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Statements

Subject Item
n2:RIV%2F62156489%3A43210%2F11%3A00190244%21RIV13-GA0-43210___
rdf:type
n9:Vysledek skos:Concept
dcterms:description
Valproic acid (VPA) and trichostatin A (TSA) exert antitumor activity as histone deacetylase inhibitors, whereas ellipticine action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of cytochrome P450 (CYP)- and peroxidase-mediated covalent DNA adducts. This is the first report on the molecular mechanism of combined treatment of human neuroblastoma UKF-NB-3 and UKF-NB-4 cells with these compounds. HPLC with UV detection was employed for the separation and characterization of ellipticine metabolites formed by microsomes and peroxidases. Covalent DNA modifications by ellipticine in neuroblastoma cells and in incubations with microsomes and peroxidases were detected by P-32-postlabeling. Expression of CYP enzymes, peroxidases and cytochrome b(5) was examined by Western blot. The cytotoxicity of ellipticine to neuroblastomas was increased by pretreating these cells with VPA or TSA. A higher sensitivity of cells to ellipticine correlated with an increase in formation of covalent ellipticine-derived DNA adducts in these cells. To evaluate the mechanisms of this finding, we invest gated the modulation by VPA and TSA of CYP- and peroxidase-mediated ellipticine-derived DNA adduct formation in vitro. The effects of ellipticine in the presence of VPA and TSA on expression of CYPs and peroxidases relevant for ellipticine activation and levels of cytochrome b(5) and P-glycoprotein in neuroblastoma cells were also investigated. Based on these studies, we attribute most of the enhancing effects of VPA and TSA on ellipticine cytotoxicity to enhanced ellipticine-DNA adduct formation caused by an increase in levels of cytochrome b5, CYP3A 4 and CYP1A1 in neuroblastoma cells. A lower sensitivity of UKF-NB-4 cells to combined effects of ellipticine with VPA and TSA than of UKF-NB-3 cells is also attributable to high levels of P-glycoprotein expressed in this cell line. Valproic acid (VPA) and trichostatin A (TSA) exert antitumor activity as histone deacetylase inhibitors, whereas ellipticine action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of cytochrome P450 (CYP)- and peroxidase-mediated covalent DNA adducts. This is the first report on the molecular mechanism of combined treatment of human neuroblastoma UKF-NB-3 and UKF-NB-4 cells with these compounds. HPLC with UV detection was employed for the separation and characterization of ellipticine metabolites formed by microsomes and peroxidases. Covalent DNA modifications by ellipticine in neuroblastoma cells and in incubations with microsomes and peroxidases were detected by P-32-postlabeling. Expression of CYP enzymes, peroxidases and cytochrome b(5) was examined by Western blot. The cytotoxicity of ellipticine to neuroblastomas was increased by pretreating these cells with VPA or TSA. A higher sensitivity of cells to ellipticine correlated with an increase in formation of covalent ellipticine-derived DNA adducts in these cells. To evaluate the mechanisms of this finding, we invest gated the modulation by VPA and TSA of CYP- and peroxidase-mediated ellipticine-derived DNA adduct formation in vitro. The effects of ellipticine in the presence of VPA and TSA on expression of CYPs and peroxidases relevant for ellipticine activation and levels of cytochrome b(5) and P-glycoprotein in neuroblastoma cells were also investigated. Based on these studies, we attribute most of the enhancing effects of VPA and TSA on ellipticine cytotoxicity to enhanced ellipticine-DNA adduct formation caused by an increase in levels of cytochrome b5, CYP3A 4 and CYP1A1 in neuroblastoma cells. A lower sensitivity of UKF-NB-4 cells to combined effects of ellipticine with VPA and TSA than of UKF-NB-3 cells is also attributable to high levels of P-glycoprotein expressed in this cell line.
dcterms:title
Anticancer agent ellipticine combined with histone deacetylase inhibitors, valproic acid and trichostatin A, is an effective DNA damage strategy in human neuroblastoma Anticancer agent ellipticine combined with histone deacetylase inhibitors, valproic acid and trichostatin A, is an effective DNA damage strategy in human neuroblastoma
skos:prefLabel
Anticancer agent ellipticine combined with histone deacetylase inhibitors, valproic acid and trichostatin A, is an effective DNA damage strategy in human neuroblastoma Anticancer agent ellipticine combined with histone deacetylase inhibitors, valproic acid and trichostatin A, is an effective DNA damage strategy in human neuroblastoma
skos:notation
RIV/62156489:43210/11:00190244!RIV13-GA0-43210___
n9:predkladatel
n20:orjk%3A43210
n3:aktivita
n11:I n11:P n11:Z
n3:aktivity
I, P(1M0505), P(GAP301/10/0356), Z(MSM0021620808), Z(MSM0021620813)
n3:cisloPeriodika
1
n3:dodaniDat
n19:2013
n3:domaciTvurceVysledku
n15:4995775 n15:9974687
n3:druhVysledku
n10:J
n3:duvernostUdaju
n14:S
n3:entitaPredkladatele
n12:predkladatel
n3:idSjednocenehoVysledku
186423
n3:idVysledku
RIV/62156489:43210/11:00190244
n3:jazykVysledku
n7:eng
n3:klicovaSlova
neuroblastom; ellipticine; DNA
n3:klicoveSlovo
n18:DNA n18:ellipticine n18:neuroblastom
n3:kodStatuVydavatele
SE - Švédské království
n3:kontrolniKodProRIV
[D182654B1C08]
n3:nazevZdroje
Neuroendocrinology Letters
n3:obor
n6:CB
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
11
n3:projekt
n16:GAP301%2F10%2F0356 n16:1M0505
n3:rokUplatneniVysledku
n19:2011
n3:svazekPeriodika
32
n3:tvurceVysledku
Kizek, René Hraběta, Jan Gottlicherova, M. Moserova, M. Stiborová, Marie Hrebackova, J. Eckschlager, Tomáš Frei, Eva Poljaková, Jitka Kopejtkova, B. Dvořáková, Marketa
n3:wos
300544100014
n3:zamer
n4:MSM0021620808 n4:MSM0021620813
s:issn
0172-780X
s:numberOfPages
16
n8:organizacniJednotka
43210