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.
Highlights
Human topoisomerase type 1 (Top1), a member of the topoisomerase family, is responsible for DNA topological problems associated with supercoiling [1]
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
By using a BrdU incorporation assay to measure the efficiency of DNA replication, we observed that CFS-1686 and CPT reduced DNA synthesis by about 70% and 80%, respectively, in comparison with control cells treated with DMSO
Summary
Human topoisomerase type 1 (Top1), a member of the topoisomerase family, is responsible for DNA topological problems associated with supercoiling [1]. Several anticancer drugs drive cancer cells toward apoptosis by inducing the Top1-DNA cleavage complex (Top1-DNAcc) [6] They are roughly classified into two groups, camptothecin (CPT) with CPT derivatives and non-CPT Top inhibitors, all belonging to the interfacial inhibitor of Top1-DNAcc [6]. In addition to the interfacial inhibitors of Top1-DNAcc, the catalytic inhibitors of Top might be worth developing for clinical and Top mechanistic studies [4] The compounds in this category can inhibit the DNA relaxation of Top and the formation of Top1-DNA complexes, but they cannot induce Top1-DNAcc [8,9,10]
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