ABSTRACTS – ORAL PRESENTATIONS - AMCA, spol. s r.o.

P72. IMPACT OF HISTONE DEACETYLASE INHIBITORS ON ANTICANCER EFFECTS OF
CYTOSTATICS
Tomáš Groh 1 , Helena Maříková 2 , Jan Hraběta 2 , Ashraf M. Khalil 2 , Tomáš Eckschlager 2 ,
Marie Stiborová 1
1
Department of Biochemistry, Faculty of Science, Charles University, Prague
2
Department of Pediatric Hematology and Oncology, 2 nd Medical School, Charles
University, Prague
grohtomasmail@gmail.com
During the last few decades, several approaches have been applied in effort to discover
more effective anticancer drugs. Many promising compounds have been investigated.
However, chemoresistance is one of the main causes of failure of treatment. Epigenetic
changes are the changes of gene expression or cellular phenotype caused by mechanisms
other than are the changes in DNA sequence. Histone acetylation has been investigated
as therapeutic target because of its importance in regulation of gene expression.
Different histone deacetylase (HDAC) inhibitors induce death of cancer cells by different
mechanisms that include changes in gene expressions and alterations of both histone
and non-histone proteins. Enhanced histone acetylation in tumors results in modification
of expression of genes involved in cell signaling. Inhibition of HDACs causes changed
expression of 2-10 % of genes involved in important biological processes. Inhibition
of HDACs leads to changes in chromatin architecture that can result in modulation of
gene transcription. Inhibitors of HDACs have also an impact on non-histone proteins.
They can change their stability and interaction with other proteins or with DNA. The
results of experiments and clinical studies have demonstrated that combination of
HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Valproic
acid (VPA) is known as an anticonvulsant used for a treatment of bipolar disorder and
epilepsy. Last decades, VPA is also studied as an inhibitor of histone deacetylases. Beside
VPA, trichostatin A (TSA) is another compound utilized as an HDAC inhibitor.
We tested the effect of non-toxic concentrations of VPA and TSA on cytotoxicity of
different cytostatics to human neuroblastoma cells. VPA increases cytotoxicity of
etoposide, cisplatin but not vincristine in co-cultivation experiments. Similar, but lower
effects exhibited TSA. Valpromide, an analogue of VPA that lack the histone deacetylase
inhibition effect, did not increase cytotoxicity of etoposide and cisplatin. Inhibition of
histone deacetylases by VPA seems to influence cell proapoptotic signals or regulate
reparation machineries of neuroblastoma cells. We have found that VPA increased
cytotoxicity of etoposide to neuroblastoma cells in vitro, if etoposide was co-cultivated
with VPA, but preincubation of these cells with VPA did not increase the etoposide
efficacy. We observed the same trend using cisplatin. The results provide additional
evidence for the use of VPA in complex anticancer therapy.
Acknowledgements
This work was supported by GAUK635712, UNCE204025/2012 and P301/10/0356.
Analytical Cytometry VII 175