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CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA
- Source :
- PLoS ONE, PLoS ONE, Vol 9, Iss 12, p e113832 (2014)
- Publication Year :
- 2014
-
Abstract
- CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.
- Subjects :
- musculoskeletal diseases
Male
Computer and Information Sciences
DNA damage
lcsh:Medicine
Apoptosis
Models, Biological
Biochemistry
S Phase
chemistry.chemical_compound
Cell Line, Tumor
Chemical Biology
medicine
Humans
DNA Breaks, Double-Stranded
lcsh:Science
Multidisciplinary
Binding Sites
biology
DNA synthesis
Cell growth
Topoisomerase
lcsh:R
DNA replication
virus diseases
Biology and Life Sciences
Cell Cycle Checkpoints
DNA, Neoplasm
DNA
Cell cycle
Molecular biology
Molecular Docking Simulation
chemistry
DNA Topoisomerases, Type I
Benzamides
biology.protein
Aminoquinolines
Enzymology
lcsh:Q
Camptothecin
medicine.drug
Research Article
Computer Modeling
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....e55cf466e47adc7b0f7961ed75f95033