-
Je něco špatně v tomto záznamu ?
The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells
J. Poljaková, T. Eckschlager, J. Hraběta, J. Hřebačková, S. Smutný, E. Frei, V. Martínek, R. Kizek, M. Stiborová
Jazyk angličtina Země Velká Británie
Grantová podpora
NR9522
MZ0
CEP - Centrální evidence projektů
- MeSH
- adukty DNA metabolismus MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- cyklooxygenasa 1 biosyntéza MeSH
- cyklooxygenasa 2 biosyntéza MeSH
- elipticiny farmakologie MeSH
- financování organizované MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- peroxidasa biosyntéza MeSH
- protinádorové látky farmakologie MeSH
- systém (enzymů) cytochromů P-450 biosyntéza MeSH
- viabilita buněk účinky léků MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the appearance of DNA fragmentation, and in inhibition of cell growth. These effects were associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by the cytochrome P450- and peroxidase-mediated ellipticine metabolites, 13-hydroxy- and 12-hydroxyellipticine. The expression of these enzymes at mRNA and protein levels and their ability to generate ellipticine-DNA adducts in neuroblastoma cells were proven, using the real-time polymerase chain reaction, Western blotting analyses and by analyzing ellipticine-DNA adducts in incubations of this drug with neuroblastoma S9 fractions, enzyme cofactors and DNA. The levels of DNA adducts correlated with toxicity of ellipticine to IMR-32 and UKF-NB-4 cells, but not with that to UKF-NB-3 cells. In addition, hypoxic cell culture conditions resulted in a decrease in ellipticine toxicity to IMR-32 and UKF-NB-4 cells and this correlated with lower levels of DNA adducts. Both these cell lines accumulated in S phase, suggesting that ellipticine-DNA adducts interfere with DNA replication. The results demonstrate that among the multiple modes of ellipticine antitumor action, formation of covalent DNA adducts by ellipticine is the predominant mechanism of cytotoxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.
Department of Biochemistry Faculty of Science Charles University Prague Czech Republic
Division of Molecular Toxicology German Cancer Research Center Heidelberg Germany
Citace poskytuje Crossref.org
- 000
- 03640naa 2200469 a 4500
- 001
- bmc11009385
- 003
- CZ-PrNML
- 005
- 20140804104452.0
- 008
- 110510s2009 xxk e eng||
- 009
- AR
- 024 __
- $a 10.1016/j.bcp.2009.01.021 $2 doi
- 035 __
- $a (PubMed)19426684
- 040 __
- $a ABA008 $b cze $c ABA008 $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxk
- 100 1_
- $a Poljaková, Jitka $7 xx0101980 $u Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
- 245 14
- $a The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells / $c J. Poljaková, T. Eckschlager, J. Hraběta, J. Hřebačková, S. Smutný, E. Frei, V. Martínek, R. Kizek, M. Stiborová
- 314 __
- $a Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.
- 520 9_
- $a Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the appearance of DNA fragmentation, and in inhibition of cell growth. These effects were associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by the cytochrome P450- and peroxidase-mediated ellipticine metabolites, 13-hydroxy- and 12-hydroxyellipticine. The expression of these enzymes at mRNA and protein levels and their ability to generate ellipticine-DNA adducts in neuroblastoma cells were proven, using the real-time polymerase chain reaction, Western blotting analyses and by analyzing ellipticine-DNA adducts in incubations of this drug with neuroblastoma S9 fractions, enzyme cofactors and DNA. The levels of DNA adducts correlated with toxicity of ellipticine to IMR-32 and UKF-NB-4 cells, but not with that to UKF-NB-3 cells. In addition, hypoxic cell culture conditions resulted in a decrease in ellipticine toxicity to IMR-32 and UKF-NB-4 cells and this correlated with lower levels of DNA adducts. Both these cell lines accumulated in S phase, suggesting that ellipticine-DNA adducts interfere with DNA replication. The results demonstrate that among the multiple modes of ellipticine antitumor action, formation of covalent DNA adducts by ellipticine is the predominant mechanism of cytotoxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.
- 590 __
- $a bohemika - dle Pubmed
- 650 _2
- $a protinádorové látky $x farmakologie $7 D000970
- 650 _2
- $a apoptóza $x účinky léků $7 D017209
- 650 _2
- $a buněčný cyklus $x účinky léků $7 D002453
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a viabilita buněk $x účinky léků $7 D002470
- 650 _2
- $a vysokoúčinná kapalinová chromatografie $7 D002851
- 650 _2
- $a cyklooxygenasa 1 $x biosyntéza $7 D051545
- 650 _2
- $a cyklooxygenasa 2 $x biosyntéza $7 D051546
- 650 _2
- $a systém (enzymů) cytochromů P-450 $x biosyntéza $7 D003577
- 650 _2
- $a adukty DNA $x metabolismus $7 D018736
- 650 _2
- $a vztah mezi dávkou a účinkem léčiva $7 D004305
- 650 _2
- $a elipticiny $x farmakologie $7 D004611
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a peroxidasa $x biosyntéza $7 D009195
- 650 _2
- $a financování organizované $7 D005381
- 700 1_
- $a Eckschlager, Tomáš, $d 1956- $7 jn20000400613 $u Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
- 700 1_
- $a Hraběta, Jan $7 xx0127445 $u Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
- 700 1_
- $a Hřebačková, Jana. $7 _AN046453 $u Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
- 700 1_
- $a Smutný, Svatopluk, $d 1954- $7 xx0110508 $u 1st Department of Surgery, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
- 700 1_
- $a Frei, Eva. $7 _AN036392 $u Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany
- 700 1_
- $a Martínek, Václav, $d 1976- $7 uk2008403107 $u Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
- 700 1_
- $a Kizek, René, $d 1972- $7 jn20001005291 $u Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University of Agriculture and Forestry, Brno, Czech Republic
- 700 1_
- $a Stiborová, Marie, $d 1950-2020 $7 jo2005259907 $u Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
- 773 0_
- $t Biochemical Pharmacology $w MED00000704 $g Roč. 77, č. 9 (2009), s. 1466-1479
- 910 __
- $a ABA008 $b x $y 2 $z 0
- 990 __
- $a 20110513104828 $b ABA008
- 991 __
- $a 20140804104813 $b ABA008
- 999 __
- $a ok $b bmc $g 838969 $s 702770
- BAS __
- $a 3
- BMC __
- $a 2009 $b 77 $c 9 $d 1466-1479 $m Biochemical pharmacology $n Biochem Pharmacol $x MED00000704
- GRA __
- $a NR9522 $p MZ0
- LZP __
- $a 2011-2B09/jvme
