and cytotoxic effects of treatment with 1 mM VPA in combination with other chemotherapeutics and its influence on the expression of CD133 in human neuroblastoma (NB) cell lines. Our results revealed that addition of VPA to DNA-damaging chemotherapeutics induced a synergistic anti-tumor effect that was associated with caspase-3 dependent induction of apoptosis in UKF-NB-4 cells. This synergism was related to the increase of the acetylation status of histones H3 and H4 and was only produced either by...
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Monitoring the expression of genes involved in pathogenesis of rhabdomyosarcomas
Vajnerová, Romana ; Krsková, Lenka (advisor) ; Schierová, Michaela (referee)
Rhabdomyosarcomas (RMS) are heterogeneous group of sarcomas with mesenchymal origin. These rhabdomyosarcomas in some detail keep their cell differentiation in structure, but they are not able to finish their differentiation cycle. At the moment RMS are the most frequently occuring malignant soft tissue tumors in paediatric pacients. In recent years, the attention is focused on the research of small single strand molecules, so called microRNA (miRNA). As highly conserved, 18 to 24 nucleotides long, uncoding molecules of RNA, they plays important role as regulators of gene expression. They are controlling both, physiological and pathological processes in organism. Their important role in pathogenesis of different tumor diseases was described at multiple levels. Abnormal levels of miRNA leads to variable, although significant consequences, what indicates miRNA expression also as tumor specific. These miRNA sometimes represents the role of oncogenes, but mostly they occur in the form of tumor suppressors. In my diploma thesis I am focusing on the family of so called myomiRNAs, muscle-specific microRNAs (miR-133a, miR-133b and miR-206), which regulates cell determination of myogenic precursors, whereas I focus on potentially changed level of their expression in the samples of alveolar, embryonal, or...
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