-
Something wrong with this record ?
7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action
P. Perlíková, G. Rylová, P. Nauš, T. Elbert, E. Tloušťová, A. Bourderioux, LP. Slavětínská, K. Motyka, D. Doležal, P. Znojek, A. Nová, M. Harvanová, P. Džubák, M. Šiller, J. Hlaváč, M. Hajdúch, M. Hocek,
Molecular cancer therapeutics.
2016 ;
15 (5) :
922-37.
[pub] 20160127
Language English Country United States
Document type Journal Article
Persistent link
https://www.medvik.cz/link/bmc17031862
Online
Full text
NLK
Free Medical Journals
from 2001 to 1 year ago
Open Access Digital Library
from 2001-11-01
Open Access Digital Library
from 2001-11-01
- MeSH
- Survival Analysis MeSH
- DNA genetics metabolism MeSH
- Fibroblasts MeSH
- Humans MeSH
- RNA, Messenger genetics metabolism MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy genetics metabolism pathology MeSH
- Cell Membrane Permeability drug effects MeSH
- DNA Damage drug effects MeSH
- Cell Proliferation drug effects MeSH
- Protein Biosynthesis drug effects MeSH
- Antineoplastic Agents chemistry metabolism pharmacology MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Protein Folding drug effects MeSH
- Tubercidin analogs & derivatives chemistry metabolism pharmacology MeSH
- Treatment Outcome MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent. Mol Cancer Ther; 15(5); 922-37. ©2016 AACR.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc17031862
- 003
- CZ-PrNML
- 005
- 20231121141646.0
- 007
- ta
- 008
- 171025s2016 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1158/1535-7163.MCT-14-0933 $2 doi
- 035 __
- $a (PubMed)26819331
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Perlíková, Pavla $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
- 245 10
- $a 7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action / $c P. Perlíková, G. Rylová, P. Nauš, T. Elbert, E. Tloušťová, A. Bourderioux, LP. Slavětínská, K. Motyka, D. Doležal, P. Znojek, A. Nová, M. Harvanová, P. Džubák, M. Šiller, J. Hlaváč, M. Hajdúch, M. Hocek,
- 520 9_
- $a 7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent. Mol Cancer Ther; 15(5); 922-37. ©2016 AACR.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a protinádorové látky $x chemie $x metabolismus $x farmakologie $7 D000970
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a permeabilita buněčné membrány $x účinky léků $7 D002463
- 650 _2
- $a proliferace buněk $x účinky léků $7 D049109
- 650 _2
- $a DNA $x genetika $x metabolismus $7 D004247
- 650 _2
- $a poškození DNA $x účinky léků $7 D004249
- 650 _2
- $a modely nemocí na zvířatech $7 D004195
- 650 _2
- $a fibroblasty $7 D005347
- 650 _2
- $a regulace genové exprese u nádorů $7 D015972
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a nádory $x farmakoterapie $x genetika $x metabolismus $x patologie $7 D009369
- 650 _2
- $a proteosyntéza $x účinky léků $7 D014176
- 650 _2
- $a sbalování proteinů $x účinky léků $7 D017510
- 650 _2
- $a messenger RNA $x genetika $x metabolismus $7 D012333
- 650 _2
- $a analýza přežití $7 D016019
- 650 _2
- $a výsledek terapie $7 D016896
- 650 _2
- $a tubercidin $x analogy a deriváty $x chemie $x metabolismus $x farmakologie $7 D014372
- 650 _2
- $a xenogenní modely - testy protinádorové aktivity $7 D023041
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Rylová, Gabriela $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
- 700 1_
- $a Nauš, Petr $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
- 700 1_
- $a Elbert, Tomáš $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
- 700 1_
- $a Tloušťová, Eva $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
- 700 1_
- $a Bourderioux, Aurelie $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
- 700 1_
- $a Slavětínská, Lenka Poštová $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
- 700 1_
- $a Motyka, Kamil $u Department of Organic Chemistry, Faculty of Natural Sciences, Palacky University, Olomouc, Czech Republic.
- 700 1_
- $a Doležal, Dalibor $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
- 700 1_
- $a Znojek, Pawel $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic. $7 xx0310353
- 700 1_
- $a Nová, Alice $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
- 700 1_
- $a Harvanová, Monika $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
- 700 1_
- $a Džubák, Petr $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
- 700 1_
- $a Šiller, Michal $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
- 700 1_
- $a Hlaváč, Jan $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic. Department of Organic Chemistry, Faculty of Natural Sciences, Palacky University, Olomouc, Czech Republic.
- 700 1_
- $a Hajdúch, Marián $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic. hocek@uochb.cas.cz marian.hajduch@upol.cz.
- 700 1_
- $a Hocek, Michal $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic. Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic. hocek@uochb.cas.cz marian.hajduch@upol.cz.
- 773 0_
- $w MED00006616 $t Molecular cancer therapeutics $x 1538-8514 $g Roč. 15, č. 5 (2016), s. 922-37
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/26819331 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20171025 $b ABA008
- 991 __
- $a 20231121141643 $b ABA008
- 999 __
- $a ok $b bmc $g 1255455 $s 992889
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2016 $b 15 $c 5 $d 922-37 $e 20160127 $i 1538-8514 $m Molecular cancer therapeutics $n Mol Cancer Ther $x MED00006616
- LZP __
- $a Pubmed-20171025
