CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA

Ru Wei Lin, Chia Ning Yang, ShengYu Ku, Cheng Jung Ho, Shih Bo Huang, Min Chi Yang, Hsin Wen Chang, Chun Mao Lin, Jaulang Hwang, Yeh Long Chen, Cherg Chyi Tzeng, Chihuei Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere113832
JournalPLoS One
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 2 2014

Fingerprint

Cell Cycle Checkpoints
crossover interference
S Phase
interphase
Camptothecin
Cells
DNA
DNA damage
DNA Cleavage
nitrofurans
benzamides
DNA Damage
prostatic neoplasms
Assays
assays
CFS-1686
cell cycle checkpoints
Topoisomerase I Inhibitors
binding sites
cell cycle

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lin, R. W., Yang, C. N., Ku, S., Ho, C. J., Huang, S. B., Yang, M. C., ... Wang, C. (2014). CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA. PLoS One, 9(12), [e113832]. https://doi.org/10.1371/journal.pone.0113832

CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA. / Lin, Ru Wei; Yang, Chia Ning; Ku, ShengYu; Ho, Cheng Jung; Huang, Shih Bo; Yang, Min Chi; Chang, Hsin Wen; Lin, Chun Mao; Hwang, Jaulang; Chen, Yeh Long; Tzeng, Cherg Chyi; Wang, Chihuei.

In: PLoS One, Vol. 9, No. 12, e113832, 02.12.2014.

Research output: Contribution to journalArticle

Lin, RW, Yang, CN, Ku, S, Ho, CJ, Huang, SB, Yang, MC, Chang, HW, Lin, CM, Hwang, J, Chen, YL, Tzeng, CC & Wang, C 2014, 'CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA', PLoS One, vol. 9, no. 12, e113832. https://doi.org/10.1371/journal.pone.0113832
Lin, Ru Wei ; Yang, Chia Ning ; Ku, ShengYu ; Ho, Cheng Jung ; Huang, Shih Bo ; Yang, Min Chi ; Chang, Hsin Wen ; Lin, Chun Mao ; Hwang, Jaulang ; Chen, Yeh Long ; Tzeng, Cherg Chyi ; Wang, Chihuei. / CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA. In: PLoS One. 2014 ; Vol. 9, No. 12.
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AU - Lin, Chun Mao

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