Abstract
The relationship of i-motif DNAs with cancer has prompted the development of specific ligands to detect and regulate their formation. Some plant flavonols show unique fluorescence and anti-cancer properties, which suggest the utility of the theranostics approach to cancer therapy related to i-motif DNA. We investigated the effect of the plant flavonol, fisetin (Fis), on the physicochemical property of i-motif DNAs. Binding of Fis to the i-motif from the promoter region of the human vascular endothelial growth factor (VEGF) gene dramatically induced the excited state intramolecular proton transfer (ESIPT) reaction that significantly enhanced the intensity of the tautomer emission band of Fis. This unique response was due to the coincidence of the structural change from i-motif to the hairpin-like structure which is stabilized via putative Watson-Crick base pairs between some guanines within the loop region of the i-motif and cytosines in the structure. As a result, the VEGF i-motif did not act as a replication block in the presence of Fis, which indicates the applicability of Fis for the regulation of gene expression of VEGF. The fluorescence and biological properties of Fis may be utilised for theranostics applications for cancers related to a specific cancer-related gene, such as VEGF.
Highlights
The relationship of i-motif DNAs with cancer has prompted the development of specific ligands to detect and regulate their formation
We explored the interaction between Fis and variants of vascular endothelial growth factor (VEGF) i-motifs (VEGF IM1, VEGF IM2, and VEGF IM3) containing mutations within the loop sequences (Table 1) and found that the guanine bases of the loop regions were essential for the identical excited state intramolecular proton transfer (ESIPT) effect of VEGF IM
The structure of VEGF IM studied by dimethylsulphate (DMS) footprinting was shown to contain six C-C+ base pairs in the tetraplex core with three loops consisting of GC, CGG, and GC bases (Fig. 1 and Table 1)[23]
Summary
The relationship of i-motif DNAs with cancer has prompted the development of specific ligands to detect and regulate their formation. Some plant flavonols show unique fluorescence and anti-cancer properties, which suggest the utility of the theranostics approach to cancer therapy related to i-motif DNA. Considering the use of specific targeted therapy based on specific targeted test (i.e., theranostics) for both diagnosis and therapeutics, some ligands that both emit a fluorescent signal upon binding to a specific i-motif and regulate the transcription or replication of the target gene are required. The gathered experiences over the years working with these classes of small molecules and the multi-functional therapeutic activities of Fis along with the very sensitive fluorescence spectroscopic property inspired us to study its interaction with different and biologically important DNA i-motifs. We investigated the binding of Fis with different i-motif forming DNA sequences from cancer-related DNA sequences present in the promoter region of oncogenes and human telomeres (Table 1 and Fig. 1). The novel fluorescence and mechanical properties of Fis for the preferred i-motifs may have potential value for cancer theranostics
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