7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26819331
DOI
10.1158/1535-7163.mct-14-0933
PII: 1535-7163.MCT-14-0933
Knihovny.cz E-resources
- 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
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA MeSH
- RNA, Messenger MeSH
- Antineoplastic Agents MeSH
- Tubercidin 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
Synthesis and Biological Profiling of Quinolino-Fused 7-Deazapurine Nucleosides
